The Relevance of Transcription Factors in Gastric and Colorectal Cancer Stem Cells Identification and Eradication

Abstract

Gastric and colorectal cancers have a high incidence and mortality worldwide. The presence of cancer stem cells (CSCs) within the tumor mass has been indicated as the main reason for tumor relapse, metastasis and therapy resistance, leading to poor overall survival. Thus, the elimination of CSCs became a crucial goal for cancer treatment. The identification of these cells has been performed by using cell-surface markers, a reliable approach, however it lacks specificity and usually differs among tumor type and in some cases even within the same type. In theory, the ideal CSC markers are those that are required to maintain their stemness features. The knowledge that CSCs exhibit characteristics comparable to normal stem cells that could be associated with the expression of similar transcription factors (TFs) including SOX2, OCT4, NANOG, KLF4 and c-Myc, and signaling pathways such as the Wnt/β-catenin, Hedgehog (Hh), Notch and PI3K/AKT/mTOR directed the attention to the use of these similarities to identify and target CSCs in different tumor types. Several studies have demonstrated that the abnormal expression of some TFs and the dysregulation of signaling pathways are associated with tumorigenesis and CSC phenotype. The disclosure of common and appropriate biomarkers for CSCs will provide an incredible tool for cancer prognosis and treatment. Therefore, this review aims to gather the new insights in gastric and colorectal CSC identification specially by using TFs as biomarkers and divulge promising drugs that have been found and tested for targeting these cells.

Introduction

Gastrointestinal malignancies are listed among the major causes of cancer death worldwide, being associated with environmental and genetic risk factors such as older age, chronic inflammation, family history, smoking, dietary patterns, overweight and physical inactivity, as well as gut microbiota (Lochhead and El-Omar, 2008; Mattiuzzi et al., 2019). Gastric cancer (GC) and colorectal cancer (CRC) are among the top five most incident and deadly cancers worldwide (Bray et al., 2018). As surgical techniques improve, as well as radiotherapy, chemotherapy and neoadjuvant therapies, the 5-year survival rate can reach up to 95% for early GC and 90% for localized CRC (Song et al., 2017; Sonbol et al., 2019). However, most patients have advanced-stage disease at diagnosis and so the best surgical window is missed (Song et al., 2017; Bray et al., 2018). They develop recurrent loco-regional disease or distant metastases with consequent decrease in survival. The heterogeneity of cancer at molecular, histological and phenotypic levels plays an important role in therapy resistance and tumor recurrence, being cancer stem cells (CSCs) among the major causative factors of cancer heterogeneity and treatment failure (Iseghohi, 2016; Gullo et al., 2018). The CSC model of tumor progression hypothesizes that a small subpopulation of cancer cells that display stem-like properties sustains tumor growth, metastasis, relapse and resistance to chemotherapy (Iseghohi, 2016). CSCs can undergo symmetric and asymmetric divisions, having the ability to give rise to all the different types of cancer cells within the tumor (Marjanovic et al., 2013). The origin of CSCs is still unclear and controversial (Dalerba et al., 2007a; Brunner et al., 2012). Various hypotheses suggest that depending on the tumor type, CSCs might be derived from adult stem cells, adult progenitor cells that underwent mutations, or differentiated cells that gained stem-like properties through dedifferentiation (Basu et al., 2016; Phi et al., 2018). A large number of studies demonstrate that CSCs share biomarkers with normal stem cells, thus specific markers for their identification have been explored in recent years. It is known that some transcription factors (TFs) can be re-expressed or reactivated in CSCs, playing a crucial role in the reprogramming of these cells. This review aims to provide a better understanding on how TFs associated with gastric and colorectal CSCs phenotype can be used for CSCs identification, characterization and targeted therapy.

The Challenges of Cancer Stem Cell Identification

The identification of normal stem cells is now an easy process due to their well-recognized set of biomarkers whereas the identification of CSCs is a challenging task resulting from their complex phenotype, that differs from one tumor to another (Pattabiraman and Weinberg, 2014). Additionally, CSCs represent a very small percentage of tumor cells within the total tumor mass making even harder their detection in heterogeneous tumors (Kim Y. et al., 2009). The use of different combinations of cell-surface markers has been the main strategy to identify CSCs in several tumor types (Magee et al., 2012). The cell-surface markers are chosen according to their expression and relevance in the tumor type allowing the separation of CSCs from non-CSCs (Pattabiraman and Weinberg, 2014). In GC and CRC, the list of cell-surface markers capable of identifying CSCs is growing (Table 1). This means that the interest in gastric and colorectal CSCs identification and targeting is rising but also means that the already used markers are not uniformly advantageous for CSCs detection. In particular, inconsistencies remain concerning which cell-surface marker may be the ideal marker to identify gastric and colorectal CSCs from cell lines and primary tumors (Takaishi et al., 2009; Zhang et al., 2011; Jiang Y. et al., 2012; Rocco et al., 2012; Wakamatsu et al., 2012; Brungs et al., 2016).

Gastric Cancer

Several cell-surface markers have emerged for gastric CSC identification. The transmembrane glycoprotein CD44 was the first described cell-surface marker used in gastric CSC identification. Takaishi et al. (2009) and his collaborators analyzed a panel of six GC cell lines and in three of them – NCI-N87, MKN-45 and MKN-74 – a small CD44⁺ cell subpopulation displayed CSC features such as self-renewal, asymmetric division, spheroid colony formation, and in vivo tumorigenic ability. They also observed that the CD44⁺ subpopulation had a higher resistance to anticancer drugs when compared to CD44^– cells (Takaishi et al., 2009). However, in the other three cell lines – AGS, Kato III and MKN28 – the CD44 cell-surface marker was not able to mark cells with stem cell properties (Takaishi et al., 2009). Clinically, CD44⁺ cancer cells at the invasive GC front are associated with poor patient survival (Nosrati et al., 2014; Kodama et al., 2017). Later, Zhang et al. (2011) combined CD44 with CD24, a signal transducer, and successfully detected a CD44⁺CD24⁺ cellular subpopulation with CSCs characteristics, such as the capability to self-renew and to originate differentiated progeny (Zhang et al., 2011). Additionally, they showed that CD44⁺CD24⁺ cells had higher ability to form tumors when injected into immunodeficient mice, compared to the CD44^–CD24^– cells (Zhang et al., 2011). The CD54 cell-surface marker, also known as ICAM-1 (intercellular adhesion molecule 1), was combined with CD44 to isolate gastric CSCs from tumor tissues and peripheral blood of patients with GC (Chen et al., 2012). The CD44⁺CD54⁺ cells exhibited in vitro and in vivo self-renewal ability, formed gastric tumorspheres and originated tumors similar to the original human tumor when injected into immunodeficient mice (Chen et al., 2012). The epithelial cell adhesion molecule (EpCAM) has also been used in combination with CD44 to mark gastric CSCs. The small EpCAM⁺/CD44⁺ subpopulation isolated from primary human GC tissues was more resistant to anticancer drugs including 5-fluorouracil (5-FU), doxorubicin, vinblastine and paclitaxel, when compared with EpCAM⁺/CD44^–, EpCAM^–/CD44⁺ and EpCAM^–/CD44^– cells (Brabletz et al., 2005; Han et al., 2011). It also showed capacity to form sphere-like structures in serum free conditions and greater ability to originate tumors in immunocompromised mice (Han et al., 2011). The tumors formed after inoculation of the EpCAM⁺/CD44⁺ cells recapitulated the heterogeneous morphology and phenotype present in the original gastric tumor (Han et al., 2011). Moreover, Fukamachi et al. (2013) identified another potential gastric CSC marker, the CD49f, an integrin α6 (ITGA6) that is a subunit of laminin receptors. Their work showed that CD49f⁺ cells from GC originated tumors when subcutaneously injected into immunodeficient mice, while CD49f^– cells did not (Fukamachi et al., 2013). They also demonstrated that some of the CD49f⁺ sphere-forming cells were more resistant to doxorubicin, 5-FU and doxifluridine than the other GC cells studied (Fukamachi et al., 2013). Another cell-surface marker identified as a gastric CSC marker is the CD71 transferrin receptor. In this case, it was demonstrated that the CD71^– subpopulation from the MKN-1 GC cell line displayed CSC features, contrary to CD71⁺ cells. The CD71^– cells were more resistant to 5-FU than CD71⁺, had higher tumorigenic ability and were mostly present in the invasive front of the tumor (Ohkuma et al., 2012). The cell-surface glycoprotein CD90 (Thy-1) appeared as a potential gastric CSC marker since it was capable of identifying a small population with in vivo tumorigenic and self-renewal ability (Jiang J. et al., 2012). Additionally, 25% of the gastric primary tumors possessed higher expression of erb-b2 receptor tyrosine kinase 2 (HER2), which was correlated with the higher expression of CD90 (Jiang J. et al., 2012). CD133 (prominin-1), a pentaspan transmembrane glycoprotein, is described as a gastric CSC marker due to the fact that its expression is positively correlated with tumor aggressiveness in GC patients (Fukamachi et al., 2011; Lee et al., 2012; Wakamatsu et al., 2012; Hashimoto et al., 2014; Nosrati et al., 2014). Zhao et al. showed that the frequency of CD133⁺ in gastric primary tumors samples was higher than CD133^– cells and CD133 was associated with poor prognosis in GC (Zhao et al., 2010). Also, spheroid cells from GC cell lines and primary GC tissues presented CD133 expression and displayed several features of CSCs (Zhang X. et al., 2016). New cell-surface markers have emerged in the study of gastric CSCs and demonstrated to be able to mark a small population in GC with stem-like features, specifically Lgr5 (leucine-rich repeat-containing G-protein coupled receptor 5) and CXCR4 (C-X-C chemokine receptor type 4) also known as CD184 (Fujita et al., 2015; Gong et al., 2016). Also, the intracellular enzyme aldehyde dehydrogenase (ALDH) has been used to identify gastric CSCs (Zhi et al., 2011; Wakamatsu et al., 2012). Zhi et al. (2011) were able to divide NCI-N87 and SNU-1 GC cell lines into ALDH⁺ and ALDH^– cells. The ALDH⁺ cells presented CSC features such as higher levels of SOX2, NANOG and Nestin, formed more sphere-like structures and had higher resistance to 5-FU and cisplatin (Zhi et al., 2011). They also showed that ALDH⁺ cells were more sensitive to salinomycin, a drug proposed to target CSCs (Zhi et al., 2011).

Colorectal Cancer

Several specific cell-surface markers were used to identify colorectal CSCs (Todaro et al., 2010; Vaiopoulos et al., 2012; Rassouli et al., 2016; Wahab et al., 2017; Zhou et al., 2017; Boesch et al., 2018; Munro et al., 2018; Parizadeh et al., 2019; van der Heijden and Vermeulen, 2019). CD133 was shown to be a robust CSC-surface marker in CRC (O’Brien et al., 2007; Ricci-Vitiani et al., 2007; Akbari et al., 2020). Positive expression of CD133 was, for the first time, associated with a significantly worse survival and poorer clinical response to 5-FU-based chemotherapy in CRC patients (Ong et al., 2010). CD44 is also a valid marker of colorectal CSCs (Du et al., 2008). In combination with EpCAM it has already been considered a better strategy, when compared to CD133 (Dalerba et al., 2007b). Furthermore, CD166 (another transmembrane glycoprotein) could be used to co-purify CSCs (Dalerba et al., 2007b). More recently, colonospheres and chemoresistant CRC cells were found to be enriched with CD133 and CD44 (Huang et al., 2015). A strategy that combines CD133 with CD44, seems to be more reliable to isolate colorectal CSCs from both cell lines and primary tumors (Abbasian et al., 2019). Horst et al. (2009) showed that CD133 may have a better prognostic capacity per se, but the combination of CD133, CD44, and CD166 markers may stratify better the risk of CRC. Lgr5 positivity identifies human colorectal CSCs and is a prognostic factor for CRC (Kemper et al., 2012; Jiang Y. et al., 2016). Lgr5 overexpression has been shown to be important in CRC progression, as a result of its role in potentiating the Wnt signaling pathway (Carmon et al., 2012). de Sousa e Melo et al. (2017) have shown that Lgr5⁺ CSCs are crucial for the formation of liver metastases, while in the primary tumor Lgr5^– cells proliferate and are capable of originating Lgr5⁺ cells, assuring a rapid tumor growth when treatment ends. Lgr5 combined with CD44 and EpCAM can further improve the identification of CSCs in CRC (Leng et al., 2018). Vermeulen et al. (2008) have shown that spheroid cultures of colon CSCs express CD133, CD166, CD44, CD29, CD24, Lgr5, and nuclear β-catenin, all of which described markers of the CSC population. Also, CD200 showed a role as a CSC marker in colon cancer, and CD49f was associated with tumor cell invasion and metastasis in colon cancer working as an important marker for identifying colorectal CSCs (Robertson et al., 2009; Haraguchi et al., 2013; Zhang S.S. et al., 2016). ALDH1 also appears as a specific marker for colonic CSCs and as an independent prognostic factor for patients with CRC (Huang et al., 2009; Lugli et al., 2010; Kahlert et al., 2012; Goossens-Beumer et al., 2014; Zhou et al., 2017; Munro et al., 2018). In patients with stage II-III rectal cancer that received radio-chemotherapy, ALDH1 expression was correlated with poor prognosis, cancer relapse and metastasis (Huang et al., 2009; Deng et al., 2014).

Transcription Factors as Potential CSC Markers

One of the challenges to target CSCs is to identify specific markers as well as to uncover targetable molecular features associated with their phenotype. It is known that normal stem cells and CSCs share core stemness signaling pathways such as Notch, Hedgehog, WNT/β-catenin and JAK/STAT, that have pivotal roles in maintaining stem cell properties and regulating their transcriptional program (Chen K. et al., 2013). SOX2, OCT4, KLF4, and NANOG are some of the key TFs known to promote stemness by upregulating genes involved in self-renewal and pluripotency, while suppressing genes involved in differentiation (Young, 2011; Tang et al., 2015; Buczek et al., 2018). Key stem cell TFs like SOX2, OCT4, and NANOG have been proven to be overexpressed in CSCs. For that reason, fluorescence reporter systems driven by portions of promoters where these proteins bind were developed to allow CSCs to be labeled and tracked in various types of cancer. These reporter systems seem to be a powerful tool to identify and study CSCs more efficiently than cell-surface markers (Saygin et al., 2016). Tang et al. (2015) developed a flexible lentiviral-based reporter system (SORE6-GFP) that allows direct visualization of CSCs based on SOX2 and OCT4 expression. By using this novel reporter system, our group was able to isolate gastric CSCs from two phenotypically different GC cell lines (AGS and Kato III) (Pádua et al., 2020). Using the same principle, other authors have been developing similar systems to identify and characterize CSCs in a variety of solid tumors. Buczek et al. (2018) established a method using a lentiviral construct carrying the promoter of NANOG to identify prostate CSCs and more recently, Ghanei et al. (2020) introduced a similar approach for the isolation of CSCs in a breast cancer cell line based on the single expression of OCT4. Although the use of cell-surface markers is the most trusted approach to detect these cells, several studies demonstrated that they lack specificity and cannot be used for real time assessment of CSCs behavior, which could give new insights about their properties and possible targets (Tang et al., 2015). Growing evidences support that specific TFs overexpressed in normal gastrointestinal stem cells may contribute to the self-renewal characteristics of CSCs in GC and CRC and are related with patient prognosis (Hadjimichael et al., 2015; Zhao et al., 2017). This makes them a powerful tool in CSCs identification and study.

SOX2 (SRY-Box Transcription Factor 2)

SOX2 is a master regulator that belongs to the family of high-mobility group TFs. It plays many roles throughout development and cell differentiation in normal tissues, namely in mammalian embryogenesis, morphogenesis and homeostasis of the foregut-derived epithelia of the esophagus, lung and trachea (Avilion et al., 2003; Sarkar and Hochedlinger, 2013). SOX2 role in stemness was strengthen with Takahashi and Yamanaka’s findings when reprogramming mouse embryonic fibroblasts into induced pluripotent stem (iPS) cells, by introducing SOX2 along with OCT3/4, c-Myc and KLF4 (Takahashi and Yamanaka, 2006). In cancer, SOX2 has increasingly been associated with a CSC phenotype in several tumors (Wuebben and Rizzino, 2017; Takeda et al., 2018). In GC, SOX2 role is still controversial: some authors associate its high expression with a more aggressive phenotype, poor prognosis and worse response to therapy whereas others have shown the opposite (Hütz et al., 2013; Camilo et al., 2014; Carrasco-Garcia et al., 2016; Zhang X. et al., 2016; Wuebben and Rizzino, 2017; Basati et al., 2020; Pádua et al., 2020). Our group identified subpopulations of gastric CSCs in two human cell lines based on the expression of SOX2 and showed that SORE6⁺ cells presented CSCs properties, including higher proliferation and ability to form gastrospheres, enhanced in vivo tumorigenesis and increased resistance to 5-FU (Pádua et al., 2020). Additionally, Hütz et al. (2013) observed that inhibition of SOX2 resulted in reduced cell proliferation and migration, increased apoptosis, changes in cell cycle and reduced tumorigenic potential of cells in vivo. Similar results were observed in vivo, where suppression of SOX2 resulted in reduced tumor growth and decreased tumorigenicity (Tian et al., 2012; Hütz et al., 2013). In CRC, SOX2 overexpression has been associated with tumor progression and disease recurrence and SOX2 de novo expression was associated with poorly differentiated and more invasive tumors and poor patient overall survival (Lundberg et al., 2014; Lundberg et al., 2016). Takeda et al. (2018) have shown that SOX2⁺ cells developed chemoresistance to oxaliplatin and 5-FU, exhibiting typical asymmetric cell division and higher CSC markers expression. They concluded that colon cancer cells expressing SOX2 behave like CSCs and are therefore associated with poor prognosis (Lundberg et al., 2016; Takeda et al., 2018). Taken together, these findings indicate that SOX2 has a critical role in several aspects of CSCs biology.

OCT4 (POU Class 5 Homeobox 1)

OCT4, a homeodomain TF of the Pit-Oct-Unc family, is expressed in embryonic stem cells, where it maintains stem cell-like properties, and in adult stem cells, being involved in their proliferation and differentiation (Loh et al., 2006; Han et al., 2014). Abnormal expression of OCT4 has been observed in different tumor types, including GC and CRC (Dai et al., 2013; Basati et al., 2020). Studies report that its expression is positively correlated with more aggressive and metastatic tumors, as well as with poorer overall prognosis (Zhang X. et al., 2016; Basati et al., 2020). Chen and collaborators demonstrated that overexpression of OCT4 in GC cells led differentiated cancer cells to become undifferentiated and acquiring self-renewal capacity (Chen et al., 2009) and another study reported that downregulation of OCT4 induced differentiation in GC cells (Tai et al., 2005). Additionally, Zhang X. et al. (2016) demonstrated a p-ERK mediated positive feedback loop between the cell surface marker CD44 and OCT4, responsible for sustaining gastric CSCs properties. OCT4 has also been reported in colon CSCs and its knockdown inhibits cell migration and invasion, suggesting it may act as a novel prognostic marker in CRC (Miyoshi et al., 2010, 2018; Dai et al., 2013; Amini et al., 2014).

KLF4 (Kruppel Like Factor 4)

KLF4, also known as the gut-enriched Kruppel like factor (GKLF), is strongly expressed in post-mitotic and terminally differentiated epithelial tissues, along with those of the gastrointestinal tract (Cho et al., 2007; Cui et al., 2013). It is suggested that it may have an anticancer role in GC, being downregulated due to hypermethylation and loss of heterozygosity in gastric CSCs (Cho et al., 2007). Several studies have shown that KLF4 low expression is negatively associated with patient overall survival and may be a useful prognostic marker in GC patients (Li et al., 2012; Zhang et al., 2012; Hsu et al., 2013; Hashimoto et al., 2017; Zhao et al., 2020). Regarding CRC, KLF4 role is still not clear. Some studies reveal KLF4 is overexpressed in colon CSCs and its knockdown affects the stemness phenotype and decreases the cells malignant profile, while others demonstrate that loss of expression is associated with stem-like features namely formation of colonospheres, cell growth arrest, uncontrolled cell proliferation, pluripotency and self-renewal (Shie et al., 2000; Wei et al., 2006; Leng et al., 2013; Hadjimichael et al., 2015).

NANOG (Nanog Homeobox)

NANOG was first discovered in embryonic stem cells (ESCs) and is a key TF involved in self-renewal and multipotency (Chambers et al., 2003). It is typically silenced in normal somatic cells, though abnormal expression has been reported in malignant tumors, such as GC and CRC (Lin et al., 2012; Hadjimichael et al., 2015). Previous studies demonstrate that NANOG is highly expressed in GC and significantly associated with tumor size and grade, along with decreased overall survival (Iv Santaliz-Ruiz et al., 2014; Basati et al., 2020). Although studies indicate NANOG is associated with a CSC phenotype, it remains unclear its role in CSC maintenance in GC (Iv Santaliz-Ruiz et al., 2014). With respect to CRC, NANOG overexpression has been associated with colony formation and stem cell properties, as well as worse prognosis (Ibrahim et al., 2012; Zhang et al., 2013; Hadjimichael et al., 2015).

c-Myc (MYC Proto-Oncogene, bHLH Transcription Factor)

c-Myc is an essential TF that regulates genes that take part in biological processes such as self-renewal, differentiation, growth and metabolism (Dang, 2013; Bretones et al., 2015). Although it is one of the most commonly activated oncogenes involved in the pathogenesis of cancer, its overexpression alone is unable to induce the transformation of normal cells into tumor cells (Yang et al., 2020). The role of c-Myc in GC is less studied than in other tumor types. It has been suggested as a CSC marker in some tumors such as small-cell lung cancer, prostate cancer, neuroblastoma, glioblastoma and hematopoietic malignancies, but the expression and relevance in GC has not yet been clarified (Yang et al., 2020). Some authors associate c-Myc deregulation with poor prognostic features (Han et al., 1999; de Souza et al., 2013; Wang et al., 2016). Upregulation of c-Myc is common in 70% of CRC cases and it has been shown to have a crucial role in maintaining chemoresistance and self-renewal, being overexpressed in colon CSCs (Muzny et al., 2012; Zhang et al., 2019). Despite some controversial results, it has been shown that high expression of c-Myc is an independent poor prognostic factor in CRC (Lee et al., 2015; Wang et al., 2017).

SOX9 (SRY-Box Transcription Factor 9)

SOX9 regulates developmental processes such as male sex determination, chondrogenesis, neurogenesis, and neural crest development (Jo et al., 2014). Also, it plays a vital role in cell fate decisions and stem cell maintenance during embryonic development and adulthood in several organs, including the gastrointestinal tract (Bastide et al., 2007; Huch and Clevers, 2011). Its role in GC is still conflicting, while some studies defend an association between lower survival and SOX9 high expression, others demonstrate poor prognosis with a decreased level of SOX9 expression (Sun et al., 2012; Santos et al., 2016; Mesquita et al., 2019). Also, both oncogenic and tumor suppressor activity of SOX9 have been implicated in CRC (Darido et al., 2008; Lu et al., 2008; Matheu et al., 2012; Prévostel and Blache, 2017). Previous studies suggest that this TF can influence tumor proliferation and progression, mainly through the regulation of the CSC pool, and could correlate with poor prognosis (Lu et al., 2008; Espersen et al., 2015; Javier et al., 2016).

GLI1 (GLI Family Zinc Finger 1)

GLI1 is part of the Sonic Hedgehog (SHH) pathway and seems to be essential for the maintenance of cancer cells with stem like properties in both GC and CRC (Zhang X. et al., 2016; Yang et al., 2018). In GC, its expression is significantly higher in metastatic cancer tissues and is positively correlated with a more aggressive tumor phenotype (Zhang X. et al., 2016). Furthermore, it has been observed that GLI1 overexpression promotes a CSC phenotype enhancing cell proliferation, migration and therapy resistance (Dong et al., 2019; Yao et al., 2019). GLI1 also plays an important role in CSC characteristics related with aggressiveness and metastatic spread of CRC cells leading to decreased survival. Furthermore, GLI1 knockdown downregulates CD133/SOX9 expression and clonogenic ability of CRC cells, indicating this TF could be a potential marker for CSCs in CRC (Yang et al., 2018).

STAT3 (Signal Transducer and Activator of Transcription 3)

STAT3 plays an important role in the regulation of various physiological functions, such as inflammation, proliferation and invasion, being highly expressed in gastric and colorectal CSCs (Yu H. et al., 2009; Lin et al., 2011; Hajimoradi et al., 2016; Sonbol et al., 2019). In gastric CSCs, high expression of STAT3 has been reported to be involved in stemness properties and invasive ability (Hajimoradi et al., 2016; Jiang et al., 2017; Sonbol et al., 2019). Regarding its prognostic value several studies report STAT3 activation as a marker of unfavorable outcome (Kim D.Y. et al., 2009; Deng et al., 2010, 2013; Ji et al., 2016). In CRC, STAT3 is one of the major oncogenic proteins associated with proliferation, angiogenesis, invasion and chemo-radiotherapy resistance (Lin et al., 2005, 2011; Munro et al., 2018). Also, its inhibition prevents tumor initiation, being an attractive therapeutic target for CRC (Lin et al., 2011).

SALL4 (Spalt Like Transcription Factor 4)

As a TF, SALL4 plays essential roles in maintaining pluripotency and self-renewal of ESCs, being downregulated or silenced in differentiated cells (Zhang et al., 2006, 2015; Yang et al., 2008). SALL4 acts as an oncogene and it is associated with cancer initiation, development, and progression (Ma et al., 2006). Zhang et al. (2014) showed that the overexpression of SALL4 is associated with gastric CSC features and could be involved in the generation and maintenance of these cells. Later, Yuan et al. (2016) suggested a novel mechanism for SALL4 role in GC, showing that this TF binds to the promoter region of CD44 and activates it expression, enhancing cell proliferation, migration and invasion. Increasing evidence indicates that upregulation of SALL4 is associated with lymph node metastasis and poorer overall prognosis (Zhang et al., 2014, 2018b). In CRC, SALL4 overexpression is detected in 87% of tumor tissues and it is correlated with tumor cell metastasis to lymph nodes being associated with poor prognosis and showing its essential role in maintaining the properties of CSCs (Forghanifard et al., 2013; Zhang et al., 2015).

β-Catenin (Catenin Beta 1)

The Wnt/β-catenin pathway is implicated in the regulation of the epithelial stem cell self-renewal (Behrens et al., 1996). Alone, β-catenin signaling has been shown as necessary for the maintenance of CSC features (Huang et al., 2007; Kanwar et al., 2010; Jiang R. et al., 2016). The dysregulation of the Wnt/β-catenin signaling pathway has been implicated in colon carcinogenesis and plays a critical role in regulating the growth and maintenance of colonospheres (Kolligs et al., 2002; Kanwar et al., 2010). The activation of this pathway can lead to the conversion of intestinal stem cells into CSCs, where expression levels of β-catenin are higher (Kanwar et al., 2010). Some studies revealed that high levels of nuclear β-catenin, in CRC patients, were associated with a poor prognosis and could be used as a biomarker for late phase CRC (Chen Z. et al., 2013). Gastric CSCs self-renewal and proliferation ability, both in vitro and in vivo, are also improved by the Wnt/β-catenin signaling (Mao et al., 2014; Chiurillo, 2015).

CSCs and Tumor Microenvironment

The close interaction between CSCs and their niche is fundamental for maintaining the stemness of CSCs and tumor progression. The CSC niche, a specific tumor microenvironment, which consists of stroma, micro-vessels, hypoxic regions, cancer-associated fibroblasts (CAFs), cancer-associated mesenchymal stem cells (MSCs), tumor-associated macrophages (TAMs) and extracellular matrix, secretes soluble factors (e.g., cytokines and growth factors) that are necessary for cancer cell survival (Quante et al., 2013; Lau et al., 2017; Yang et al., 2020). Growth factors and cytokines regulate Wnt, Notch, JAK-STAT3 and other signaling pathways thereby stimulating growth, epithelial-to-mesenchymal transition (EMT), invasion, angiogenesis, metastasis and inhibiting apoptosis (Yang et al., 2020). These pathways are required for the self-renewal and maintenance of CSCs. For instance, growth factors like hepatocyte growth factor (HGF), secreted by the stromal myofibroblasts, activate the Wnt-signaling in a subset of colon cancer cells that maintain the CSC phenotype (Vermeulen et al., 2010). Another example is hypoxia, which also maintains a stem-like phenotype in CRC and GC through the increased expression of hypoxia-inducible factors (HIFs), the transcription factors HIF-1α and HIF-2α, that maintain the Wnt/β-catenin signaling pathway and activate stemness-related TFs such as OCT4 (Gidekel et al., 2003; Liu et al., 2008; Mazumdar et al., 2010; Yeung et al., 2011; Vadde et al., 2017). On the other hand, cancer cells also secrete growth factors and proteases to promote changes in their microenvironment (Ishimoto et al., 2014). One significant example of this crosstalk between cancer cells and the microenvironment is the secretion of cytokines like interleukin-6 (IL-6) by the cancer-associated mesenchymal stem cells that enhance the progression of CRC through the IL-6/JAK2/STAT3 signaling (Zhang et al., 2018a). The same is observed in GC through the secretion of interleukin-8 (Li W. et al., 2015). On the other hand, cancer cells mediate the production of inflammatory cytokines with pro-tumorigenic roles or the inhibition of cytokines involved in immune surveillance, altering the composition of the immune cells in the tumor microenvironment (Quante et al., 2013; West et al., 2015). Specifically, Rezalotfi et al. (2019) suggested that CSCs could alter the cytokines in the tumor microenvironment by demonstrating that the balance between suppressive regulatory T cells (Treg) and T helper cells producing IL17 (Th17) could be affected. Chaudhry et al. (2009) disclosed further that STAT3 is fundamental for the inhibition of Treg cells development and Th17 differentiation. In fact, the STAT3 transcription factor, in collaboration with NFκB, regulates the expression of these genes encoding critical cancer-promoting inflammatory mediators, establishing a crosstalk between cancer and immune cells of the microenvironment and perpetuating the effects of STAT3 activation in cancer cells (Yu et al., 2007; Grivennikov and Karin, 2010; Yang et al., 2019). However, despite the growing evidences on the interaction of gastric and colorectal CSCs with the tumor microenvironment, the specific molecules involved and their signaling pathways still need further investigation in order to design safe therapies.

Therapeutic Approaches to Target CSCs

The therapeutic approach in GC and CRC is determined by the stage of the disease at the time of diagnosis. Patients are treated with surgery, chemotherapy and/or radiation. In GC, surgery remains the main treatment for stage I. It can also be performed at stages II and III but chemotherapy (perioperative, neoadjuvant or adjuvant) is necessary to improve overall survival of the patients. For stage IV, chemotherapy with doublet or triplet platinum/fluoro-pyrimidine combinations or capecitabine is the main treatment (Neri et al., 2007; Smyth et al., 2016). Resective surgery is the main curative treatment used in non-metastasized CRC, although neo-adjuvant treatments are also administered in rectal carcinoma (Kuipers et al., 2015). After surgery, 5-FU-based chemotherapy is used to reduce the risk of tumor recurrence and improve overall survival of patients (Dienstmann et al., 2017). Currently, the decision of giving adjuvant treatment to early-stage CRC patients is recommended to high risk patients with one or more risk factors (Kannarkatt et al., 2017). Patients with very high risk – microsatellite stable (MSS) and T4 may be considered for the addition of oxaliplatin (Labianca et al., 2013). However, in some cases of GC and CRC, after a believed efficacious treatment, the cancer reappears locally or in distant metastasis. This results from the presence of CSCs that were able to resist the therapy applied, revealing that the existence of CSCs is one of the biggest difficulties in cancer treatment (Dean et al., 2005). Thus, direct targeting of CSCs seems to be the key for tumor complete elimination. The therapy against CSCs using specific molecules should eradicate these cells while the conventional therapy eliminates the non-CSCs present in the tumor bulk. Nevertheless, this type of treatment should be administrated in combination due to the possibility of cell plasticity that facilitates the appearance of de novo CSCs from non-CSCs. Moreover, targeting specific TFs or signaling pathways responsible for maintaining the CSC phenotype could become novel therapies against GC and CRC. For that reason, several clinical trials are being undertaken to explore the efficacy of diverse compounds, that are capable of modulating or inactivating proteins that gastric and colorectal CSCs use to grow and survive, allowing their elimination. Additionally, it is worth to mention that several studies have been conducted to evaluate the efficacy of small molecules in targeting CSCs in vitro and in vivo, compounds capable of eliminating or reducing the CSC population that could also be part of the path in cancer therapy targeting CSCs (Gupta et al., 2009; Abetov et al., 2015; Shapiro et al., 2016; Müller et al., 2017; Park et al., 2017; Pádua et al., 2020). Table 2 lists the drugs that have been or are being investigated in clinical trials, alone or in combination with other compounds, to treat GC and CRC.

Immunotherapy

Cancer immunotherapy has emerged as a potential tool for cancer treatment (Farkona et al., 2016). Several immunotherapeutic strategies have been developed including cancer vaccines, oncolytic viruses, monoclonal antibodies or recombinant proteins, chimeric antigen receptor T cell (CAR-T) cells and other cellular therapies, lymphocyte-activating cytokines and checkpoint inhibitors (Riley et al., 2019). Immunotherapy aims to improve the immune system response against cancer cells through natural mechanisms (Riley et al., 2019). Therefore, it can be used to target cancer cells and also CSCs in the tumor microenvironment (Badrinath and Yoo, 2019). Many immunotherapeutic agents targeting CSCs have been tested in clinical trials (Menon et al., 2016). Monoclonal antibodies that specifically target CSC surface biomarkers have been used in gastric and colorectal cancer. Ongoing there is a Phase I study of RO5429083, a monoclonal antibody against CD44 in patients with metastatic and/or locally advanced malignant solid tumors (NCT01358903). Also used were EpCAM antibodies, such as edrecolomab, that was tested in patients with resected stage II adenocarcinoma of the colon (Niedzwiecki et al., 2011) and adecatumumab, that is being tested in a Phase II study to evaluate efficacy and safety, alone or with FOLFOX, in metastasized CRC (NCT00866944). A Phase I dose finding study is evaluating the bispecific antibody targeting EGFR and Lgr5 (MCLA-158) in metastatic CRC and other advanced solid tumors (NCT03526835). In addition, CAR-T cell therapies, have been developed to target CSCs in GC and CRC. There are three Phase I or II clinical trials in GC using CAR-T cells targeting EpCAM (NCT03013712, NCT03563326, and NCT02725125), one of them consisting in the intraperitoneal infusion in advanced GC with peritoneal metastasis. NCT03013712 includes patients with colon cancer. Moreover, there is a Phase I/II clinical study of CAR-T cells targeting CD133 in relapsed and/or chemotherapy refractory malignancies including CRC (NCT02541370).

Targeting the Transcription Factor STAT3

From the list of TFs strongly associated with CSC phenotype in GC and CRC, STAT3 became crucial as a molecular target for cancer therapy because napabucasin (BBI608), the first-in-class cancer stemness (CSCs) inhibitor that works by targeting STAT3, effectively blocks cancer relapse and metastasis in xenografted human cancers (Li Y. et al., 2015; Zhang Y. et al., 2016). Napabucasin is a naturally occurring drug orally administered. It inhibits CSC self-renewal and induces apoptosis in CSCs by targeting CSC signaling pathways (STAT3, NANOG and β-catenin) in GC (Bekaii-Saab and El-Rayes, 2017). In CRC, napabucasin has been investigated in several studies. A phase I/II clinical trial investigated napabucasin with other standard therapeutic treatments for advanced gastrointestinal malignancies (Bendell et al., 2017). Another study – CanStem303C – a randomized phase III clinical trial done in adult patients with previously treated metastatic CRC evaluated napabucasin in combination with FOLFIRI (Grothey et al., 2017). Napabucasin monotherapy has been reported in a published phase III trial. The CO.23 trial evaluated the efficacy of napabucasin monotherapy versus placebo in metastasized CRC, which failed to demonstrate a significant difference in the napabucasin group survival. However, in a pre-specified biomarker analysis, phosphorylated STAT3 (pSTAT3)-positive patients experienced a significant survival benefit from napabucasin over placebo (Jonker et al., 2018; Sonbol et al., 2019). Another ongoing trial involving STAT3 inhibition is the phase II trial MODULATE (NCT03647839) which specifically aims to study the modulation of the tumor microenvironment using either vascular disrupting agents (BNC105) or STAT3 inhibition (BBI608), in synergy with an immune checkpoint protein (PD1) inhibitor (nivolumab). This trial is recruiting microsatellite stable, refractory CRC cases.

Targeting the Wnt/β-Catenin Signaling Pathway

Wnt/β-catenin signaling pathway is a major regulator of normal intestinal development and its over-activation behaves as a hallmark of CRC, being particularly significant in drug resistance and stemness maintenance of colorectal CSCs (Takebe et al., 2011; Basu et al., 2016). The activation of the Wnt/β-catenin signaling pathway is associated with poor prognosis (Janssen et al., 2006). It results mostly from the accumulation of mutations in the APC tumor suppressor gene, oncogenic KRAS-signaling pathway, β-catenin and p53. Mutations that do not allow the formation of the APC/Axin/GSK3β destruction complex result in the accumulation and nuclear translocation of β-catenin that binds to transcription factors of T cell factor family (TCF4) and activates target genes like c-Myc, cyclinD1 and survivin, some involved in maintaining stemness (Myant et al., 2013; Lee et al., 2015; Zhou et al., 2017). It has been shown that loss of APC in CRC triggered the expression of a Rac1 GTPase via the induced expression of c-Myc, necessary to intestinal stem cell proliferation and CRC initiation (Myant et al., 2013). On the other hand, p53 may affect the outcome of Wnt signaling in CRC development (Voorneveld et al., 2015), having a role in the acquisition of pluripotency during reprogramming (Takahashi and Yamanaka, 2006; Krizhanovsky and Lowe, 2009). The Wnt signaling pathway is also dysregulated in GC (Chiurillo, 2015). However, the involvement and mechanisms are not yet as fully understood as in CRC. A number of studies suggest β-catenin and APC as driver genes, revealing somatic mutations in both genes that might have relevance in GC (Horii et al., 1992; Nakatsuru et al., 1993; Woo et al., 2001; Clements et al., 2002; Zhang and Xue, 2008). Genomic analysis of several gastric primary tumors disclosed that Wnt/β-catenin, together with NF-κB and proliferation/stem cell pathways, were deregulated in more than 70% of the primary tumors. Patient stratification by combinations of these oncogenic pathways revealed to be a great tool for GC clinical behavior assessment (Ooi et al., 2009). Many molecules have been used to target the Wnt/β-catenin in gastrointestinal CSCs (Chiurillo, 2015; Parizadeh et al., 2019; Patel et al., 2019; Yang et al., 2020). Genistein, a soy-derived compound, was tested in a Phase I/II research trial, in combination with FOLFOX or FOLFOX-Bevacizumab, where it was demonstrated to be well tolerated by patients and may have improved efficacy in the treatment of metastatic CRC (Pintova et al., 2019). In vitro and in vivo studies have shown that Genistein affects mainly Wnt/β-catenin and PI3K/AKT pathways (Su et al., 2003; Kim et al., 2005; Zhang and Chen, 2011; Wang et al., 2012).

Targeting the Hedgehog Signaling Pathway

The dysregulation of Hedgehog (Hh) signaling pathway has been reported as another main cause of CSCs self-renewal and chemoresistance, being associated with poor clinical outcome in patients with GC or CRC (Ma et al., 2005; Varnat et al., 2009; Takebe et al., 2011; Usui et al., 2018). In this pathway, target gene expression is predominantly regulated by the Smoothened (SMO) protein but GLI inhibitors are also used (Rimkus et al., 2016; Didiasova et al., 2018). In GC cells, SMO regulates nuclear translocation of GLI-1 that in turn promotes transcription of target genes, such as CD44 (Yoon et al., 2014). Yoon et al. (2014) showed that in AGS, MKN-45, and NCI-N87 GC cell lines, the Hh pathway inhibition using SMO shRNA or small-molecule inhibitors significantly decreased spheroid formation ability and tumor growth. Vismodegib (GDC-0449), the first Hh pathway inhibitor used in cancer research, is currently undergoing Phase II trials in advanced GC and in metastatic CRC (Gupta et al., 2010; Berlin et al., 2013). Examination of tumor samples revealed that Vismodegib has not increased progression-free or overall survival as a whole, but only in a limited subset of patients with high CD44 expression (Cohen et al., 2013; Yoon et al., 2014). Disappointingly, these treatments with Vismodegib, did not increase progression-free survival in CRC patients (Low and de Sauvage, 2010; McMillan and Matsui, 2012). When the SMO inhibitor AY9944 was used in combination with the GLI-1 inhibitor GANT61, there was an increased response to anti-cancer drugs in tumor organoids and a decreased capacity to form colonies in SW480 and HCT116 CRC cells (Usui et al., 2018). These results indicate that this strategy might be worthwhile in CRC.

Targeting the Notch Signaling Pathway

The Notch signaling pathway is one of the most activated signaling pathways in cancer, namely in GC and CRC, and promotes metastization (Du et al., 2014; Hayakawa et al., 2019). It has a key role in the maintenance and differentiation of CSCs (Quail et al., 2012; Lu et al., 2013; Yang et al., 2020). In GC and CRC, the expression of Notch1 or Jagged1 is associated with poor prognosis (Yeh et al., 2009; Kang et al., 2012; Jackstadt et al., 2019; Kim et al., 2019; Mohamed et al., 2019). In CRC, Notch1 is associated with more aggressive subtypes, recruiting neutrophils to drive metastasis (Jackstadt et al., 2019). Due to the fact that the Notch pathway is related to CSC self-renewal and angiogenesis, targeting this pathway became a potential anti-CSC therapeutic approach (Venkatesh et al., 2018). Strategies used to inhibit Notch signaling include γ-secretase inhibition (GSI), Notch receptor (e.g., Notch1, Notch2, and Notch3) or ligand (e.g., Jagged1 and Jagged2) antibodies and combination therapy with inhibitors of other pathways. The inhibition of Notch receptors using two GSIs has allowed to disclose the importance of Notch pathway in the growth and survival of GC cells (Brzozowa et al., 2013). Furthermore, GSIs lead to the induction of apoptosis and inhibition of tumor-sphere formation of CD44⁺ gastric CSCs (Barat et al., 2017). However, it is important to mention that GSIs do not only target Notch-related proteins but also proteases involved in numerous cellular processes, which could originate adverse effects in vivo (Shih Ie and Wang, 2007; Wang et al., 2010; Brzozowa et al., 2013). Nevertheless, various clinical trials have been performed to evaluate the efficacy of targeting the Notch signaling pathway in GC and CRC (Table 2). RO4929097, a selective GSI, showed good anti-tumor activity in preclinical and early trials but it was not good enough for metastatic CRC (Luistro et al., 2009; Strosberg et al., 2012; Tolcher et al., 2012). Combinations of RO4929097 with other drugs in advanced solid tumors, including CRC, were well tolerated and presented some clinical benefit (Sahebjam et al., 2013; LoConte et al., 2015). LY900009 is another GSI tested in advanced cancers, including those of gastrointestinal tract. It is currently in a phase I trial and revealed a safety profile, with the majority of patients experiencing low-grade gastrointestinal adverse effects (Pant et al., 2016). Furthermore, it was demonstrated to have an inhibitory effect on Notch signaling pathway, inducing goblet cell differentiation and increased mucin production, similarly to that observed in rats (Pant et al., 2016). Moreover, MEDI0639 is a monoclonal antibody that specifically binds to DLL4 and prevents its interaction with Notch receptors, thereby inhibiting Notch-mediated signaling and target gene transcription, which may block tumor angiogenesis and eventually tumor cell growth (Ishigami et al., 2013). A phase I study in advanced solid tumors demonstrated that MEDI0639 is well tolerated and preliminary results show evidence of antitumor activity (Falchook et al., 2015).

Targeting the PI3K/AKT/mTOR Signaling Pathway

The PI3K/AKT/mammalian target of rapamycin (mTOR) signaling pathway is typically abnormally activated in many carcinomas (Michl and Downward, 2005; Johnson et al., 2010; Narayanankutty, 2019). It is thought to be crucial in angiogenesis, cell proliferation, metabolism, survival, metastasis and drug resistance (Cantley, 2002; Edinger and Thompson, 2002; Fingar et al., 2004; Al-Batran et al., 2012; Tapia et al., 2014). AKT is commonly overexpressed in tumors and plays an important role in the metabolic reprogramming of cancer (Yap et al., 2011; Iida et al., 2013). Although the PI3K/AKT/mTOR pathway has been extensively studied, there are few studies in CSCs. In GC and CRC, activation of mTOR appears to cause tumor progression and poor patient survival (Lang et al., 2007; Murayama et al., 2009; Xiao et al., 2009; Yu G. et al., 2009; An et al., 2010). Thus, its inhibition seems to be fundamental for GC and CRC therapy. A phase II study using RAD001 (everolimus) in previously treated unresectable or metastatic esophageal cancer or GC was performed over the rational that everolimus may stop tumor growth by blocking some of the fundamental enzymes for cell growth and by blocking angiogenesis. Everolimus was well tolerated by the patients however this study displayed a strong weakness by being single-arm and non-comparative. However, mTOR suppression decreased ALDH1 activity, which is a marker of CSCs in CRC (Xia and Xu, 2015). Growth inhibition, using a dual PI3K/mTOR inhibitor, PF-04691502, was observed in vitro and in xenografted CRC tumors (Fang et al., 2013). Another mTOR inhibitor decreased survival and invasion of colorectal CSCs in vitro, and suppressed tumor growth in vivo (Francipane and Lagasse, 2013). The allosteric AKT inhibitor (MK-2206) led to a decrease in CSCs proliferation, and reduction of the capacity to form colonospheres in vitro and to initiate tumor formation in vivo. Mice with xenografted tumors showed a significant decrease in tumor progression. Also, MK-2206 significantly inhibited the growth of patient-derived tumorspheres (Malkomes et al., 2016). A phase II study in advanced gastric or gastroesophageal junction cancer has revealed that MK-2206, as second-line therapy, at a dose of 60 mg was well tolerated by patients and showed some modest evidence of activity, however, the overall survival (5.1 months) was lower than the study efficacy endpoint (6.5 months) (Ramanathan et al., 2015). However, there is a Phase II clinical trial with MK-2206, to study patients with previously treated colon or rectal cancer that has spread and cannot be removed by surgery, concluding that in contrast to robust preclinical data, it does not have effect in these tumors (Dasari et al., 2016). MK-2206 was also used in combination with AZD6244 (Selumetinib), a mitogen-activated protein extracellular signal-regulated kinase (MEK)1/2 inhibitor, in a Phase II trial but the level of target inhibition obtained with the maximum non-toxic dose was not the expected (Do et al., 2015). SAR245409 (Voxtalisib) was tested in a Phase I research trial in combination with another MEK inhibitor, MSC1936369B (Pimasertib), in advanced or metastatic solid tumors (Schram et al., 2018). The primary purpose of the study was to determine the maximum tolerated dose of the drug combination. The drug RAD001 (Everolimus) downregulates mTOR. A combination of RAD001, mFOLFOX-6 and Bevacizumab has been shown to be efficacious and safe in metastatic CRC (Weldon Gilcrease et al., 2019). A multicenter phase II study for patients with refractory, metastatic CRC concluded good tolerability and efficacy of Everolimus combined with Tivozanib (an oral VEGF receptor-1, -2, -3 inhibitor) with 50% of the patients having stable disease at 2 months (Wolpin et al., 2013).

Discussion

The identification of CSCs remains a challenging task, particularly in solid tumors like GC and CRC. The use of cell surface markers as a primary tool to identify gastric and colorectal CSCs has disclosed some weaknesses and for that reason the uncovering of more reliable biomarkers must become a priority. These biomarkers should include the TFs that are required for the maintenance of gastric and colorectal CSCs phenotype, as well as components of the signaling pathways that have key roles in CSC features. This explains why TFs such as STAT3 and signaling pathways like Wnt/β-catenin, Hedgehog, NOTCH and PI3K/AKT/mTOR emerged as powerful targets, whose inactivation or modulation could eliminate gastric and colorectal CSCs. This fact is corroborated by several completed and ongoing clinical trials targeting these potential biomarkers in both tumor types, where some of the molecules have shown promising results. The incapacity to achieve the wanted levels of target inhibition was the major shortcoming of the clinical trials. Yet, the use of higher doses is not possible due to toxicity problems, which led to the development of combinations of drugs targeting different pathways. Furthermore, it is more advisable to measure the outcome of the treatments in terms of CSCs behavior, by assessing capacity to metastasize and re-growth after removing the drug.

Future Perspectives

The validation of potential gastric and colorectal CSCs biomarkers and their association with GC and CRC stage is imperative to understand patient prognosis and apply a more suitable therapy. The development of a robust therapy combining CSC targets with conventional chemotherapy could be the solution to overcome resistance to anti-cancer drugs and completely eliminate cancer. Considering these issues, it is crucial that future studies further explore the role of TFs and components of signaling pathways on cancer stemness in order to develop therapies that could eradicate CSCs.

References

• 1

  AbbasianM.MousaviE.Arab-BafraniZ.SahebkarA. (2019). The most reliable surface marker for the identification of colorectal cancer stem-like cells: a systematic review and meta-analysis.J. Cell. Physiol.2348192–8202. 10.1002/jcp.27619

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 2

  AbetovD.MustapovaZ.SalievT.BulaninD.BatyrbekovK.GilmanC. P. (2015). Novel small molecule inhibitors of cancer stem cell signaling pathways.Stem Cell Rev. Rep.11909–918. 10.1007/s12015-015-9612-x

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 3

  AkbariM.ShomaliN.FarajiA.ShanehbandiD.AsadiM.MokhtarzadehA.et al (2020). CD133: an emerging prognostic factor and therapeutic target in colorectal cancer.Cell Biol. Int.44368–380. 10.1002/cbin.11243

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 4

  Al-BatranS. E.DucreuxM.OhtsuA. (2012). mTOR as a therapeutic target in patients with gastric cancer.Int. J. Cancer130491–496. 10.1002/ijc.26396

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 5

  AminiS.FathiF.MobalegiJ.SofimajidpourH.GhadimiT. (2014). The expressions of stem cell markers: Oct4, Nanog, Sox2, nucleostemin, Bmi, Zfx, Tcl1, Tbx3, Dppa4, and Esrrb in bladder, colon, and prostate cancer, and certain cancer cell lines.Anat. Cell Biol.471–11. 10.5115/acb.2014.47.1.1

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 6

  AnJ. Y.KimK. M.ChoiM. G.NohJ. H.SohnT. S.BaeJ. M.et al (2010). Prognostic role of p-mTOR expression in cancer tissues and metastatic lymph nodes in pT2b gastric cancer.Int. J. Cancer1262904–2913. 10.1002/ijc.24872

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 7

  AvilionA. A.NicolisS. K.PevnyL. H.PerezL.VivianN.Lovell-BadgeR. (2003). Multipotent cell lineages in early mouse development depend on SOX2 function.Genes Dev.17126–140. 10.1101/gad.224503

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 8

  BadrinathN.YooS. Y. (2019). Recent advances in cancer stem cell-targeted immunotherapy.Cancers11:310. 10.3390/cancers11030310

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 9

  BaratS.ChenX.BuiC. K.BozkoP.GötzeJ.ChristgenM.et al (2017). Gamma-secretase inhibitor IX (GSI) impairs concomitant activation of notch and wnt-beta-catenin pathways in CD44+ gastric cancer stem cells.Stem Cells Transl. Med.6819–829. 10.1002/sctm.16-0335

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 10

  BasatiG.MohammadpourH.Emami RazaviA. (2020). Association of high expression levels of SOX2, NANOG, and OCT4 in gastric cancer tumor tissues with progression and poor prognosis.J. Gastrointest. Cancer5141–47. 10.1007/s12029-018-00200-x

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 11

  BastideP.DaridoC.PannequinJ.KistR.RobineS.Marty-DoubleC.et al (2007). Sox9 regulates cell proliferation and is required for Paneth cell differentiation in the intestinal epithelium.J. Cell Biol.178635–648. 10.1083/jcb.200704152

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 12

  BasuS.HaaseG.Ben-Ze’evA. (2016). Wnt signaling in cancer stem cells and colon cancer metastasis.F1000Res.5:F1000 Faculty Rev-699. 10.12688/f1000research.7579.1

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 13

  BehrensJ.von KriesJ. P.KuhlM.BruhnL.WedlichD.GrosschedlR.et al (1996). Functional interaction of beta-catenin with the transcription factor LEF-1.Nature382638–642. 10.1038/382638a0

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 14

  Bekaii-SaabT.El-RayesB. (2017). Identifying and targeting cancer stem cells in the treatment of gastric cancer.Cancer1231303–1312. 10.1002/cncr.30538

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 15

  BendellJ. C.HubbardJ. M.O’NeilB. H.JonkerD. J.StarodubA.PeytonJ. D.et al (2017). Phase 1b/II study of cancer stemness inhibitor napabucasin (BBI-608) in combination with FOLFIRI +/- bevacizumab (bev) in metastatic colorectal cancer (mCRC) patients (pts).J. Clin. Oncol.353529–3529. 10.1200/JCO.2017.35.15_suppl.3529

  • CrossRef
  • Google Scholar

• 16

  BerlinJ.BendellJ. C.HartL. L.FirdausI.GoreI.HermannR. C.et al (2013). A randomized phase II trial of vismodegib versus placebo with FOLFOX or FOLFIRI and bevacizumab in patients with previously untreated metastatic colorectal cancer.Clin. Cancer Res.19258–267. 10.1158/1078-0432.CCR-12-1800

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 17

  BoeschM.SpizzoG.SeeberA. (2018). Concise review: aggressive colorectal cancer: role of epithelial cell adhesion molecule in cancer stem cells and epithelial-to-mesenchymal transition.Stem Cells Transl. Med.7495–501. 10.1002/sctm.17-0289

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 18

  BrabletzT.JungA.SpadernaS.HlubekF.KirchnerT. (2005). Opinion: migrating cancer stem cells - an integrated concept of malignant tumour progression.Nat. Rev. Cancer5744–749. 10.1038/nrc1694

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 19

  BrayF.FerlayJ.SoerjomataramI.SiegelR. L.TorreL. A.JemalA. (2018). Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries.CA Cancer J. Clin.68394–424. 10.3322/caac.21492

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 20

  BretonesG.DelgadoM. D.LeónJ. (2015). Myc and cell cycle control.Biochim. Biophys. Acta1849506–516. 10.1016/j.bbagrm.2014.03.013

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 21

  BrungsD.AghmeshehM.VineK. L.BeckerT. M.CarolanM. G.RansonM. (2016). Gastric cancer stem cells: evidence, potential markers, and clinical implications.J. Gastroenterol.51313–326. 10.1007/s00535-015-1125-5

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 22

  BrunnerT. B.Kunz-SchughartL. A.Grosse-GehlingP.BaumannM. (2012). Cancer stem cells as a predictive factor in radiotherapy.Semin. Radiat. Oncol.22151–174. 10.1016/j.semradonc.2011.12.003

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 23

  BrzozowaM.MielańczykL.MichalskiM.MalinowskiL.Kowalczyk-ZiomekG.HelewskiK.et al (2013). Role of Notch signaling pathway in gastric cancer pathogenesis.Contemp. Oncol.171–5. 10.5114/wo.2013.33765

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 24

  BuczekM. E.ReederS. P.RegadT. (2018). “Identification and isolation of cancer stem cells using NANOG-EGFP reporter system,” in Cancer Stem Cells: Methods and Protocols, edsPapaccioG.DesiderioV. (New York, NY: Springer), 139–148.

  • Google Scholar

• 25

  CamiloV.BarrosR.CelestinoR.CastroP.VieiraJ.TeixeiraM. R.et al (2014). Immunohistochemical molecular phenotypes of gastric cancer based on SOX2 and CDX2 predict patient outcome.BMC Cancer14:753. 10.1186/1471-2407-14-753

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 26

  CantleyL. C. (2002). The phosphoinositide 3-kinase pathway.Science2961655–1657. 10.1126/science.296.5573.1655

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 27

  CarmonK. S.LinQ.GongX.ThomasA.LiuQ. (2012). LGR5 interacts and cointernalizes with Wnt receptors to modulate Wnt/β-catenin signaling.Mol. Cell. Biol.322054–2064.

  • Google Scholar

• 28

  Carrasco-GarciaE.SantosJ. C.GarciaI.BriantiM.García-PugaM.PedrazzoliJ.et al (2016). Paradoxical role of SOX2 in gastric cancer.Am. J. Cancer Res.6701–713.

  • Pubmed Abstract
  • Google Scholar

• 29

  ChambersI.ColbyD.RobertsonM.NicholsJ.LeeS.TweedieS.et al (2003). Functional expression cloning of nanog, a pluripotency sustaining factor in embryonic stem cells.Cell113643–655.

  • Pubmed Abstract
  • Google Scholar

• 30

  ChaudhryA.RudraD.TreutingP.SamsteinR. M.LiangY.KasA.et al (2009). CD4+ regulatory T cells control TH17 responses in a Stat3-dependent manner.Science326986–991. 10.1126/science.1172702

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 31

  ChenK.HuangY.-H.ChenJ.-L. (2013). Understanding and targeting cancer stem cells: therapeutic implications and challenges.Acta Pharmacol. Sin.34732–740. 10.1038/aps.2013.27

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 32

  ChenT.YangK.YuJ.MengW.YuanD.BiF.et al (2012). Identification and expansion of cancer stem cells in tumor tissues and peripheral blood derived from gastric adenocarcinoma patients.Cell Res.22248–258. 10.1038/cr.2011.109

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 33

  ChenZ.HeX.JiaM.LiuY.QuD.WuD.et al (2013). β-catenin overexpression in the nucleus predicts progress disease and unfavourable survival in colorectal cancer: a meta-analysis.PLoS One8:e63854. 10.1371/journal.pone.0063854

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 34

  ChenZ.XuW. R.QianH.ZhuW.BuX. F.WangS.et al (2009). Oct4, a novel marker for human gastric cancer.J. Surg. Oncol.99414–419. 10.1002/jso.21270

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 35

  ChiurilloM. A. (2015). Role of the Wnt/β-catenin pathway in gastric cancer: an in-depth literature review.World J. Exp. Med.584–102. 10.5493/wjem.v5.i2.84

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 36

  ChoY. G.SongJ. H.KimC. J.NamS. W.YooN. J.LeeJ. Y.et al (2007). Genetic and epigenetic analysis of the KLF4 gene in gastric cancer.APMIS115802–808. 10.1111/j.1600-0463.2007.apm_643.x

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 37

  ClementsW. M.WangJ.SarnaikA.KimO. J.MacDonaldJ.Fenoglio-PreiserC.et al (2002). beta-Catenin mutation is a frequent cause of Wnt pathway activation in gastric cancer.Cancer Res.623503–3506.

  • Pubmed Abstract
  • Google Scholar

• 38

  CohenD. J.ChristosP. J.KindlerH. L.CatenacciD. V. T.Bekaii-SaabT. B.TahiriS.et al (2013). Vismodegib (V), a hedgehog (HH) pathway inhibitor, combined with FOLFOX for first-line therapy of patients (pts) with advanced gastric and gastroesophageal junction (GEJ) carcinoma: a New York Cancer Consortium led phase II randomized study.J. Clin. Oncol.314011–4011. 10.1200/jco.2013.31.15_suppl.4011

  • CrossRef
  • Google Scholar

• 39

  CuiJ.ShiM.QuanM.XieK. (2013). Regulation of EMT by KLF4 in gastrointestinal cancer.Curr. Cancer Drug Targets13986–995. 10.2174/15680096113136660104

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 40

  DaiX.GeJ.WangX.QianX.ZhangC.LiX. (2013). OCT4 regulates epithelial-mesenchymal transition and its knockdown inhibits colorectal cancer cell migration and invasion.Oncol. Rep.29155–160. 10.3892/or.2012.2086

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 41

  DalerbaP.ChoR. W.ClarkeM. F. (2007a). Cancer stem cells: models and concepts.Annu. Rev. Med.58267–284. 10.1146/annurev.med.58.062105.204854

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 42

  DalerbaP.DyllaS. J.ParkI.-K.LiuR.WangX.ChoR. W.et al (2007b). Phenotypic characterization of human colorectal cancer stem cells.Proc. Natl. Acad. Sci. U.S.A.10410158–10163. 10.1073/pnas.0703478104

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 43

  DangC. V. (2013). MYC, metabolism, cell growth, and tumorigenesis.Cold Spring Harb. Perspect. Med.3:a014217. 10.1101/cshperspect.a014217

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 44

  DaridoC.BuchertM.PannequinJ.BastideP.ZalzaliH.MantamadiotisT.et al (2008). Defective claudin-7 regulation by Tcf-4 and Sox-9 disrupts the polarity and increases the tumorigenicity of colorectal cancer cells.Cancer Res.684258–4268.

  • Pubmed Abstract
  • Google Scholar

• 45

  DasariA.OvermanM. J.FogelmanD. R.KeeB. K.MenterD.RaghavK. P. S.et al (2016). A phase II and co-clinical study of an AKT inhibitor in patients (pts) with biomarker-enriched, previously treated metastatic colorectal cancer (mCRC).J. Clin. Oncol.343563–3563. 10.1200/JCO.2016.34.15_suppl.3563

  • CrossRef
  • Google Scholar

• 46

  de Sousa e MeloF.KurtovaA. V.HarnossJ. M.KljavinN.HoeckJ. D.HungJ.et al (2017). A distinct role for Lgr5+ stem cells in primary and metastatic colon cancer.Nature543676–680. 10.1038/nature21713

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 47

  de SouzaC. R. T.LealM. F.CalcagnoD. Q.Costa SozinhoE. K.BorgesB. D. N.MontenegroR. C.et al (2013). MYC deregulation in gastric cancer and its clinicopathological implications.PLoS One8:e64420. 10.1371/journal.pone.0064420

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 48

  DeanM.FojoT.BatesS. (2005). Tumour stem cells and drug resistance.Nat. Rev. Cancer5275–284. 10.1038/nrc1590

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 49

  DengJ.LiangH.ZhangR.SunD.PanY.LiuY.et al (2013). STAT3 is associated with lymph node metastasis in gastric cancer.Tumour Biol.342791–2800. 10.1007/s13277-013-0837-5

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 50

  DengJ.-Y.SunD.LiuX.-Y.PanY.LiangH. (2010). STAT-3 correlates with lymph node metastasis and cell survival in gastric cancer.World J. Gastroenterol.165380–5387. 10.3748/wjg.v16.i42.5380

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 51

  DengY.ZhouJ.FangL.CaiY.KeJ.XieX.et al (2014). ALDH1 is an independent prognostic factor for patients with stages II-III rectal cancer after receiving radiochemotherapy.Br. J. Cancer110430–434. 10.1038/bjc.2013.767

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 52

  DidiasovaM.SchaeferL.WygreckaM. (2018). Targeting GLI transcription factors in cancer.Molecules23:1003. 10.3390/molecules23051003

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 53

  DienstmannR.VermeulenL.GuinneyJ.KopetzS.TejparS.TaberneroJ. (2017). Consensus molecular subtypes and the evolution of precision medicine in colorectal cancer.Nat. Rev. Cancer1779–92. 10.1038/nrc.2016.126

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 54

  DoK.SperanzaG.BishopR.KhinS.RubinsteinL.KindersR. J.et al (2015). Biomarker-driven phase 2 study of MK-2206 and selumetinib (AZD6244, ARRY-142886) in patients with colorectal cancer.Invest. New Drugs33720–728. 10.1007/s10637-015-0212-z

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 55

  DongH.LiuH.ZhouW.ZhangF.LiC.ChenJ.et al (2019). GLI1 activation by non-classical pathway integrin α(v)β(3)/ERK1/2 maintains stem cell-like phenotype of multicellular aggregates in gastric cancer peritoneal metastasis.Cell Death Dis.10574–574. 10.1038/s41419-019-1776-x

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 56

  DuL.WangH.HeL.ZhangJ.NiB.WangX.et al (2008). CD44 is of functional importance for colorectal cancer stem cells.Clin. Cancer Res.146751–6760. 10.1158/1078-0432.CCR-08-1034

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 57

  DuX.ChengZ.WangY.-H.GuoZ.-H.ZhangS.-Q.HuJ.-K.et al (2014). Role of Notch signaling pathway in gastric cancer: a meta-analysis of the literature.World J. Gastroenterol.209191–9199. 10.3748/wjg.v20.i27.9191

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 58

  EdingerA. L.ThompsonC. B. (2002). Akt maintains cell size and survival by increasing mTOR-dependent nutrient uptake.Mol. Biol. Cell132276–2288.

  • Pubmed Abstract
  • Google Scholar

• 59

  EspersenM. L.OlsenJ.LinnemannD.HogdallE.TroelsenJ. T. (2015). Clinical implications of intestinal stem cell markers in colorectal cancer.Clin. Colorectal Cancer1463–71. 10.1016/j.clcc.2014.12.004

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 60

  FalchookG. S.DowlatiA.NaingA.GribbinM. J.JenkinsD. W.ChangL. L.et al (2015). Phase I study of MEDI0639 in patients with advanced solid tumors.J. Clin. Oncol.333024–3024. 10.1200/jco.2015.33.15_suppl.3024

  • CrossRef
  • Google Scholar

• 61

  FangD. D.ZhangC. C.GuY.JaniJ. P.CaoJ.TsaparikosK.et al (2013). Antitumor efficacy of the dual PI3K/mTOR inhibitor PF-04691502 in a Human Xenograft tumor model derived from colorectal cancer stem cells harboring a PIK3CA mutation.PLoS One8:e67258. 10.1371/journal.pone.0067258

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 62

  FarkonaS.DiamandisE. P.BlasutigI. M. (2016). Cancer immunotherapy: the beginning of the end of cancer?BMC Med.14:73. 10.1186/s12916-016-0623-5

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 63

  FingarD. C.RichardsonC. J.TeeA. R.CheathamL.TsouC.BlenisJ. (2004). mTOR controls cell cycle progression through its cell growth effectors S6K1 and 4E-BP1/eukaryotic translation initiation factor 4E.Mol. Cell. Biol.24200–216. 10.1128/mcb.24.1.200-216.2004

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 64

  ForghanifardM. M.MoghbeliM.RaeisossadatiR.TavassoliA.MallakA. J.Boroumand-NoughabiS.et al (2013). Role of SALL4 in the progression and metastasis of colorectal cancer.J. Biomed. Sci.20:6. 10.1186/1423-0127-20-6

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 65

  FrancipaneM. G.LagasseE. (2013). Selective targeting of human colon cancer stem-like cells by the mTOR inhibitor Torin-1.Oncotarget41948–1962. 10.18632/oncotarget.1310

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 66

  FujitaT.ChiwakiF.TakahashiR. U.AoyagiK.YanagiharaK.NishimuraT.et al (2015). Identification and characterization of CXCR4-positive gastric cancer stem cells.PLoS One10:e0130808. 10.1371/journal.pone.0130808

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 67

  FukamachiH.SeolH. S.ShimadaS.FunasakaC.BabaK.KimJ. H.et al (2013). CD49f(high) cells retain sphere-forming and tumor-initiating activities in human gastric tumors.PLoS One8:e72438. 10.1371/journal.pone.0072438

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 68

  FukamachiH.ShimadaS.ItoK.ItoY.YuasaY. (2011). CD133 is a marker of gland-forming cells in gastric tumors and Sox17 is involved in its regulation.Cancer Sci.1021313–1321. 10.1111/j.1349-7006.2011.01947.x

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 69

  GhaneiZ.JamshidizadA.JoupariM. D.ShamsaraM. (2020). Isolation and characterization of breast cancer stem cell-like phenotype by Oct4 promoter-mediated activity.J. Cell. Physiol.10.1002/jcp.29437[Epub ahead of print].

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 70

  GidekelS.PizovG.BergmanY.PikarskyE. (2003). Oct-3/4 is a dose-dependent oncogenic fate determinant.Cancer Cell4361–370.

  • Pubmed Abstract
  • Google Scholar

• 71

  GongX.AzhdariniaA.GhoshS. C.XiongW.AnZ.LiuQ.et al (2016). LGR5-targeted antibody–drug conjugate eradicates gastrointestinal tumors and prevents recurrence.Mol. Cancer Ther.151580–1590. 10.1158/1535-7163.MCT-16-0114

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 72

  Goossens-BeumerI. J.ZeestratenE. C.BenardA.ChristenT.ReimersM. S.KeijzerR.et al (2014). Clinical prognostic value of combined analysis of Aldh1, Survivin, and EpCAM expression in colorectal cancer.Br. J. Cancer1102935–2944. 10.1038/bjc.2014.226

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 73

  GrivennikovS. I.KarinM. (2010). Dangerous liaisons: STAT3 and NF-kappaB collaboration and crosstalk in cancer.Cytokine Growth Factor Rev.2111–19. 10.1016/j.cytogfr.2009.11.005

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 74

  GrotheyA.ShahM. A.YoshinoT.CutsemE. V.TaiebJ.XuR.et al (2017). CanStem303C trial: a phase III study of napabucasin (BBI-608) in combination with 5-fluorouracil (5-FU), leucovorin, irinotecan (FOLFIRI) in adult patients with previously treated metastatic colorectal cancer (mCRC).J. Clin. Oncol.35TS3619–TS3619. 10.1200/JCO.2017.35.15_suppl.TPS3619

  • CrossRef
  • Google Scholar

• 75

  GulloI.CarneiroF.OliveiraC.AlmeidaG. M. (2018). Heterogeneity in gastric cancer: from pure morphology to molecular classifications.Pathobiology8550–63. 10.1159/000473881

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 76

  GuptaP. B.OnderT. T.JiangG.TaoK.KuperwasserC.WeinbergR. A.et al (2009). Identification of selective inhibitors of cancer stem cells by high-throughput screening.Cell138645–659. 10.1016/j.cell.2009.06.034

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 77

  GuptaS.TakebeN.LorussoP. (2010). Targeting the Hedgehog pathway in cancer.Ther. Adv. Med. Oncol.2237–250. 10.1177/1758834010366430

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 78

  HadjimichaelC.ChanoumidouK.PapadopoulouN.ArampatziP.PapamatheakisJ.KretsovaliA. (2015). Common stemness regulators of embryonic and cancer stem cells.World J. Stem Cells71150–1184. 10.4252/wjsc.v7.i9.1150

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 79

  HajimoradiM.Mohammad HassanZ.EbrahimiM.SoleimaniM.BakhshiM.FirouziJ.et al (2016). STAT3 is overactivated in gastric cancer stem-like cells.Cell J.17617–628. 10.22074/cellj.2016.3834

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 80

  HanM.-E.JeonT.-Y.HwangS.-H.LeeY.-S.KimH.-J.ShimH.-E.et al (2011). Cancer spheres from gastric cancer patients provide an ideal model system for cancer stem cell research.Cell. Mol. Life Sci.68:3589. 10.1007/s00018-011-0672-z

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 81

  HanS.KimH. Y.ParkK.ChoH. J.LeeM. S.KimH. J.et al (1999). c-Myc expression is related with cell proliferation and associated with poor clinical outcome in human gastric cancer.J. Korean Med. Sci.14526–530. 10.3346/jkms.1999.14.5.526

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 82

  HanS.-M.HanS.-H.CohY.-R.JangG.Chan RaJ.KangS.-K.et al (2014). Enhanced proliferation and differentiation of Oct4- and Sox2-overexpressing human adipose tissue mesenchymal stem cells.Exp. Mol. Med.46:e101. 10.1038/emm.2014.28

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 83

  HaraguchiN.IshiiH.MimoriK.OhtaK.UemuraM.NishimuraJ.et al (2013). CD49f-positive cell population efficiently enriches colon cancer-initiating cells.Int. J. Oncol.43425–430. 10.3892/ijo.2013.1955

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 84

  HashimotoI.NagataT.SekineS.MoriyamaM.ShibuyaK.HojoS.et al (2017). Prognostic significance of KLF4 expression in gastric cancer.Oncol. Lett.13819–826. 10.3892/ol.2016.5499

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 85

  HashimotoK.AoyagiK.IsobeT.KouhujiK.ShirouzuK. (2014). Expression of CD133 in the cytoplasm is associated with cancer progression and poor prognosis in gastric cancer.Gastric Cancer1797–106. 10.1007/s10120-013-0255-9

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 86

  HayakawaY.TsuboiM.AsfahaS.KinoshitaH.NiikuraR.KonishiM.et al (2019). BHLHA15-positive secretory precursor cells can give rise to tumors in intestine and colon in mice.Gastroenterology1561066.e–1081.e. 10.1053/j.gastro.2018.11.024

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 87

  HoriiA.NakatsuruS.MiyoshiY.IchiiS.NagaseH.KatoY.et al (1992). The APC gene, responsible for familial adenomatous polyposis, is mutated in human gastric cancer.Cancer Res.523231–3233.

  • Pubmed Abstract
  • Google Scholar

• 88

  HorstD.KrieglL.EngelJ.KirchnerT.JungA. (2009). Prognostic significance of the cancer stem cell markers CD133, CD44, and CD166 in colorectal cancer.Cancer Invest.27844–850. 10.1080/07357900902744502

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 89

  HsuL.-S.ChanC.-P.ChenC.-J.LinS.-H.LaiM.-T.HsuJ.-D.et al (2013). Decreased Kruppel-like factor 4 (KLF4) expression may correlate with poor survival in gastric adenocarcinoma.Med. Oncol.30:632. 10.1007/s12032-013-0632-6

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 90

  HuangE. H.HynesM. J.ZhangT.GinestierC.DontuG.AppelmanH.et al (2009). Aldehyde dehydrogenase 1 is a marker for normal and malignant human colonic stem cells (SC) and tracks SC overpopulation during colon tumorigenesis.Cancer Res.693382–3389. 10.1158/0008-5472.CAN-08-4418

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 91

  HuangR.WangG.SongY.TangQ.YouQ.LiuZ.et al (2015). Colorectal cancer stem cell and chemoresistant colorectal cancer cell phenotypes and increased sensitivity to Notch pathway inhibitor.Mol. Med. Rep.122417–2424. 10.3892/mmr.2015.3694

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 92

  HuangW. S.WangJ. P.WangT.FangJ. Y.LanP.MaJ. P. (2007). ShRNA-mediated gene silencing of beta-catenin inhibits growth of human colon cancer cells.World J. Gastroenterol.136581–6587. 10.3748/wjg.v13.i48.6581

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 93

  HuchM.CleversH. (2011). Sox9 marks adult organ progenitors.Nat. Genet.439–10. 10.1038/ng0111-9

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 94

  HützK.Mejías-LuqueR.FarsakovaK.OgrisM.KrebsS.AntonM.et al (2013). The stem cell factor SOX2 regulates the tumorigenic potential in human gastric cancer cells.Carcinogenesis35942–950. 10.1093/carcin/bgt410

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 95

  IbrahimE. E.Babaei-JadidiR.SaadeddinA.Spencer-DeneB.HossainiS.AbuzinadahM.et al (2012). Embryonic NANOG activity defines colorectal cancer stem cells and modulates through AP1- and TCF-dependent mechanisms.Stem Cells302076–2087. 10.1002/stem.1182

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 96

  IidaM.BrandT. M.CampbellD. A.StarrM. M.LutharN.TraynorA. M.et al (2013). Targeting AKT with the allosteric AKT inhibitor MK-2206 in non-small cell lung cancer cells with acquired resistance to cetuximab.Cancer Biol. Ther.14481–491. 10.4161/cbt.24342

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 97

  IseghohiS. O. (2016). Cancer stem cells may contribute to the difficulty in treating cancer.Genes Dis.37–10. 10.1016/j.gendis.2016.01.001

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 98

  IshigamiS.ArigamiT.UenosonoY.OkumuraH.KuraharaH.UchikadoY.et al (2013). Clinical implications of DLL4 expression in gastric cancer.J. Exp. Clin. Cancer Res.32:46. 10.1186/1756-9966-32-46

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 99

  IshimotoT.SawayamaH.SugiharaH.BabaH. (2014). Interaction between gastric cancer stem cells and the tumor microenvironment.J. Gastroenterol.491111–1120. 10.1007/s00535-014-0952-0

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 100

  Iv Santaliz-RuizL. E.XieX.OldM.TeknosT. N.PanQ. (2014). Emerging role of nanog in tumorigenesis and cancer stem cells.Int. J. Cancer1352741–2748. 10.1002/ijc.28690

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 101

  JackstadtR.van HooffS. R.LeachJ. D.Cortes-LavaudX.LohuisJ. O.RidgwayR. A.et al (2019). Epithelial NOTCH signaling rewires the tumor microenvironment of colorectal cancer to drive poor-prognosis subtypes and metastasis.Cancer Cell36319.e–336.e. 10.1016/j.ccell.2019.08.003

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 102

  JanssenK. P.AlbericiP.FsihiH.GasparC.BreukelC.FrankenP.et al (2006). APC and oncogenic KRAS are synergistic in enhancing Wnt signaling in intestinal tumor formation and progression.Gastroenterology1311096–1109. 10.1053/j.gastro.2006.08.011

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 103

  JavierB. M.YaegerR.WangL.Sanchez-VegaF.ZehirA.MiddhaS.et al (2016). Recurrent, truncating SOX9 mutations are associated with SOX9 overexpression, KRAS mutation, and TP53 wild type status in colorectal carcinoma.Oncotarget750875–50882. 10.18632/oncotarget.9682

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 104

  JiK.ZhangM.ChuQ.GanY.RenH.ZhangL.et al (2016). The role of p-STAT3 as a prognostic and clinicopathological marker in colorectal cancer: a systematic review and meta-analysis.PLoS One11:e0160125. 10.1371/journal.pone.0160125

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 105

  JiangJ.ZhangY.ChuaiS.WangZ.ZhengD.XuF.et al (2012). Trastuzumab (herceptin) targets gastric cancer stem cells characterized by CD90 phenotype.Oncogene31671–682. 10.1038/onc.2011.282

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 106

  JiangR.NiuX.HuangY.WangX. (2016). β-Catenin is important for cancer stem cell generation and tumorigenic activity in nasopharyngeal carcinoma.Acta Biochim. Biophys. Sin.48229–237. 10.1093/abbs/gmv134

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 107

  JiangY.HeY.LiH.LiH. N.ZhangL.HuW.et al (2012). Expressions of putative cancer stem cell markers ABCB1, ABCG2, and CD133 are correlated with the degree of differentiation of gastric cancer.Gastric Cancer15440–450. 10.1007/s10120-012-0140-y

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 108

  JiangY.LiW.HeX.ZhangH.JiangF.ChenZ. (2016). Lgr5 expression is a valuable prognostic factor for colorectal cancer: evidence from a meta-analysis.BMC Cancer16:12. 10.1186/s12885-015-1985-3

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 109

  JiangY. X.YangS. W.LiP. A.LuoX.LiZ. Y.HaoY. X.et al (2017). The promotion of the transformation of quiescent gastric cancer stem cells by IL-17 and the underlying mechanisms.Oncogene361256–1264. 10.1038/onc.2016.291

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 110

  JoA.DenduluriS.ZhangB.WangZ.YinL.YanZ.et al (2014). The versatile functions of Sox9 in development, stem cells, and human diseases.Genes Dis.1149–161. 10.1016/j.gendis.2014.09.004

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 111

  JohnsonS. M.GulhatiP.RampyB. A.HanY.RychahouP. G.DoanH. Q.et al (2010). Novel expression patterns of PI3K/Akt/mTOR signaling pathway components in colorectal cancer.J. Am. Coll. Surg.210767–776, 776–778. 10.1016/j.jamcollsurg.2009.12.008

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 112

  JonkerD. J.NottL.YoshinoT.GillS.ShapiroJ.OhtsuA.et al (2018). Napabucasin versus placebo in refractory advanced colorectal cancer: a randomised phase 3 trial.Lancet Gastroenterol. Hepatol.3263–270. 10.1016/S2468-1253(18)30009-8

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 113

  KahlertC.GaitzschE.SteinertG.MoglerC.HerpelE.HoffmeisterM.et al (2012). Expression analysis of aldehyde dehydrogenase 1A1 (ALDH1A1) in colon and rectal cancer in association with prognosis and response to chemotherapy.Ann. Surg. Oncol.194193–4201. 10.1245/s10434-012-2518-9

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 114

  KangH.AnH. J.SongJ. Y.KimT. H.HeoJ. H.AhnD. H.et al (2012). Notch3 and Jagged2 contribute to gastric cancer development and to glandular differentiation associated with MUC2 and MUC5AC expression.Histopathology61576–586. 10.1111/j.1365-2559.2012.04274.x

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 115

  KannarkattJ.JosephJ.KurnialiP. C.Al-JanadiA.HrinczenkoB. (2017). Adjuvant chemotherapy for stage II colon cancer: a clinical dilemma.J. Oncol. Pract.13233–241. 10.1200/jop.2016.017210

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 116

  KanwarS. S.YuY.NautiyalJ.PatelB. B.MajumdarA. P. (2010). The Wnt/beta-catenin pathway regulates growth and maintenance of colonospheres.Mol. Cancer9:212. 10.1186/1476-4598-9-212

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 117

  KemperK.PrasetyantiP. R.De LauW.RodermondH.CleversH.MedemaJ. P. (2012). Monoclonal antibodies against Lgr5 identify human colorectal cancer stem cells.Stem Cells302378–2386. 10.1002/stem.1233

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 118

  KimD.-Y.ChaS.-T.AhnD.-H.KangH.-Y.KwonC.-I.KoK.-H.et al (2009). STAT3 expression in gastric cancer indicates a poor prognosis.J. Gastroenterol. Hepatol.24646–651. 10.1111/j.1440-1746.2008.05671.x

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 119

  KimE. J.ShinH.-K.ParkJ. H. Y. (2005). Genistein inhibits insulin-like growth factor-I receptor signaling in HT-29 human colon cancer cells: a possible mechanism of the growth inhibitory effect of Genistein.J. Med. Food8431–438. 10.1089/jmf.2005.8.431

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 120

  KimH. B.LimH. J.LeeH. J.ParkJ. H.ParkS. G. (2019). Evaluation and clinical significance of Jagged-1-activated notch signaling by APEX1 in colorectal cancer.Anticancer Res.396097–6105. 10.21873/anticanres.13817

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 121

  KimY.JooK. M.JinJ.NamD.-H. (2009). Cancer stem cells and their mechanism of chemo-radiation resistance.Int. J. Stem Cells2109–114. 10.15283/ijsc.2009.2.2.109

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 122

  KodamaH.MurataS.IshidaM.YamamotoH.YamaguchiT.KaidaS.et al (2017). Prognostic impact of CD44-positive cancer stem-like cells at the invasive front of gastric cancer.Br. J. Cancer116186–194. 10.1038/bjc.2016.401

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 123

  KolligsF. T.BommerG.GokeB. (2002). Wnt/beta-catenin/tcf signaling: a critical pathway in gastrointestinal tumorigenesis.Digestion66131–144. 10.1159/000066755

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 124

  KrizhanovskyV.LoweS. W. (2009). Stem cells: the promises and perils of p53.Nature4601085–1086. 10.1038/4601085a

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 125

  KuipersE. J.GradyW. M.LiebermanD.SeufferleinT.SungJ. J.BoelensP. G.et al (2015). Colorectal cancer.Nat. Rev. Dis. Primers1:15065. 10.1038/nrdp.2015.65

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 126

  LabiancaR.NordlingerB.BerettaG. D.MosconiS.MandalàM.CervantesA.et al (2013). Early colon cancer: ESMO clinical practice guidelines for diagnosis, treatment and follow-up.Ann. Oncol.24 (Suppl. 6), vi64–vi72. 10.1093/annonc/mdt354

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 127

  LangS. A.GaumannA.KoehlG. E.SeidelU.BatailleF.KleinD.et al (2007). Mammalian target of rapamycin is activated in human gastric cancer and serves as a target for therapy in an experimental model.Int. J. Cancer1201803–1810. 10.1002/ijc.22442

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 128

  LauE. Y.-T.HoN. P.-Y.LeeT. K.-W. (2017). Cancer stem cells and their microenvironment: biology and therapeutic implications.Stem Cells Int.2017:3714190. 10.1155/2017/3714190

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 129

  LeeH. H.SeoK. J.AnC. H.KimJ. S.JeonH. M. (2012). CD133 expression is correlated with chemoresistance and early recurrence of gastric cancer.J. Surg. Oncol.106999–1004. 10.1002/jso.23178

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 130

  LeeK. S.KwakY.NamK. H.KimD. W.KangS. B.ChoeG.et al (2015). c-MYC copy-number gain is an independent prognostic factor in patients with colorectal cancer.PLoS One10:e0139727. 10.1371/journal.pone.0139727

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 131

  LengZ.TaoK.XiaQ.TanJ.YueZ.ChenJ.et al (2013). Kruppel-like factor 4 acts as an oncogene in colon cancer stem cell-enriched spheroid cells.PLoS One8:e56082. 10.1371/journal.pone.0056082

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 132

  LengZ.XiaQ.ChenJ.LiY.XuJ.ZhaoE.et al (2018). Lgr5+CD44+EpCAM+ strictly defines cancer stem cells in human colorectal cancer.Cell. Physiol. Biochem.46860–872. 10.1159/000488743

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 133

  LiM. X.WangQ.WangB.YanD. W.TangH. M.PengZ. H.et al (2012). [Association between gut-enriched Kruppel-like factor and prognosis of patients with gastric cancer].Zhonghua Wei Chang Wai Ke Za Zhi15732–735.

  • Google Scholar

• 134

  LiW.ZhouY.YangJ.ZhangX.ZhangH.ZhangT.et al (2015). Gastric cancer-derived mesenchymal stem cells prompt gastric cancer progression through secretion of interleukin-8.J. Exp. Clin. Cancer Res.34:52. 10.1186/s13046-015-0172-3

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 135

  LiY.RogoffH. A.KeatesS.GaoY.MurikipudiS.MikuleK.et al (2015). Suppression of cancer relapse and metastasis by inhibiting cancer stemness.Proc. Natl. Acad. Sci. U.S.A.1121839–1844. 10.1073/pnas.1424171112

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 136

  LinL.LiuA.PengZ.LinH. J.LiP. K.LiC.et al (2011). STAT3 is necessary for proliferation and survival in colon cancer-initiating cells.Cancer Res.717226–7237. 10.1158/0008-5472.CAN-10-4660

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 137

  LinQ.LaiR.ChirieacL. R.LiC.ThomazyV. A.GrammatikakisI.et al (2005). Constitutive activation of JAK3/STAT3 in colon carcinoma tumors and cell lines: inhibition of JAK3/STAT3 signaling induces apoptosis and cell cycle arrest of colon carcinoma cells.Am. J. Pathol.167969–980. 10.1016/s0002-9440(10)61187-x

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 138

  LinT.DingY.-Q.LiJ.-M. (2012). Overexpression of Nanog protein is associated with poor prognosis in gastric adenocarcinoma.Med. Oncol.29878–885. 10.1007/s12032-011-9860-9

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 139

  LiuL.NingX.SunL.ZhangH.ShiY.GuoC.et al (2008). Hypoxia-inducible factor-1 alpha contributes to hypoxia-induced chemoresistance in gastric cancer.Cancer Sci.99121–128. 10.1111/j.1349-7006.2007.00643.x

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 140

  LochheadP.El-OmarE. M. (2008). Gastric cancer.Br. Med. Bull.8587–100. 10.1093/bmb/ldn007

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 141

  LoConteN. K.RazakA. R. A.IvyP.TevaarwerkA.LeverenceR.KolesarJ.et al (2015). A multicenter phase 1 study of γ -secretase inhibitor RO4929097 in combination with capecitabine in refractory solid tumors.Invest. New Drugs33169–176. 10.1007/s10637-014-0166-6

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 142

  LohY.-H.WuQ.ChewJ.-L.VegaV. B.ZhangW.ChenX.et al (2006). The Oct4 and Nanog transcription network regulates pluripotency in mouse embryonic stem cells.Nat. Genet.38431–440. 10.1038/ng1760

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 143

  LowJ. A.de SauvageF. J. (2010). Clinical experience with Hedgehog pathway inhibitors.J. Clin. Oncol.285321–5326. 10.1200/jco.2010.27.9943

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 144

  LuB.FangY.XuJ.WangL.XuF.XuE.et al (2008). Analysis of SOX9 expression in colorectal cancer.Am. J. Clin. Pathol.130897–904. 10.1309/ajcpw1w8gjbqgcni

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 145

  LuJ.YeX.FanF.XiaL.BhattacharyaR.BellisterS.et al (2013). Endothelial cells promote the colorectal cancer stem cell phenotype through a soluble form of Jagged-1.Cancer Cell23171–185. 10.1016/j.ccr.2012.12.021

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 146

  LugliA.IezziG.HostettlerI.MuraroM. G.MeleV.TornilloL.et al (2010). Prognostic impact of the expression of putative cancer stem cell markers CD133, CD166, CD44s, EpCAM, and ALDH1 in colorectal cancer.Br. J. Cancer103382–390. 10.1038/sj.bjc.6605762

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 147

  LuistroL.HeW.SmithM.PackmanK.VilenchikM.CarvajalD.et al (2009). Preclinical profile of a potent γ-secretase inhibitor targeting notch signaling with in vivo efficacy and pharmacodynamic properties.Cancer Res.697672–7680. 10.1158/0008-5472.Can-09-1843

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 148

  LundbergI. V.EdinS.EklofV.ObergA.PalmqvistR.WikbergM. L. (2016). SOX2 expression is associated with a cancer stem cell state and down-regulation of CDX2 in colorectal cancer.BMC Cancer16:471. 10.1186/s12885-016-2509-5

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 149

  LundbergI. V.Lofgren BurstromA.EdinS.EklofV.ObergA.StenlingR.et al (2014). SOX2 expression is regulated by BRAF and contributes to poor patient prognosis in colorectal cancer.PLoS One9:e101957. 10.1371/journal.pone.0101957

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 150

  MaX.ChenK.HuangS.ZhangX.AdegboyegaP. A.EversB. M.et al (2005). Frequent activation of the hedgehog pathway in advanced gastric adenocarcinomas.Carcinogenesis261698–1705. 10.1093/carcin/bgi130

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 151

  MaY.CuiW.YangJ.QuJ.DiC.AminH. M.et al (2006). SALL4, a novel oncogene, is constitutively expressed in human acute myeloid leukemia (AML) and induces AML in transgenic mice.Blood1082726–2735.

  • Pubmed Abstract
  • Google Scholar

• 152

  MageeJ. A.PiskounovaE.MorrisonS. J. (2012). Cancer stem cells: impact, heterogeneity, and uncertainty.Cancer Cell21283–296. 10.1016/j.ccr.2012.03.003

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 153

  MalkomesP.LungerI.LuettickeA.OppermannE.HaetscherN.ServeH.et al (2016). Selective AKT inhibition by MK-2206 represses colorectal cancer-initiating stem cells.Ann. Surg. Oncol.232849–2857. 10.1245/s10434-016-5218-z

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 154

  MaoJ.FanS.MaW.FanP.WangB.ZhangJ.et al (2014). Roles of Wnt/β-catenin signaling in the gastric cancer stem cells proliferation and salinomycin treatment.Cell Death Dis.5:e1039. 10.1038/cddis.2013.515

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 155

  MarjanovicN. D.WeinbergR. A.ChafferC. L. (2013). Cell plasticity and heterogeneity in cancer.Clin. Chem.59168–179. 10.1373/clinchem.2012.184655

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 156

  MatheuA.ColladoM.WiseC.ManterolaL.CekaiteL.TyeA. J.et al (2012). Oncogenicity of the developmental transcription factor Sox9.Cancer Res.721301–1315. 10.1158/0008-5472.CAN-11-3660

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 157

  MattiuzziC.Sanchis-GomarF.LippiG. (2019). Concise update on colorectal cancer epidemiology.Ann. Transl. Med.7:609. 10.21037/atm.2019.07.91

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 158

  MazumdarJ.O’BrienW. T.JohnsonR. S.LaMannaJ. C.ChavezJ. C.KleinP. S.et al (2010). O₂ regulates stem cells through Wnt/β-catenin signalling.Nat. Cell Biol.121007–1013. 10.1038/ncb2102

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 159

  McMillanR.MatsuiW. (2012). Molecular pathways: the hedgehog signaling pathway in cancer.Clin. Cancer Res.184883–4888.

  • Google Scholar

• 160

  MenonS.ShinS.DyG. (2016). Advances in cancer immunotherapy in solid tumors.Cancers8:E106. 10.3390/cancers8120106

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 161

  MesquitaP.FreireA. F.LopesN.GomesR.AzevedoD.BarrosR.et al (2019). Expression and clinical relevance of SOX9 in gastric cancer.Dis. Markers2019:8267021. 10.1155/2019/8267021

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 162

  MichlP.DownwardJ. (2005). Mechanisms of disease: PI3K/AKT signaling in gastrointestinal cancers.Z. Gastroenterol.431133–1139.

  • Pubmed Abstract
  • Google Scholar

• 163

  MiyoshiN.FujinoS.OhueM.YasuiM.TakahashiY.SugimuraK.et al (2018). The POU5F1 gene expression in colorectal cancer: a novel prognostic marker.Surg. Today48709–715. 10.1007/s00595-018-1644-9

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 164

  MiyoshiN.IshiiH.NagaiK.HoshinoH.MimoriK.TanakaF.et al (2010). Defined factors induce reprogramming of gastrointestinal cancer cells.Proc. Natl. Acad. Sci. U.S.A.10740–45. 10.1073/pnas.0912407107

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 165

  MohamedS. Y.KafR. M.AhmedM. M.ElwanA.AshourH. R.IbrahimA. (2019). The prognostic value of cancer stem cell markers (Notch1, ALDH1, and CD44) in primary colorectal carcinoma.J. Gastrointest. Cancer50824–837. 10.1007/s12029-018-0156-6

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 166

  MüllerS.CañequeT.AcevedoV.RodriguezR. (2017). Targeting cancer stem cells with small molecules.Isr. J. Chem.57239–250. 10.1002/ijch.201600109

  • CrossRef
  • Google Scholar

• 167

  MunroM. J.WickremesekeraS. K.PengL.TanS. T.ItinteangT. (2018). Cancer stem cells in colorectal cancer: a review.J. Clin. Pathol.71110–116. 10.1136/jclinpath-2017-204739

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 168

  MurayamaT.InokuchiM.TakagiY.YamadaH.KojimaK.KumagaiJ.et al (2009). Relation between outcomes and localisation of p-mTOR expression in gastric cancer.Br. J. Cancer100782–788. 10.1038/sj.bjc.6604915

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 169

  MuznyD. M.BainbridgeM. N.ChangK.DinhH. H.DrummondJ. A.FowlerG.et al (2012). Comprehensive molecular characterization of human colon and rectal cancer.Nature487330–337. 10.1038/nature11252

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 170

  MyantK. B.CammareriP.McGheeE. J.RidgwayR. A.HuelsD. J.CorderoJ. B.et al (2013). ROS production and NF-κB activation triggered by RAC1 facilitate WNT-driven intestinal stem cell proliferation and colorectal cancer initiation.Cell Stem Cell12761–773. 10.1016/j.stem.2013.04.006

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 171

  NakatsuruS.YanagisawaA.FurukawaY.IchiiS.KatoY.NakamuraY.et al (1993). Somatic mutations of the APC gene in precancerous lesion of the stomach.Hum. Mol. Genet.21463–1465. 10.1093/hmg/2.9.1463

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 172

  NarayanankuttyA. (2019). PI3K/ Akt/ mTOR pathway as a therapeutic target for colorectal cancer: a review of preclinical and clinical evidence.Curr. Drug Targets201217–1226. 10.2174/1389450120666190618123846

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 173

  NeriB.PantaleoP.GiommoniE.GrifoniR.PaolettiC.RotellaV.et al (2007). Oxaliplatin, 5-fluorouracil/leucovorin and epirubicin as first-line treatment in advanced gastric carcinoma: a phase II study.Br. J. Cancer961043–1046. 10.1038/sj.bjc.6603644

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 174

  NiedzwieckiD.BertagnolliM. M.WarrenR. S.ComptonC. C.KemenyN. E.BensonA. B.et al (2011). Documenting the natural history of patients with resected stage II adenocarcinoma of the colon after random assignment to adjuvant treatment with edrecolomab or observation: results from CALGB 9581.J. Clin. Oncol.293146–3152. 10.1200/jco.2010.32.5357

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 175

  NosratiA.NaghshvarF.KhanariS. (2014). Cancer stem cell markers CD44, CD133 in primary gastric adenocarcinoma.Int. J. Mol. Cell. Med.3279–286.

  • Pubmed Abstract
  • Google Scholar

• 176

  O’BrienC. A.PollettA.GallingerS.DickJ. E. (2007). A human colon cancer cell capable of initiating tumour growth in immunodeficient mice.Nature445106–110. 10.1038/nature05372

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 177

  OhkumaM.HaraguchiN.IshiiH.MimoriK.TanakaF.KimH. M.et al (2012). Absence of CD71 transferrin receptor characterizes human gastric adenosquamous carcinoma stem cells.Ann. Surg. Oncol.191357–1364. 10.1245/s10434-011-1739-7

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 178

  OngC. W.KimL. G.KongH. H.LowL. Y.IacopettaB.SoongR.et al (2010). CD133 expression predicts for non-response to chemotherapy in colorectal cancer.Mod. Pathol.23450–457. 10.1038/modpathol.2009.181

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 179

  OoiC. H.IvanovaT.WuJ.LeeM.TanI. B.TaoJ.et al (2009). Oncogenic pathway combinations predict clinical prognosis in gastric cancer.PLoS Genet.5:e1000676. 10.1371/journal.pgen.1000676

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 180

  PáduaD.BarrosR.AmaralA. L.MesquitaP.FreireA. F.SousaM.et al (2020). A SOX2 reporter system identifies gastric cancer stem-like cells sensitive to monensin.Cancers12:495. 10.3390/cancers12020495

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 181

  PantS.JonesS. F.KurkjianC. D.InfanteJ. R.MooreK. N.BurrisH. A.et al (2016). A first-in-human phase I study of the oral Notch inhibitor, LY900009, in patients with advanced cancer.Eur. J. Cancer561–9. 10.1016/j.ejca.2015.11.021

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 182

  ParizadehS. M.Jafarzadeh-EsfehaniR.HassanianS. M.ParizadehS. M. R.VojdaniS.GhandehariM.et al (2019). Targeting cancer stem cells as therapeutic approach in the treatment of colorectal cancer.Int. J. Biochem. Cell Biol.11075–83. 10.1016/j.biocel.2019.02.010

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 183

  ParkJ. H.ChungS.MatsuoY.NakamuraY. (2017). Development of small molecular compounds targeting cancer stem cells.Medchemcomm873–80. 10.1039/c6md00385k

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 184

  PatelS.AlamA.PantR.ChattopadhyayS. (2019). Wnt signaling and its significance within the tumor microenvironment: novel therapeutic insights.Front. Immunol.10:2872. 10.3389/fimmu.2019.02872

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 185

  PattabiramanD. R.WeinbergR. A. (2014). Tackling the cancer stem cells - what challenges do they pose?Nat. Rev. Drug Discov.13497–512. 10.1038/nrd4253

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 186

  PhiL. T. H.SariI. N.YangY.-G.LeeS.-H.JunN.KimK. S.et al (2018). Cancer Stem Cells (CSCs) in drug resistance and their therapeutic implications in cancer treatment.Stem Cells Int.2018:5416923. 10.1155/2018/5416923

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 187

  PintovaS.DharmupariS.MoshierE.ZubizarretaN.AngC.HolcombeR. F. (2019). Genistein combined with FOLFOX or FOLFOX–Bevacizumab for the treatment of metastatic colorectal cancer: phase I/II pilot study.Cancer Chemother. Pharmacol.84591–598. 10.1007/s00280-019-03886-3

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 188

  PrévostelC.BlacheP. (2017). The dose-dependent effect of SOX9 and its incidence in colorectal cancer.Eur. J. Cancer86150–157. 10.1016/j.ejca.2017.08.037

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 189

  QuailD. F.TaylorM. J.PostovitL. M. (2012). Microenvironmental regulation of cancer stem cell phenotypes.Curr. Stem Cell Res. Ther.7197–216. 10.2174/157488812799859838

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 190

  QuanteM.VargaJ.WangT. C.GretenF. R. (2013). The gastrointestinal tumor microenvironment.Gastroenterology14563–78. 10.1053/j.gastro.2013.03.052

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 191

  RamanathanR. K.McDonoughS. L.KenneckeH. F.IqbalS.BarandaJ. C.SeeryT. E.et al (2015). Phase 2 study of MK-2206, an allosteric inhibitor of AKT, as second-line therapy for advanced gastric and gastroesophageal junction cancer: a SWOG cooperative group trial (S1005).Cancer1212193–2197. 10.1002/cncr.29363

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 192

  RassouliF. B.MatinM. M.SaeinasabM. (2016). Cancer stem cells in human digestive tract malignancies.Tumor Biol.377–21. 10.1007/s13277-015-4155-y

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 193

  RezalotfiA.AhmadianE.AazamiH.SolgiG.EbrahimiM. (2019). Gastric cancer stem cells effect on Th17/Treg Balance; a bench to beside perspective.Front. Oncol.9:226. 10.3389/fonc.2019.00226

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 194

  Ricci-VitianiL.LombardiD. G.PilozziE.BiffoniM.TodaroM.PeschleC.et al (2007). Identification and expansion of human colon-cancer-initiating cells.Nature445111–115. 10.1038/nature05384

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 195

  RileyR. S.JuneC. H.LangerR.MitchellM. J. (2019). Delivery technologies for cancer immunotherapy.Nat. Rev. Drug Discov.18175–196. 10.1038/s41573-018-0006-z

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 196

  RimkusT. K.CarpenterR. L.QasemS.ChanM.LoH. W. (2016). Targeting the sonic hedgehog signaling pathway: review of smoothened and GLI inhibitors.Cancers8:22. 10.3390/cancers8020022

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 197

  RobertsonJ. H.YangS. Y.WinsletM. C.SeifalianA. M. (2009). Functional blocking of specific integrins inhibit colonic cancer migration.Clin. Exp. Metastasis26769–780. 10.1007/s10585-009-9276-5

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 198

  RoccoA.LiguoriE.PirozziG.TirinoV.CompareD.FrancoR.et al (2012). CD133 and CD44 cell surface markers do not identify cancer stem cells in primary human gastric tumors.J. Cell. Physiol.2272686–2693. 10.1002/jcp.23013

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 199

  SahebjamS.BedardP. L.CastonguayV.ChenZ.ReedijkM.LiuG.et al (2013). A phase I study of the combination of ro4929097 and cediranib in patients with advanced solid tumours (PJC-004/NCI 8503).Br. J. Cancer109943–949. 10.1038/bjc.2013.380

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 200

  SantosJ. C.Carrasco-GarciaE.Garcia-PugaM.AldazP.MontesM.Fernandez-ReyesM.et al (2016). SOX9 elevation acts with canonical WNT signaling to drive gastric cancer progression.Cancer Res.766735–6746. 10.1158/0008-5472.CAN-16-1120

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 201

  SarkarA.HochedlingerK. (2013). The sox family of transcription factors: versatile regulators of stem and progenitor cell fate.Cell Stem Cell1215–30. 10.1016/j.stem.2012.12.007

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 202

  SayginC.SamourM.ChumakovaA.JarrarA.LathiaJ. D.ReizesO. (2016). “Reporter systems to study cancer stem cells,” in Stem Cell Heterogeneity: Methods and Protocols, ed.TurksenK. (New York, NY: Springer), 319–333.

  • Google Scholar

• 203

  SchramA. M.GandhiL.MitaM. M.DamstrupL.CampanaF.HidalgoM.et al (2018). A phase Ib dose-escalation and expansion study of the oral MEK inhibitor pimasertib and PI3K/MTOR inhibitor voxtalisib in patients with advanced solid tumours.Br. J. Cancer1191471–1476. 10.1038/s41416-018-0322-4

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 204

  ShapiroG.BedardP.InfanteJ.BauerT.PrawiraA.LaksinO.et al (2016). Phase 1 results of PTC596, a novel small molecule targeting cancer stem cells (CSCs) by reducing levels of BMI1 protein.Eur. J. Cancer69S148.

  • Google Scholar

• 205

  ShieJ. L.ChenZ. Y.O’BrienM. J.PestellR. G.LeeM. E.TsengC. C. (2000). Role of gut-enriched Kruppel-like factor in colonic cell growth and differentiation.Am. J. Physiol. Gastrointest. Liver Physiol.279G806–G814. 10.1152/ajpgi.2000.279.4.G806

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 206

  Shih IeM.WangT. L. (2007). Notch signaling, gamma-secretase inhibitors, and cancer therapy.Cancer Res.671879–1882.

  • Google Scholar

• 207

  SmythE. C.VerheijM.AllumW.CunninghamD.CervantesA.ArnoldD.et al (2016). Gastric cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up^†.Ann. Oncol.27(Suppl._5), v38–v49. 10.1093/annonc/mdw350

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 208

  SonbolM. B.AhnD. H.Bekaii-SaabT. (2019). Therapeutic targeting strategies of cancer stem cells in gastrointestinal malignancies.Biomedicines7:17. 10.3390/biomedicines7010017

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 209

  SongZ.WuY.YangJ.YangD.FangX. (2017). Progress in the treatment of advanced gastric cancer.Tumor Biol.39:1010428317714626. 10.1177/1010428317714626

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 210

  StrosbergJ. R.YeatmanT.WeberJ.CoppolaD.SchellM. J.HanG.et al (2012). A phase II study of RO4929097 in metastatic colorectal cancer.Eur. J. Cancer48997–1003. 10.1016/j.ejca.2012.02.056

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 211

  SuS.-J.ChowN.-H.KungM.-L.HungT.-C.ChangK.-L. (2003). Effects of soy isoflavones on apoptosis induction and G2-M arrest in human hepatoma cells involvement of caspase-3 activation, Bcl-2 and Bcl-XL downregulation, and Cdc2 kinase activity.Nutr. Cancer45113–123. 10.1207/S15327914NC4501_13

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 212

  SunM.UozakiH.HinoR.KunitaA.ShinozakiA.UshikuT.et al (2012). SOX9 expression and its methylation status in gastric cancer.Virchows Arch.460271–279. 10.1007/s00428-012-1201-7

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 213

  TaiM.-H.ChangC.-C.OlsonL. K.TroskoJ. E. (2005). Oct4 expression in adult human stem cells: evidence in support of the stem cell theory of carcinogenesis.Carcinogenesis26495–502. 10.1093/carcin/bgh321

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 214

  TakahashiK.YamanakaS. (2006). Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors.Cell126663–676. 10.1016/j.cell.2006.07.024

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 215

  TakaishiS.OkumuraT.TuS.WangS. S. W.ShibataW.VigneshwaranR.et al (2009). Identification of gastric cancer stem cells using the cell surface marker CD44.Stem Cells271006–1020. 10.1002/stem.30

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 216

  TakebeN.HarrisP. J.WarrenR. Q.IvyS. P. (2011). Targeting cancer stem cells by inhibiting Wnt, Notch, and Hedgehog pathways.Nat. Rev. Clin. Oncol.897–106. 10.1038/nrclinonc.2010.196

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 217

  TakedaK.MizushimaT.YokoyamaY.HiroseH.WuX.QianY.et al (2018). Sox2 is associated with cancer stem-like properties in colorectal cancer.Sci. Rep.8:17639.

  • Google Scholar

• 218

  TangB.RavivA.EspositoD.FlandersK. C.DanielC.NghiemB. T.et al (2015). A flexible reporter system for direct observation and isolation of cancer stem cells.Stem Cell Rep.4155–169. 10.1016/j.stemcr.2014.11.002

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 219

  TapiaO.RiquelmeI.LealP.SandovalA.AedoS.WeberH.et al (2014). The PI3K/AKT/mTOR pathway is activated in gastric cancer with potential prognostic and predictive significance.Virchows Arch.46525–33. 10.1007/s00428-014-1588-4

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 220

  TianT.ZhangY.WangS.ZhouJ.XuS. (2012). Sox2 enhances the tumorigenicity and chemoresistance of cancer stem-like cells derived from gastric cancer.J. Biomed. Res.26336–345. 10.7555/JBR.26.20120045

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 221

  TodaroM.FrancipaneM. G.MedemaJ. P.StassiG. (2010). Colon cancer stem cells: promise of targeted therapy.Gastroenterology1382151–2162. 10.1053/j.gastro.2009.12.063

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 222

  TolcherA. W.MessersmithW. A.MikulskiS. M.PapadopoulosK. P.KwakE. L.GibbonD. G.et al (2012). Phase I Study of RO4929097, a gamma secretase inhibitor of notch signaling, in patients with refractory metastatic or locally advanced solid tumors.J. Clin. Oncol.302348–2353. 10.1200/jco.2011.36.8282

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 223

  UsuiT.SakuraiM.UmataK.ElbadawyM.OhamaT.YamawakiH.et al (2018). Hedgehog signals mediate anti-cancer drug resistance in three-dimensional primary colorectal cancer organoid culture.Int. J. Mol. Sci.19:1098. 10.3390/ijms19041098

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 224

  VaddeR.VemulaS.JinkaR.MerchantN.BramhachariP. V.NagarajuG. P. (2017). Role of hypoxia-inducible factors (HIF) in the maintenance of stemness and malignancy of colorectal cancer.Crit. Rev. Oncol. Hematol.11322–27. 10.1016/j.critrevonc.2017.02.025

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 225

  VaiopoulosA. G.KostakisI. D.KoutsilierisM.PapavassiliouA. G. (2012). Colorectal cancer stem cells.Stem Cells30363–371. 10.1002/stem.1031

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 226

  van der HeijdenM.VermeulenL. (2019). Stem cells in homeostasis and cancer of the gut.Mol. Cancer18:66. 10.1186/s12943-019-0962-x

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 227

  VarnatF.DuquetA.MalerbaM.ZbindenM.MasC.GervazP.et al (2009). Human colon cancer epithelial cells harbour active HEDGEHOG-GLI signalling that is essential for tumour growth, recurrence, metastasis and stem cell survival and expansion.EMBO Mol. Med.1338–351. 10.1002/emmm.200900039

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 228

  VenkateshV.NatarajR.ThangarajG. S.KarthikeyanM.GnanasekaranA.KaginelliS. B.et al (2018). Targeting Notch signalling pathway of cancer stem cells.Stem Cell Investig.5:5. 10.21037/sci.2018.02.02

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 229

  VermeulenL.De SousaE.MeloF.van der HeijdenM.CameronK.de JongJ. H.et al (2010). Wnt activity defines colon cancer stem cells and is regulated by the microenvironment.Nat. Cell Biol.12468–476. 10.1038/ncb2048

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 230

  VermeulenL.TodaroM.de Sousa MelloF.SprickM. R.KemperK.Perez AleaM.et al (2008). Single-cell cloning of colon cancer stem cells reveals a multi-lineage differentiation capacity.Proc. Natl. Acad. Sci. U.S.A.10513427–13432. 10.1073/pnas.0805706105

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 231

  VoorneveldP. W.KodachL. L.JacobsR. J.van NoeselC. J.PeppelenboschM. P.KorkmazK. S.et al (2015). The BMP pathway either enhances or inhibits the Wnt pathway depending on the SMAD4 and p53 status in CRC.Br. J. Cancer112122–130. 10.1038/bjc.2014.560

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 232

  WahabS. M. R.IslamF.GopalanV.LamA. K. (2017). The identifications and clinical implications of cancer stem cells in colorectal cancer.Clin. Colorectal Cancer1693–102. 10.1016/j.clcc.2017.01.011

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 233

  WakamatsuY.SakamotoN.OoH. Z.NaitoY.UraokaN.AnamiK.et al (2012). Expression of cancer stem cell markers ALDH1, CD44 and CD133 in primary tumor and lymph node metastasis of gastric cancer.Pathol. Int.62112–119. 10.1111/j.1440-1827.2011.02760.x

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 234

  WangH.LiQ.ChenH. (2012). Genistein affects histone modifications on Dickkopf-Related Protein 1 (DKK1) gene in SW480 human colon cancer cell line.PLoS One7:e40955. 10.1371/journal.pone.0040955

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 235

  WangW.DengJ.WangQ.YaoQ.ChenW.TanY.et al (2017). Synergistic role of Cul1 and c-Myc: prognostic and predictive biomarkers in colorectal cancer.Oncol. Rep.38245–252. 10.3892/or.2017.5671

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 236

  WangX.LiuY.ShaoD.QianZ.DongZ.SunY.et al (2016). Recurrent amplification of MYC and TNFRSF11B in 8q24 is associated with poor survival in patients with gastric cancer.Gastric Cancer19116–127. 10.1007/s10120-015-0467-2

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 237

  WangZ.LiY.AhmadA.AzmiA. S.BanerjeeS.KongD.et al (2010). Targeting Notch signaling pathway to overcome drug resistance for cancer therapy.Biochim. Biophys. Acta1806258–267. 10.1016/j.bbcan.2010.06.001

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 238

  WeiD.KanaiM.HuangS.XieK. (2006). Emerging role of KLF4 in human gastrointestinal cancer.Carcinogenesis2723–31. 10.1093/carcin/bgi243

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 239

  Weldon GilcreaseG.StenehjemD. D.WadeM. L.WeisJ.McGregorK.WhisenantJ.et al (2019). Phase I/II study of everolimus combined with mFOLFOX-6 and bevacizumab for first–line treatment of metastatic colorectal cancer.Invest. New Drugs37482–489. 10.1007/s10637-018-0645-2

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 240

  WestN. R.McCuaigS.FranchiniF.PowrieF. (2015). Emerging cytokine networks in colorectal cancer.Nat. Rev. Immunol.15615–629. 10.1038/nri3896

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 241

  WolpinB. M.NgK.ZhuA. X.AbramsT.EnzingerP. C.McClearyN. J.et al (2013). Multicenter phase II study of tivozanib (AV-951) and everolimus (RAD001) for patients with refractory, metastatic colorectal cancer.Oncologist18377–378. 10.1634/theoncologist.2012-0378

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 242

  WooD. K.KimH. S.LeeH. S.KangY. H.YangH. K.KimW. H. (2001). Altered expression and mutation of beta-catenin gene in gastric carcinomas and cell lines.Int. J. Cancer95108–113.

  • Pubmed Abstract
  • Google Scholar

• 243

  WuebbenE. L.RizzinoA. (2017). The dark side of SOX2: cancer - a comprehensive overview.Oncotarget844917–44943. 10.18632/oncotarget.16570

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 244

  XiaP.XuX. Y. (2015). PI3K/Akt/mTOR signaling pathway in cancer stem cells: from basic research to clinical application.Am. J. Cancer Res.51602–1609.

  • Pubmed Abstract
  • Google Scholar

• 245

  XiaoL.WangY. C.LiW. S.DuY. (2009). The role of mTOR and phospho-p70S6K in pathogenesis and progression of gastric carcinomas: an immunohistochemical study on tissue microarray.J. Exp. Clin. Cancer Res.28:152. 10.1186/1756-9966-28-152

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 246

  YangJ.ChaiL.FowlesT. C.AlipioZ.XuD.FinkL. M.et al (2008). Genome-wide analysis reveals Sall4 to be a major regulator of pluripotency in murine-embryonic stem cells.Proc. Natl. Acad. Sci. U.S.A.10519756–19761. 10.1073/pnas.0809321105

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 247

  YangL.ShiP.ZhaoG.XuJ.PengW.ZhangJ.et al (2020). Targeting cancer stem cell pathways for cancer therapy.Signal Transduct. Target. Ther.5:8. 10.1038/s41392-020-0110-5

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 248

  YangZ.ZhangC.QiW.CuiY.XuanY. (2018). GLI1 promotes cancer stemness through intracellular signaling pathway PI3K/Akt/NFkappaB in colorectal adenocarcinoma.Exp. Cell Res.373145–154. 10.1016/j.yexcr.2018.10.006

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 249

  YangZ. H.DangY. Q.JiG. (2019). Role of epigenetics in transformation of inflammation into colorectal cancer.World J. Gastroenterol.252863–2877. 10.3748/wjg.v25.i23.2863

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 250

  YaoY.ZhouD.ShiD.ZhangH.ZhanS.ShaoX.et al (2019). GLI1 overexpression promotes gastric cancer cell proliferation and migration and induces drug resistance by combining with the AKT-mTOR pathway.Biomed. Pharmacother.111993–1004. 10.1016/j.biopha.2019.01.018

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 251

  YapT. A.YanL.PatnaikA.FearenI.OlmosD.PapadopoulosK.et al (2011). First-in-man clinical trial of the oral pan-AKT inhibitor MK-2206 in patients with advanced solid tumors.J. Clin. Oncol.294688–4695. 10.1200/jco.2011.35.5263

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 252

  YehT. S.WuC. W.HsuK. W.LiaoW. J.YangM. C.LiA. F.et al (2009). The activated Notch1 signal pathway is associated with gastric cancer progression through cyclooxygenase-2.Cancer Res.695039–5048. 10.1158/0008-5472.CAN-08-4021

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 253

  YeungT. M.GandhiS. C.BodmerW. F. (2011). Hypoxia and lineage specification of cell line-derived colorectal cancer stem cells.Proc. Natl. Acad. Sci. U.S.A.1084382–4387. 10.1073/pnas.1014519107

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 254

  YoonC.ParkD. J.SchmidtB.ThomasN. J.LeeH.-J.KimT. S.et al (2014). CD44 expression denotes a subpopulation of gastric cancer cells in which hedgehog signaling promotes chemotherapy resistance.Clin. Cancer Res.203974–3988. 10.1158/1078-0432.CCR-14-0011

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 255

  YoungR. A. (2011). Control of the embryonic stem cell state.Cell144940–954. 10.1016/j.cell.2011.01.032

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 256

  YuG.WangJ.ChenY.WangX.PanJ.LiG.et al (2009). Overexpression of phosphorylated mammalian target of rapamycin predicts lymph node metastasis and prognosis of chinese patients with gastric cancer.Clin. Cancer Res.151821–1829. 10.1158/1078-0432.CCR-08-2138

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 257

  YuH.KortylewskiM.PardollD. (2007). Crosstalk between cancer and immune cells: role of STAT3 in the tumour microenvironment.Nat. Rev. Immunol.741–51. 10.1038/nri1995

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 258

  YuH.PardollD.JoveR. (2009). STATs in cancer inflammation and immunity: a leading role for STAT3.Nat. Rev. Cancer9798–809. 10.1038/nrc2734

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 259

  YuanX.ZhangX.ZhangW.LiangW.ZhangP.ShiH.et al (2016). SALL4 promotes gastric cancer progression through activating CD44 expression.Oncogenesis5:e268. 10.1038/oncsis.2016.69

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 260

  ZhangC.LiC.HeF.CaiY.YangH. (2011). Identification of CD44+CD24+ gastric cancer stem cells.J. Cancer Res. Clin. Oncol.1371679–1686. 10.1007/s00432-011-1038-5

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 261

  ZhangH.XueY. (2008). Wnt pathway is involved in advanced gastric carcinoma.Hepatogastroenterology551126–1130.

  • Pubmed Abstract
  • Google Scholar

• 262

  ZhangH. L.WangP.LuM. Z.ZhangS. D.ZhengL. (2019). c-Myc maintains the self-renewal and chemoresistance properties of colon cancer stem cells.Oncol. Lett.174487–4493. 10.3892/ol.2019.10081

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 263

  ZhangJ.EspinozaL. A.KindersR. J.LawrenceS. M.PfisterT. D.ZhouM.et al (2013). NANOG modulates stemness in human colorectal cancer.Oncogene324397–4405. 10.1038/onc.2012.461

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 264

  ZhangJ.TamW. L.TongG. Q.WuQ.ChanH. Y.SohB. S.et al (2006). Sall4 modulates embryonic stem cell pluripotency and early embryonic development by the transcriptional regulation of Pou5f1.Nat. Cell Biol.81114–1123. 10.1038/ncb1481

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 265

  ZhangL.XuZ.XuX.ZhangB.WuH.WangM.et al (2014). SALL4, a novel marker for human gastric carcinogenesis and metastasis.Oncogene335491–5500. 10.1038/onc.2013.495

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 266

  ZhangN.ZhangJ.WangZ. W.ZhaL.HuangZ. (2012). Altered expression of Krüppel-like factor 4 and β-catenin in human gastric cancer.Oncol. Lett.31017–1022. 10.3892/ol.2012.619

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 267

  ZhangS. S.HuangZ. W.LiL. X.FuJ. J.XiaoB. (2016). Identification of CD200+ colorectal cancer stem cells and their gene expression profile.Oncol. Rep.362252–2260. 10.3892/or.2016.5039

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 268

  ZhangX.HuaR.WangX.HuangM.GanL.WuZ.et al (2016). Identification of stem-like cells and clinical significance of candidate stem cell markers in gastric cancer.Oncotarget79815–9831. 10.18632/oncotarget.6890

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 269

  ZhangY.JinZ.ZhouH.OuX.XuY.LiH.et al (2016). Suppression of prostate cancer progression by cancer cell stemness inhibitor napabucasin.Cancer Med.51251–1258. 10.1002/cam4.675

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 270

  ZhangX.HuF.LiG.LiG.YangX.LiuL.et al (2018a). Human colorectal cancer-derived mesenchymal stem cells promote colorectal cancer progression through IL-6/JAK2/STAT3 signaling.Cell Death Dis.9:25. 10.1038/s41419-017-0176-3

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 271

  ZhangX.YuanX.ZhuW.QianH.XuW. (2015). SALL4: an emerging cancer biomarker and target.Cancer Lett.35755–62. 10.1016/j.canlet.2014.11.037

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 272

  ZhangX.ZhangP.ShaoM.ZangX.ZhangJ.MaoF.et al (2018b). SALL4 activates TGF-β/SMAD signaling pathway to induce EMT and promote gastric cancer metastasis.Cancer Manag. Res.104459–4470. 10.2147/cmar.S177373

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 273

  ZhangY.ChenH. (2011). Genistein attenuates WNT signaling by up-regulating sFRP2 in a human colon cancer cell line.Exp. Biol. Med.236714–722. 10.1258/ebm.2011.010347

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 274

  ZhaoP.LiY.LuY. (2010). Aberrant expression of CD133 protein correlates with Ki-67 expression and is a prognostic marker in gastric adenocarcinoma.BMC Cancer10:218. 10.1186/1471-2407-10-218

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 275

  ZhaoR.LiuZ.XuW.SongL.RenH.OuY.et al (2020). Helicobacter pylori infection leads to KLF4 inactivation in gastric cancer through a TET1-mediated DNA methylation mechanism.Cancer Med.9, 2551–2563. 10.1002/cam4.2892

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 276

  ZhaoW.LiY.ZhangX. (2017). Stemness-related markers in cancer.Cancer Transl. Med.387–95. 10.4103/ctm.ctm_69_16

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 277

  ZhiQ. M.ChenX. H.JiJ.ZhangJ. N.LiJ. F.CaiQ.et al (2011). Salinomycin can effectively kill ALDH(high) stem-like cells on gastric cancer.Biomed. Pharmacother.65509–515. 10.1016/j.biopha.2011.06.006

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 278

  ZhouY.XiaL.WangH.OyangL.SuM.LiuQ.et al (2017). Cancer stem cells in progression of colorectal cancer.Oncotarget933403–33415. 10.18632/oncotarget.23607

  • Pubmed Abstract
  • CrossRef
  • Google Scholar