Degrading of basal membrane and extracellular matrix, which is caused by proteolytic agents such as matrix metalloproteinases (MMPs), can lead to peritumoral matrix destruction and subsequent invasive growth pattern (Brooks et al., 2010). To that end, MMP plays a crucial role in the invasion and metastases through entering the lymphatic system and blood circulation and then increasing the dissemination of tumor cells from the primary tumors into the enclosing tissues and secondary tumor sites.

In various in vivo and in vitro experimental studies, the upregulated expression level of MMPs has been correlated with significant growth and proliferation behavior of tumoral cells (Bachmeier et al., 2000a; Bachmeier et al., 2000b; Bachmeier et al., 2001; Murphy and Nagase, 2008). MMPs play pivotal functions in various tumor development features via affecting numerous biological processes. These features include activation of growth factor (Egeblad and Werb, 2002), tumor growth, induction of invasiveness, tumor-related inflammation, revascularization, and metastasis (Han et al., 2001; Philip et al., 2001). Hence, controlling expression levels of MMPs and suppression of its activation can be considered an optimal strategy for the prevention of cancer development.

Gene transcription is the first level that MMP expression inhibition initiates at that level. The promoter regions contribute to encoding the MMP-1, -2, -3, -7, -9, -12, and -13 genes, which are similar to NF-κB elements, carry a proximal activating-protein-1 (AP-1) binding site about 70 base pair 5′ for starting the transcription (Vincenti et al., 1998; Westermarck and Kähäri, 1999; Bond et al., 2001; Vincenti, 2001).

The properties of curcumin on the expression level of MMP and its functions have been investigated in different experimental studies in various kinds of inflammatory diseases and cancer models (Lin et al., 1998; Banerji et al., 2004; Swarnakar et al., 2005; Hong et al., 2006; Mitra et al., 2006; Su et al., 2006; Bachmeier et al., 2007; Shakibaei et al., 2007). By downregulating the expression of AP-1 and NF-κB, curcumin has been demonstrated to be a significant suppressor of MMPs synthesis (Bachmeier et al., 2007). Kim et al. reported that, through suppressing the activation of NF-κB and AP-1, curcumin inhibited the expression of MMP-9 and accompanied cell invasion mediated by12-O-tetradecanoylphorbol-13-acetate treatment (Kim et al., 2012a).

Bachmeier and colleagues demonstrated that the MMP-1 and MMP-2 mRNA expression and protein levels were considerably diminished after treatment with curcumin in breast cancer cells. In contrast, there was no considerable decrease in the expression levels of MMP-3 and -9 (Bachmeier et al., 2007). Furthermore, gelatinolytic activity has been evaluated by zymography, revealed that gelatinases MMP-2 and -9 proteolytic activities, down-regulated after treatment with curcumin.

An in vitro investigation on human fibrosarcoma cells demonstrated that the MMP-2 and MMP-9 expression levels were remarkably suppressed after treatment with three separate curcuminoids (demethoxycurcumin, bisdemethoxycurcumin, and curcumin). In comparison, there were no remarkable properties of the invasiveness of these cells and the urokinase plasmin activator (uPA) (Yodkeeree et al., 2008). To that end, in laryngeal squamous carcinoma cells, curcumin treatment induced significant down-regulatory impacts on the MMP-2, MT1-MMP expression, integrin receptors, and focal adhesion kinase (FAK), which led to a remarkable reduction in the invasiveness features of the tumoral cells. It is essential to state that the expression levels of MT1-MMP, MMP-2, integrin receptors, and FAK were similar to regulated expression levels after drug withdrawal (Mitra et al., 2006). Treatment with curcumin in human colon cancer cells caused a significant up and downregulation of MMP-9 and MMP-2, respectively. But any remarkable effect on the MMP-7 expression has not been observed, as evidenced by protein levels in Western blotting assay (Su et al., 2006). Curcumin treatment caused a noteworthy reduction in MMP-2 and MMP-9 expression, in conjunction with reduced cellular invasion in vitro in prostate cancer cells (DU-145). Besides, curcumin treatment diminished tumorigenicity in a xenograft model (Hong et al., 2006). Fifteen days of intervention with curcumin in a metastatic model of murine melanoma cells B16F10 remarkably decreased MMP-2 activity (Banerji et al., 2004). Besides, curcumin also reduced FAK and MT1-MMP expression. Results showed that even following 28 days, drug withdrawal could not return the MMP-2, MT1-MMP, and FAK expression to control levels. In the same study, curcumin caused a significant reduction in the level of invasiveness and migration and, reversely, promoted apoptosis in vitro (Philip and Kundu, 2003; Philip et al., 2004). In glioma cell lines, curcumin suppressed the TPA-mediated expression level of MMP-1, -3, -9, and -14-related mRNAs (Woo et al., 2005). On the other hand, following the curcumin intervention, the expression of numerous cell survival and proliferative inducer agents, such as cyclin D1, COX-2, IL-6, MMP-9, and Bcl-2, were significantly suppressed in the squamous carcinoma cells of the head and neck (Aggarwal et al., 2004). Following the curcumin treatment in a xenograft model of prostatic cancer, MMP-9 and MMP-2 expression remarkably decreased. Furthermore, a remarkable inhibitory effect on the invasion ability of the tumoral cells was observed in vitro. In this study, tumor volume, several metastatic nodules in the animal model, and the MP-2 and MMP-9 activity in the tumor-bearing site reduced significantly (Hong et al., 2006). Along with inhibition of ER downstream pS2 and TGFβ target genes, curcumin treatment in MCF-7 cell lines of breast cancer and estrogen presence significantly suppressed the estrogen receptor (ER) expression. By this study, curcumin treatment also showed significant down-regulatory effects on MMP-2 expression, while TIMP-1 (tissue inhibitor of metalloproteinase) expression was markedly upregulated after curcumin treatment (Shao et al., 2002).

Besides, different studies also have evaluated the properties of curcumin on the invasiveness of lung cancer models: through suppression of MMP-2, -9, and VEGF expression, curcumin significantly decreased migration features and invasiveness of A549 cell line in a time-dose-dependent manner (Lin et al., 2009). The above-mentioned effects were also observed in an in vivo model by affecting the expression of the 801D cell. Inhibition of the Rac-dependent pathway by curcumin caused a remarkable decrease in the MMP-2 and -9 expression levels (Chen et al., 2014).

Overall, considering slight differences in the efficiency of curcumin in the inhibition of MMPs in some cell lines or studies, it seems that curcumin has significant modulatory effects in virtually all of MMPs. These minor discrepancies may result from slight differences in curcumin-related responsivity and partial resistance of some cell lines (Bachmeier et al., 2009). Furthermore, it is evident that curcumin considerably plays pivotal functions in inhibiting degradation in some of the extracellular matrix and basal membrane components. These effects are due to its potential action in regulating MMP/TIMP activity and expression, which was led to the significant impacts on the reversion of tumor invasion and growth.

The RAF/MEK/RAS/ERK signaling pathway is the primary modulator of different cellular processes. This signaling pathway contributes to the modulation of cell differentiation, proliferation, survival, and motility. It provides the transduction of signals from the cell surface to the nucleus and cytoplasm as well. Moreover, abnormal regulation of this signaling pathway is a potential reason for the initiation and progression of tumoral cells. Cell surface receptors-mediated activation of small GTPase rat sarcoma oncogene (RAS) homolog leads to binding binds and the consequent rapid activation of accelerated fibrosarcoma kinase (RAF). H-, K-, and N-RAS have been considered the most related members of the RAS family, clinically. RAF has three isoforms, including a-, b-, c-RAF, considering the major role b-RAF in tumorigenesis. RAF contributes to phosphorylation of MAPK and ERK kinase (MEK), which for its parts has crucial roles in the mitogen-activated protein kinases (MAPKs) activation. The primary MAPKs members have been reported as extracellular signal-regulated kinases (ERK) 1 and 2. Considering their important roles, ERK-1/-2 with a variety of substrates also have been considered major effectors of this pathway (Figure 4).

Activating RAS or b-RAF mutations has been significantly associated with higher RAS/RAF/MEK/ERK signaling activation. Moreover, various studies have demonstrated that K-RAS is the principal mutated RAS gene in the pancreas, lung, and colon adenocarcinoma samples (Bos, 1989; Campbell and Der, 2004). Besides, some of the receptor tyrosine kinases, such as EGFR, were correlated to the activation of RAS. Mutational activation or overexpressed level of EGFR has been associated with lower cancer prognosis. It is also associated with upregulation of signaling pathways, including RAS/RAF/MEK/ERK, PI3K/Akt/mTOR, protein kinase C (PKC), phospholipase D signal transducer, and activator of transcription (STAT) (Roberts and Der, 2007). Curcumin has been shown to exhibit anticancer effects by interfering with signaling pathways associated with the initiation, promotion, and progression of multistage carcinogenesis. Curcumin inhibits the ERK signaling pathway, thus blocking the cell cycle and downregulates the expression of Bcl-2, concomitantly inhibiting cell proliferation and inducing apoptosis (Zhu et al., 2016).

Wnt signaling pathway plays pivotal functions regulating cell polarity, cell proliferation, and cell fate determination during embryonic development. It has been shown that in the absence of the Wnt signaling pathway, the multiprotein complex has the responsibility of regulating intracellular β-catenin levels. Investigations have displayed that adenomatous polyposis coli protein (APC) as a tumor suppressor, casein kinase 1 (CK1), glycogen synthase kinase-3β (GSK3β), and the scaffolding protein Axin are involved in the multiprotein complex structure. It has been reported that Cytoplasmic β-catenin is an essential target for induction of ubiquitination and proteasomal degradation by the destruction of complex-mediated binding and phosphorylating. As this elimination process continues, β-catenin cannot reach the nucleus any longer. Another important family of transcription factors is the DNA-bound T-cell factor/lymphoid enhancer factor (TCF/LEF), which has been suggested to be one of the principal regulators of β-catenin gene expression. Lacking the nuclear β-catenin, through inactivating Groucho/TLE, as transcriptional corepressors by binding to them, TCF/LEF contributes to suppressing gene expression. Wnt has a crucial role in Wnt/β-catenin pathway activation by binding its ligands to its co-receptor–low-density lipoprotein receptor-related proteins (LRP)—and also the Frizzled receptor. As a result, these receptors will be activated. Activation of Wnt/β-catenin pathway significantly hinders the destruction complex, and finally can lead to enhanced aggregation and nucleic translocation of β-catenin. It has been proved that, through binding to TCF/LEF and accompanied inactivation of them, and via dislocating the Groucho/TLE, transcriptional co-repressors, β-catenin activates Wnt target gene expression in the nucleus (Figure 5) (Daniels and Weis, 2005; Fodde and Brabletz, 2007). Curcumin inhibits tumor epithelial–mesenchymal transition by downregulating the Wnt signaling pathway and upregulating NKD2 expression in cancer cells (Zhang et al., 2016). Furthermore, curcumin suppresses cancer cell migration by inhibiting the Wnt signaling pathway (Kim et al., 2013).

Curcumin-mediated effects on metastasis in pancreatic cancer cells are associated with their properties on various heterotypic cells—these cells, including endothelial cells, macrophages, cancer-associated fibroblasts (CAFs). CAFs have been implicated in different malignancies, such as pancreatic ductal adenocarcinoma (PDAC), breast cancer, and gastric carcinoma (Kasashima et al., 2014; Sun et al., 2014). By targeting numerous cellular events in cancerous cells such as cell viability, tumor growth, metastasis, revascularization, immune surveillance, and CAFs, curcumin plays a crucial role in regulating tumor behavior (Lunardi et al., 2014). It has been reported that the expression level of α-smooth muscle actin (α-SMA) and vimentin is significantly correlated with the process of attaining an activated phenotype by CAFs. Besides, for transforming into fibroblast-like cells, tumoral cells can potentially make use of EMT (Kalluri and Zeisberg, 2006). EMT has been introduced to be a transcriptional and epigenetic process in which some of the mesenchymal features, including enhanced motility and decreased cellular junctions, can be acquired by epithelial cells, which have important roles in the dissemination of primary tumor sites and cancer seeding at distant organs (Thiery, 2002; Friedl, 2004). In addition to CAFs capabilities for affecting the EMT of cancer cells, it has been proven that the expression of fibroblast-like cancer cells is considerably associated with higher invasion and metastatic features. Reduced expression of E-cadherin, which has been associated with tumor progression and development, is an important sign of EMT (Cowin et al., 2005; Christofori, 2006; Francí et al., 2006).

Wang and colleagues theorized that CAFs might be a possible target of curcumin for inhibiting pancreatic cancer cells’ metastases (Wang et al., 2017). Their results have shown that curcumin significantly suppressed the CAF-induced promotion of metastasis and migration abilities in pancreatic cancer cells. Overall, by decreasing the mesenchymal features of CAFs, data provided substantial evidence that curcumin suppressed pancreatic cancer cells’ metastasis and migration characteristics. It resulted in the reversed mediation of EMT phenotypes in pancreatic cancer cells (Wang et al., 2017).

Hypoxia is low oxygen tension traditionally found in solid tumors, which is considerably associated with decreased prognosis in cancer patients (Lei et al., 2013; Chang and Erler, 2014). Results have shown that tumor hypoxia-induced behavior of tumoral cells is significantly correlated with promoted invasion, angiogenesis, and metastasis in distant tumor sites (Chang and Erler, 2014). Hypoxia-inducible factor-1 (HIF-1) is a member of the primary helix-loop-helix-periodic acid-Schiff domain transcription factor family and has been implicated in several types of solid tumors, such as pancreatic cancer. HIF-1haskey functions in the mediation of hypoxia-induced cellular responses (Lei et al., 2013). In their study, Sun et al. (2013) demonstrated that via inhibiting the Hh signaling pathway, the progression of pancreatic cancer was diminished after curcumin intervention. As a crucial pathway in tumorigenesis, the Hh signaling pathway has been shown to be implicated in pancreatic cancer samples while it is quiescent in adult pancreas cells in a normal situation (Lei et al., 2013). In a recent study, Lei et al. have shown that hypoxia-mediated invasiveness and occurrence of EMT is closely associated with the Hedgehog signaling pathway (Lei et al., 2013). Cao and colleagues hypothesized that curcumin is a prominent inhibitor for preventing hypoxia-induced invasiveness, proliferation, metastasis, and EMT progression in pancreatic cancer. Besides, they have been shown that curcumin strongly suppressed hypoxia-induced activation of Hedgehog signaling pathway. It suggested that curcumin may be a potential novel treatment for optimizing current therapeutic treatments against pancreatic cancer (Cao et al., 2016a). The results reported that in addition to its properties against hypoxia-mediated activation of Hedgehog signaling pathway, cell migration, proliferation, and invasiveness of pancreatic cancer, curcumin also mediated the EMT-related agent’s expression including vimentin, E-cadherin, and N-cadherin. Taken together, Cao and colleagues have demonstrated that via suppressing the Hh signaling pathway, curcumin plays critical roles for the inhibition of hypoxia-mediated metastasis of pancreatic cancer (Cao et al., 2016a).

Hydrogen peroxide (H2O2) and superoxide anion as reactive oxygen species (ROS) are some chemically oxygen-derived reactive agents. They are generated by the mitochondrial respiratory chain. In various studies, the state of intracellular redox has been correlated with cellular signaling transduction, and regulation of multiple intracellular events (Lee and Kang, 2013). Despite their significant roles for suppressing cancer cells, via affecting cell viability, proliferation, invasion, and metastasis, sublethal concentrations production of ROS has been associated with tumor progression (Nishikawa et al., 2009). For example, Nishikawa et al. showed that sublethal concentrations of H2O2 (0–200 µM) resulted in pancreatic cancer development in a dose-dependent manner. In contrast, > 200 µM concentrations of H2O2 were cytotoxic for cancerous cells (Li et al., 2015).

Recently, a study demonstrated that curcumin had strong protective properties against the EMT process in the prostate cancer cells. Curcumin abrogated CAF-induced invasion and EMT, and inhibited ROS production and CXCR4 and IL-6 receptor expression in prostate cancer cells. These effects were mediated by inhibiting MAOA/mTOR/HIF-1α signaling. It was found that this protective effect correlated with MAOA/mTOR/HIF-1α signaling pathway-induced inhibition of CAFs-mediated ROS generation (Du et al., 2015). As crucial downstream signaling cascades of ROSs, MAPK signaling pathways have been demonstrated to participate in tumor progression (Wu et al., 2008). P38 MAPK, extracellular signal-regulated kinase (ERK), and c-jun NH-2 terminal kinase (JNK) are the most critical MAPK family members. Li et al. have declared that via activating p38 MAPK and ERK signaling pathways, moderate amounts of H2O2 are associated with promoted pancreatic cancer metastasis and invasion (Li et al., 2015).

Cao et al. showed that curcumin intervention in Panc-1 and BxPC-3 pancreatic cancer cells reversely regulated the cancer invasion, migration, and MMP-2 expression. Besides, H2O2-mediated upregulation of phosphorylated ERK and phosphorylated NF-κB was decreased after NAC, curcumin, and PD 98059 treatment (an ERK inhibitor). Considering this valuable information, it can be concluded that curcumin inhibited pancreatic cancer cell migration and invasiveness via inhibiting the ROS/ERK/NF-κB signaling pathway. Furthermore, this study suggested that curcumin application might be a possible drug target for upregulating pancreatic cancer migration (Cao et al., 2016b). Table 1 lists various studies on antimetastatic effects in pancreatic cancer. Figure 6 illustrates the effects of curcumin on metastasis in GI cancers.

It has been demonstrated that high mobility group box 1 (HMGB1), as an essential nuclear and extracellular protein, is a crucial mediator in various pathologic and physiologic situations such as inflammation, immune response, and cancer. HMGB1 is also a diagnostic biomarker for the early stages of gastric cancer (Chung et al., 2009). Curcumin treatment in human endothelial cells caused considerable down-regulatory properties on the expression of the cell surface receptor of HMGB1 (Kim et al., 2011). Studies have reported that HMGB1 expression is highly increased in esophageal squamous cell carcinoma (ESCC). HMGB1 has a crucial role in promoting lymphangiogenesis by regulating vascular endothelial growth factors (VEGF)-C. Lymph node metastasis has been considered one of the critical determinants of progression in gastric cancer patients. Studies have declared that HMGB1 expression is associated with tumor lymphangiogenesis and new lymphatic vessel formation (Tawada et al., 2012). Curcumin treatment resulted in VEGF receptors’ downregulation, including (VEGFR-2/3) and lymphangiogenic VEGF-C (Da et al., 2015). HMGB1 and VEGF-D are involved in tumor lymphangiogenesis, and VEGF-C and VEGF-D are also essential members of the VEGF family.

In a recent study, Da and colleagues hypothesized that by suppression of HMGB1/VEGF-D signaling, curcumin might have potential anti-lymphangiogenesis properties. Therefore, it can be applied as a potential treatment in patients with gastric cancer (Da et al., 2019). Results have demonstrated that curcumin treatment in AGS and SGC-7901 gastric cancer cells caused a significant cell viability reduction through activating caspase-3. In contrast, it resulted in an apoptosis increase in a concentration-dependent manner. Besides, curcumin intervention remarkably eliminated the HMGB1 and VEGF-D expression levels. Considering their findings, they have suggested that curcumin might be an anti-lymphangiogenesis agent in the treatment of gastric cancer by inhibiting HMGB1/VEGF-D signaling (Da et al., 2019).

Late-stage diagnosis, which is seen in most gastric cancer patients, causes poor prognosis and therapeutic outcome. This problem results in tumor cell dissemination into circulation and distant organs as circulating tumor cells (CTCs), which leads to cancer seeding, and formation of a distal tumor, especially in hepatic tissue (Saito et al., 2013; Hatakeyama et al., 2015; Xia et al., 2015). In addition to their presence in blood circulation, CTCs have been identified with a number of specific cell surface markers. Among them, CXCR4, which is known as the stromal cell-derived factor-1 (SDF-1) receptor, has been characterized by different cancer types (Reckamp et al., 2009; Franco et al., 2012; Mego et al., 2016). In their previous study, Zhu et al. have declared that CD90⁺ and CXCR4+ hepatocellular carcinoma (HCC) cells may be CTCs. Therefore, selective inhibition of CD90⁺ and CXCR4+ cells, resulting in reduced cancer metastasis, may provide significant improvements in the current therapeutic approaches in HCC patients (Zhu et al., 2015).

Gu et al. have evaluated the antimetastatic capabilities of curcumin in the reduction of tumor formation in liver in mice-bearing proximal gastric carcinoma (PGC) (Gu et al., 2019). Results showed that formation of hepatic tumor and presence of CTCs were considerably reduced after curcumin treatment. Furthermore, treatment with curcumin in PGCs in vivo and in vitro downregulated the CXCR4 expression, and hence by inhibiting the SDF-1/CXCR4 signaling pathway, suppressed metastasis of PGC (Gu et al., 2019).

By suppressing the activity of MMP-2, curcumin administration has been associated with inhibiting cancer progression (Mitra et al., 2006; Lee et al., 2015a; Liu et al., 2017). Moreover, due to its low solubility, bioavailability and efficacy of curcumin is decreased. Various in vivo investigations have demonstrated that induction of structural modifications in the β-diketone moiety, aromatic rings, or the flanking double bonds coupled with the β-diketone moiety of curcumin may be an optimal strategy for improving its bioavailability and anticancer activities. Selected CH-5 (4,4′-[(2-Oxo-1,3-cyclohexanediylidene)-di(E) methylylidene]dibenzonitrile) and monoketone curcumin analogs have been screened to be evaluated for their anticancer properties in numerous tumor cell lines (Lima et al., 2018).

Silva and colleagues investigated the antimetastatic properties of CH-5 in human HGC-27 gastric cancer cell line (Silva et al., 2018). Initially, they have observed cell viability was decreased, while apoptosis was increased in a dose-dependent way. Additionally, through decreased expression and collagenase activity of MMP-2, a remarkable decrease in the invasiveness and migration of HGC-27 cells was observed after CH-5 treatment. Herein, via the upregulation of apoptosis and the downregulation of invasion and migration, CH-5 treatment in gastric cancer cells showed anticancer properties. It implies that the application of CH-5 molecule can be considered an optimal antimetastatic medicine for the prevention of gastric cancer development (Silva et al., 2018). Table 2 lists various studies on antimetastatic effects of in gastric cancer.

Cancer stem cells (CSCs) are a small subpopulation of immortal cells. They are essential agents in chemoresistance, tumor invasion, and relapse. CSCs have crucial functions in metastasis induction, which is considered the leading factor of cancer-related mortalities (Muñoz et al., 2012). Numerous studies have shown that curcumin targeted Wnt/β-catenin, Notch, and Sonic Hedgehog (SHH) signaling pathways. These are involved in the self-renewal of tumoral cells, targeting CSCs to prevent cancer invasion (Takebe et al., 2015). Some investigators believe the anti-inflammatory properties of curcumin are additionally engaged in its antimetastatic characteristics.

It has been demonstrated that overexpression of insulin-like growth factor-1 (IGF-1) and insulin is an essential agent in cancer progression and metastasis (Adachi et al., 2002; Sarfstein et al., 2010; Liu et al., 2011; Orrù and Nigro, 2017). There is a lot of resemblance in action between insulin and IGF-1 signaling; herein, there is a possibility of recruitment of each other’s receptors by their ligands (Panda et al., 2013). Besides, through affecting similar mechanisms, both these receptors play crucial roles in the activation of similar intracellular pathways (Han et al., 2017). Inhibition of IGF-1 in some specific cancer types, such as pancreatic carcinomas, led to decreased cancer growth and metastasis. In contrast, the role of insulin receptor downregulation in the suppression of cancer development has not yet been fully understood (Subramani et al., 2014). Larsson and colleagues demonstrated that hyperinsulinemia is positively associated with progression of colorectal cancer in diabetic patients (Larsson et al., 2005). They also reported that through modulating mitogen-activated protein kinase (MAPK) and IRS1/phosphoinositide 3-kinase (PI3K)/Akt signaling pathways, insulin significantly increases the mRNA expression of (MMP-2) in HCT-116 human colorectal cells (Larsson et al., 2005).

Various investigations have suggested that anti-inflammatory properties of curcumin are involved into its inhibitory effects on migration of tumoral cells. Insulin and IGF-1 receptors and signaling pathways were regulated by curcumin. As an essential pathway, insulin signaling participates in tumor progression and initiation. To that end, Hosseini and colleagues hypothesized that via downregulating insulin and IGF-1 receptors, curcumin could show its antimetastatic properties (Hosseini et al., 2019). In their study, the effects of curcumin treatment were measured in 5-fluorouracil (5-FU)-treated viable resistant SW480 colorectal cells. Their results showed that the expression of avian myelocytomatosis virus oncogene cellular homolog (MYC), IGF-1 receptors, and insulin was remarkably decreased after treatment with curcumin. Therefore, insulin and IGF-1 receptors downregulation in chemoresistant colorectal cancer cells caused a greater reduction in the migration and proliferation of tumoral cells (Hosseini et al., 2019).

Application of curcumin in combination with different medicines including 5-FU (Toden et al., 2015), to lfenamic acid (Sankpal et al., 2016), and ulinastatin (Shen et al., 2014) can make its utilization more effective, reverse chemoresistance, inhibit cell growth, and metastasis. More than 300 numerous constituents, including free arabinose (1%), curcumin (3–5%), essential oil (2–7%), and acid glycans named ukonan, were extracted from turmeric, which is known as the significant source of curcumin (Kim et al., 2012b). Moreover, various studies demonstrated that besides curcumin, different components in turmeric have been introduced to be more potent for displaying antitumor activities, and can be used as potential enhancer of curcumin bioavailability (Anand et al., 2007; Kim et al., 2012b). Yue et al. demonstrated that the accumulation of curcumin within colonic cells was increased in the presence of turmerones in the extract of turmeric (Yue et al., 2012). Furthermore, curcumin plus turmerones or curcumin in the extract of turmeric can promote the antitumor properties in the colorectal cancer model in vivo (Yue et al., 2016). Thus far, a few investigations evaluated the turmeric extract antimetastatic properties on colorectal cancer. According to Kim et al., CXC motif receptor 4 (CXCR4) expression, as a chemokine receptor that has a role in metastasis in vitro, was inhibited after turmeric extract treatment (Kim et al., 2012b).

Using an aggressive orthotopic CRC model with spontaneous metastasis, Li et al. evaluated antimetastatic and antitumor properties of turmeric extract and first-line chemotherapeutics (FOLFOX) (134). Their results showed turmeric extract significantly induced a cytotoxic effect, suppressed colony formation, reduced cell motility, migration, and EMT in murine colorectal cancer cells. Turmeric extract showed all these functions using various signaling pathways such as cofilin, ERK, FAK/p-Src, STAT3, and AKT. Besides, in vivo treatment with turmeric extract (200 mg/kg) caused a great reduction burden of a colon tumor, and suppressed hepatic and lung metastasis. Also, turmeric extract treatment significantly promoted immune response via stimulating T cell, altered tumor microenvironment, and displayed antimetastatic properties. For evaluating its antitumoral and antimetastatic properties, turmeric extract was applied for the first time in vivo and in vitro. These results suggested that turmeric extract can be used as an essential factor for the treatment or prevention of metastasis in colorectal cancer patients (Li et al., 2018b).

As mentioned earlier, the poor water solubility of curcumin has limited its bioavailability after oral intake and therefore, correlated with low efficacy of therapeutic usage of this compound (Wang et al., 1997; Aggarwal et al., 2007). For overcoming pharmacokinetic and bioavailability restrictions of curcumin's oral administration, investigators have formulated a curcumin liposome for intravenous application and introduced an optimal drug delivery strategy (Li et al., 2005; Li et al., 2007; Mach et al., 2009; Helson et al., 2012; Ranjan et al., 2013; Storka et al., 2015). Different studies evaluated the efficacy of liposomal curcumin anticancer activities in pancreatic cell lines (MiaPaCa-2 or BxPC-3) xenograft models (Li et al., 2005; Mach et al., 2009; Ranjan et al., 2013). Two and eighth after liposomal curcumin constant infusions in beagle dogs, Helson et al. evaluated curcumin and its active metabolite tetrahydrocurcumin pharmacokinetics, organ, and tissue distribution. Results demonstrated that 2h infusions caused greater curcumin and tetrahydrocurcumin plasma concentrations compared with 8h infusions (Helson et al., 2012), although after the 8h infusions, organ and tissue curcumin and THC distributions were overall higher than 2 h infusions (Matabudul et al., 2012). Curcumin liposomes were tested in a placebo-controlled, randomized, dose-escalation, double-blind study in 49 healthy female and male subjects. Volunteers received an individual IV dose of curcumin liposomes (10–400 mg/m²; n = 2–6 per group, total n = 39) or placebo (n = 10) for 2 h. It was tolerated well, but at dosages ≥120 mg/m², a transient red blood cell echinocyte formation occurred with both liposomes and curcumin. Besides, the mean cellular volume was increased (Storka et al., 2015).

In a study, tolerability and safety of increasing concentrations of liposomal curcumin were investigated in metastatic cancer patients (Greil et al., 2018). Curcumin pharmacokinetics and anticancer activities were investigated as secondary aims in different studies. This clinical trial was conducted as a phase I, open-label study, and single-center. The liposomal curcumin intravenous infusion was performed weekly in patients with metastatic tumors for 8 weeks. Initiate dose was 100 mg/m² over 8 h, following continuous increasing concentrations, the dose raised to 300 mg/m² over 6 h. At 100–300 mg/m² concentrations over 8 h, no dose-limiting toxicity was reported in 26 subjects. While hemolysis was developed in one of the patients who received 300 mg/m² over 6 h, furthermore in three patients who received the same concentrations hemoglobin was decreased> 2 g/dl. Pharmacokinetic analyses demonstrated that after the infusion, plasma concentrations of curcumin were decreased to undetectable levels. Based on RECIST V1.1, curcumin did not show antitumor activities. Transient clinical benefit and tumor marker responses improved significantly in two subjects. The maximum tolerated concentration of liposomal curcumin was 300 mg/m² over 6 h in pretreated patients, and therefore, starting with this dose is suggested for performing anticancer clinical trials (Greil et al., 2018). Table 3 lists various studies on antimetastatic effects in colorectal cancer.

Slug, Twist, and Snail transcription factors have been introduced as direct suppressors of E-cadherin through interacting between their COOH-terminal with a 5′-CACCTG-3′ sequence in the promoter of E-cadherin (Yang et al., 2004). Various studies have reported that numerous EMT modulators, including Twist, Slug, E-cadherin, and Snail, have pivotal functions in inhibiting cancer invasion and metastatic capabilities. Through decreasing the level of E-cadherin expression, overexpression of Snail or Twist has been reported to be an essential agent for induction of tumor progression, further aberrant regulation of Snail or Twist has also been demonstrated in different types of epithelial tumors, such as gastric (Rosivatz et al., 2002), prostate (Yuen et al., 2007), breast (Martin et al., 2005), head and neck cancer (Yang et al., 2008). Emerging evidence has shown that E-cadherin downregulation is reversely connected with general survival in patients with different epithelial tumors (Richmond et al., 1997; Zhou et al., 2002; Faleiro-Rodrigues et al., 2004; Tseng et al., 2010; Huber et al., 2011). For example, Fan et al. reported expression levels of Snail and Twist were upregulated. In contrast, E-cadherin expression level was downregulated in oral squamous cell carcinoma (OSCC) patients. Besides, E-cadherin lower expression has been introduced to be an individual prognostic marker in patients with OSCC (Fan et al., 2013).

Lee et al. evaluated curcumin antiinvasive properties on the level of MMPs expression and EMT modulators in OSCC SCC-25 cell line (Lee et al., 2015a). Their results demonstrated that MMP-2 and MMP-9 expression significantly decreased, and hence, invasiveness of oral cancer cells was inhibited after curcumin treatment. Curcumin strongly regulated the expression level of EMT-related factors, including Twist, Snail, and E-cadherin. Besides, curcumin treatment upregulated the p53 expression level, which has been demonstrated to be a crucial factor for repressing EMT. Throughout, it can be said that curcumin has critical functions for preventing cancer development, invasion, and metastasis in oral cancer (Lee et al., 2015a).

Epidermal growth factor receptor (EGFR) is a transmembrane protein with 170-kDa molecular weight, and ErbB family member belongs to receptor tyrosine kinases. It has an extracellular ligand-binding, a transmembrane, and an intracellular domain, which have been reported to be associated with tyrosine kinase activity. Binding of ErbB to epidermal growth factor (EGF) as its primary ligand resulted in the EGFR-mediated formation of heterodimers or homodimers with other ErbB protein family members, including ErbB2, ErbB3, and ErbB4. This causes autophosphorylation, which led to the downstream signaling activation, including MAPK/Ras/Raf/ERK, JAK2/STAT3, and PI3K/Akt/mTOR pathways. These signaling pathways have crucial roles in regulating cancer cell proliferation, differentiation, invasion, and migration (Yarden and Sliwkowski, 2001). Studies have shown that activity and upregulation of EGFR are strongly related to increased tumor invasiveness, multiplication, and metastasis (Doumiati et al., 2012; Lin et al., 2014a). Poor prognosis and inadequate responses to chemotherapy have been observed in positive pEGFR tumors (Aquino et al., 2012). Hence, EGFR has been introduced as an essential anticancer drug target (Rabinowits and Haddad, 2012). Classic EGFR inhibitors have been divided into two major categories, including anti-EGFRs monoclonal antibodies and cetuximab, panitumumab, and trastuzumab are anti-EGFRs monoclonal antibodies, while gefitinib, erlotinib, and lapatinib are categorized as tyrosine kinases inhibitors. Currently, the mentioned drugs are used for the treatment of some epithelium-originated carcinomas, such as colorectal (Soeda et al., 2014), head and neck (Maseki et al., 2013), lung (Sgambato et al., 2014), and breast cancer (Nechushtan et al., 2014). Moreover, because of their extended side effects and chemoresistance, the application of these inhibitors has been very limited in treating most patients with cancer.

Through decreasing Egr-1 trans-activation activities, it has been shown that curcumin inhibited the EGFR-mediated growth of human colon cancer cells (Chen et al., 2006). Furthermore, via repressing EGFR expression, cell apoptosis was significantly promoted in breast cancer cells after curcumin treatment (Sun et al., 2012).

Zhen et al. studied the effectiveness of curcumin on invasion and proliferation in SCC-25 cell lines (Zhen et al., 2014). Based on their results, considerable inhibitory effects were observed from curcumin on the SCC-25 cells’ proliferation. Furthermore, curcumin caused the arrest of the cell cycle in the G2/M phase in a dose-dependent manner. Curcumin downregulated the MMP-2, MMP-9, uPA, and uPAR expression, which led to the inhibited invasion of SCC-25 cells. Curcumin downregulated the MMP-9, MMP-2, uPAR, and uPA expression, which led to the inhibited invasion of SCC-25 cells. It has also been revealed that curcumin regulated Akt, ERK1/2, and STAT3 as downstream signaling targets of p-EGFR and EGFR. Besides, as the most important finding of their study, EGF-triggered EGFR phosphorylation and EGF-mediated invasion of SCC-25 cells were suppressed after treatment with curcumin (Zhen et al., 2014).

In various cancer types, hepatocyte growth factor (HGF) and c-Met, its receptor, have been explained to be implicated in the EMT program (Huang et al., 2019). Remarkably, emerging evidence has shown that the HGF/c-Met signaling pathway activation promoted cancer cell migration and invasiveness. Chemopreventive and antitumoral activities of Curcumin have been comprehensively investigated in colorectal cancer (Ismail and Othman, 2019; Wong et al., 2019). Moreover, curcumin has been introduced to be a prominent EMT suppressor in various cancers (Jiao et al., 2016; Liang et al., 2017; Wang et al., 2017; Bahrami et al., 2019b).

In a study, Ohnishi et al. studied the potential impacts of curcumin on HGF-induced EMT in OSCC (Ohnishi et al., 2020). They reported that via activating HGF receptor c-Met, and downstream ERK pathway in HSC4 and Ca9-22 OSCC cell lines, the HGF signaling pathway induced EMT process. Furthermore, via repressing c-Met, HGF-mediated EMT and cell motility were inhibited by curcumin treatment in HSC-4 and Ca9-22 cells. Through downregulating the expression levels of phosphorylated c-Met, and ERK, curcumin effectively inhibited the HGF-triggered upregulation of vimentin. Taking everything into account, the findings of the reviewed investigation demonstrated that possibly by inhibiting c-Met expression, curcumin has pivotal roles in reversed regulating of HGF-induced EMT in oral cancer cells (Ohnishi et al., 2020). Table 4 lists various studies on antimetastatic effects in oral cancer.

As an important member of the CXC subfamily, stromal cell-derived factor 1a (SDF-1a) interacts with the C-X-C chemokine receptor type 4 (CXCR4), seven-transmembrane G protein-coupled receptor (7TMGPCR). It is also a principal agent in the induction of metastasis and invasion in cancer cells (Vandercappellen et al., 2008). Various in vivo studies have shown that SDF-1a is a key agent for triggering migration and metastasis in breast cancer cells (Müller et al., 2001). Moreover, suppression of CXCR4 gene expression mediated by Short hairpin RNA (shRNA) significantly inhibited cell proliferation of esophageal carcinoma (EC). Upregulation of CXCR4 has been reported to be related to poor prognosis, poor clinical outcomes, and raised metastatic features in EC cells (Kaifi et al., 2005).

Lipid rafts are plasma membrane firmly packed microdomains that consist of dynamic assemblies of cholesterol, glycosphingolipid, and proteins. The rafts can affect signal transduction via the recruitment of membrane-associated protein kinases (Zajchowski and Robbins, 2002). The interaction between the growth factors and their receptors plays a critical role in specific adapter proteins and protein kinases translocation to lipid rafts. It provides essential signals for the regulation of cell proliferation (Pike, 2005). Numerous authors demonstrate that the CXCR4 connection with lipid rafts is involved in effective signaling processes (Chinni et al., 2008; Altenburg and Siddiqui, 2009). Ectopic expression of a CXCR4-GFP fusion protein in CXCR4-deficient human hematopoietic progenitor cell lines showed that lipid rafts are crucial in the SDF-1a-induced CXCR4 signaling and surface expression (van Buul et al., 2003).

The colocalization of Rho GTP-binding protein Rac1 and CXCR4 in lipid rafts resulted in increased activation of Rac1 GTPase. It also led to the sensitivity of hematopoietic cells to SDF-1α (Wysoczynski et al., 2005). SDF-1a/CXCR4 axis-mediated cell migration needs the activation of phosphatidylinositol 3- kinase (PI3K)/protein kinase B (Akt) in breast cancer cells (Lee et al., 2004). Numerous investigations demonstrated that hormones, growth factors, and cytokines stimulated the MMP-2 expression via nuclear factor-kappaB (NF-kB) activation (Han et al., 2001; Philip et al., 2004). NF-kB transcription factor constitutive activation in EC has been related to metastatic ability and chemotherapy resistance (Izzo et al., 2006). Besides, active Rac1 (GTP bound Rac1; GTP-Rac1) is required for collagen-mediated MMP-2 activation (Zhuge and Xu, 2001).

Lin et al. investigated these features by evaluating the CXCR4 suppression effects along with a CXCR4-neutralizing antibody and the CXCR4-specific inhibitor AMD3100 treatments (Lin et al., 2014b). Curcumin prevents SDF-1α-mediated cell migration, cell surface localization of CXCR4 at lipid rafts, the activity of matrix metalloproteinase-2 (MMP-2) promoter, and also signaling of lipid raft-related ras-related C3 botulinum toxin substrate 1 (Rac1)/phosphatidylinositol 3-kinase (PI3K) p85α/Akt. Furthermore, curcumin inhibits SDF-1α-mediated cell metastasis by knockdown of the signaling complex of Rac1-PI3K at lipid rafts but did not abolish lipid raft generation. Researchers also explain that the decreasing lipid raft-related Rac1 activity by curcumin was the requirement for preventing cell surface localization of CXCR4 at lipid rafts, SDF-1α-mediated PI3K/Akt/NF-κB activation, cell invasion, and MMP-2 promoter activity. Overall, their findings displayed that curcumin hinders SDF-1α-mediated EC cell invasion by suppressing the lipid raft formation-related Rac1-PI3K-Akt signaling complex, MP-2 promoter activity, likely through the inhibition of Rac1 activity, and the cell surface localization of CXCR4 with lipid rafts (Lin et al., 2014b).