Abstract
Colorectal cancer (CRC) is the second-leading cause of cancer death in developed countries. While early detection (e.g., colonoscopy) generally yields excellent outcomes, metastatic and drug-resistant disease is uniformly fatal, and non-compliance for screening remains over 25%. Familial CRCs (10% of total cases) primarily include mutations in the gene APC. Somatic disease is linked to several environmental several risk factors, including mutations in WNT, KRAS, and TGFβ. To reflect the genesis/progression of CRC, a series of five discrete stages, from normal colon mucosa to fully invasive carcinoma, each regulated by specific “gatekeeper” genes, remains well-accepted after 20 years. However, many CRC tumors do not possess those particular mutations, suggesting alternative mechanisms. More recently, embryo-like “cancer stem cells” have been proposed to undergo self-renewal and drive tumorigenesis (and possibly, metastasis), as governed by specific “epigenomic” alterations. Here, we review recent literature describing possible mechanisms that underlie these phenotypes, including cancer “stemness,” believed by many to associate with the epithelial-to-mesenchymal transition (EMT). We further propose that the maintenance of undifferentiated phenotypes, by the activity of distinct transcription factors, facilitates chromatin remodeling and phenotypic plasticity. With that regard, we support recent assertions that EMT is not an “either/or” event, but rather a continuous spectrum of mesenchymal vs. epithelial phenotypes (in various degrees of aberrant differentiation/undifferentiation). Finally, we discuss possible methods of pharmacologically targeting such aberrant epigenomes, with regard to their possible relevance toward halting, or even reversing, colorectal cancer progression.
Introduction
Colorectal cancer (CRC) is the second-leading cause of cancer deaths in the United States, with an estimated 50,130 deaths in 2014, a national expenditure of $14 billion, and an individual lifetime risk of 1 in 20. While the 5-year survival rate for localized CRC is >90%, only 40% of cases are detected at this (largely asymptomatic) stage, and for metastatic disease, survival falls to 8–12%. The risk of CRC increases with age (>50 years), diets high in red and processed meats, sedentary lifestyle, obesity, history of inflammatory bowel disease, and smoking. Non-compliance with screening for these at-risk individuals remains approximately 25% (), and 5–10% of CRC cases are due to hereditary conditions, the majority of which include mutations in the tumor suppressor gene APC. Consequently, while optimism persists for increased compliance with preventative screening, possibly due to healthcare reforms to alleviate cost, it appears a large number of advanced cases will remain ().
In this review, we set forth a model whereby “epigenomic” anomalies in normal colon crypt stem cells, and their terminally differentiated progeny cells, transform to an embryonic-like state, followed by further benign and malignant progression. Consideration of these mechanisms may support further study of “epigenetic” therapies for this life-threatening pathology.
Initiation and Pathology of Colorectal Cancer
Colon Development
The colon is a quadrate-shaped organ possessing six substructures, facilitating progression of solid waste through the cecum (attached to the ilium of the small intestine), which is then transported through the ascending, traverse, descending, and sigmoid colon, which attaches to the rectum/anus () The colon serves to remove water, salt, and nutrients throughout the progressive elimination of solid waste, in symbiosis with over 700 species of bacteria and various simple eukaryotes (gut flora) (). Six major colonic cell types include surface columnar epithelial (absorptive “colonocytes”), goblet (mucus-secreting) cells, vacuolated cells, deep crypt secretory cells, M-fold cells, and crypt colonic stem cells ().
Colorectal Tumorigenesis
Colorectal cancer is well-accepted to proceed through five distinct stages: (1) aberrant foci; (2) small adenoma (adenomatous polyps); (3) large adenoma; (4) adenocarcinoma; and (5) invasion/metastasis. The pathology of non-familial CRCs is often associated with overactivity of the epidermal growth factor receptor (EGFR), mutations in Wnt, loss of APC, activating KRAS mutations, and mutations in NRAS, BRAF (8–12%), PIK3CA, and TP53 (50% of cases). Additionally, a balance between “gatekeeper” (anti-proliferation), “caretaker” (maintain genomic stability) and “drivers” (oncogenes) has been hypothesized to regulate other CRC phenotypes, including (1) the development of microsatellite instability (MSI) (due largely to loss of DNA mismatch repair), leading to overactivity of COX-2, EGFR, and/or Wnt pathways (leading to small adenomas); (2) KRAS and/or PIK3CA pathway overactivity (leading to large adenomas); and (3) inactivation of the tumor suppressor gene TP53 and downregulation of TGF-β signaling, leading to invasive/metastatic carcinomas (; ; ). With regard to specific gene mutations in non-hereditary (i.e., somatic) CRC, APC is mutated in 85%, TP53 in 40–50%, PIK3CA in 35% (activating mutations), and TGFBR2 in 45–50% of sporadic CRCs ().
While there is hope that increased screening (e.g., colonoscopy, laproscopy, highly sensitive human occult fecal blood testing, etc. for persons over age 50) compliance will further increase early detection and treatment, due to increased education, access to health insurance, etc. However, at present, the only option for unresectable metastatic disease is conventional cytotoxic chemotherapy. While response to those initial chemotherapy regimens usually occur, resistance generally ensues within 6 months. Life-extending agents include conventional cytotoxics, such as 5-fluoracil, capecitabine, and topotecan, in various combinations with one another, and “targeted” therapeutics, such as bevacizumab (VEGFR antagonist) and the EGFR-inhibitory drugs cetuximab and panitumumab (; ), Unfortunately, resistance to these agents eventually ensues, with a mere 13.3-month subsequent survival rate ().
Epigenetics
Although mutated genes unequivocally contribute to the progression of CRC, gatekeeper, caretaker, and driver genes are not always altered in all CRC stages (). Consequently, many cancer investigators are now focusing on the importance of epigenetics to the phenotypic plasticity that is crucial for CRC tumor progression (; ). Epigenetics refers to the regulation of gene transcription absent DNA-coding sequence alterations, and includes post-translational modifications to DNA and histones, nucleosome repositioning, and microRNA regulation of mRNA translation and/or stability (). The most well-known of these, methylation of deoxycytosine (commonly referred to as the “fifth base” comprising DNA), within CG dinucleotides, is universally throughout higher eukaryotes, particularly in heterochromatin and large intergenic regions (). However, specific CG-rich (>60%) regions of <1000 base pairs (“CpG islands”), associated with over 70% of gene promoters are protected from transcriptionally repressive DNA methylation in normal cells (). A hallmark of cancer is a redistribution of DNA methylation patterns, i.e., hypermethylation of CpG islands, often resulting in repression of tumor suppressor genes, and loss of methylation in heterochromatin, resulting in genomic instability (). Moreover, early deoxycytosine methylation may occur in DNA repair genes (e.g., MLH1, MSH2, etc.), further favoring MSI and genetic mutations ().
Epigenetics in Colorectal Cancer Development
In CRC specifically, it has been asserted that epigenetic changes occur very early in tumorigenesis. Specifically, MSI, and DNA methylation/silencing of DNA mismatch repair (MMR) genes, lead to a poorly understood phenomenon known as “CIMP” (CpG island methylator phenotype). The CIMP phenotype involves widespread (but not random) promoter methylation throughout the genome (). Moreover, it has been reported that typical metastatic CRCs possess ∼61 infrequently mutated genes, with 15 of these designated as driver genes, and the remainder representing mutated passenger genes (). By contrast, one recent genome-wide analysis revealed that approximately 5% of the total CRC tumor genome (>1000 genes) harbors abnormal DNA methylation (). Thus, it would appear prudent to consider both genetic and epigenetic aberrations in the etiology of CRC (). For example, while 85% of sporadic CRCs possess transcriptional loss of APC, in addition to inactivating mutations, this gatekeeper can also be silenced by promoter DNA methylation ().
Another example of epigenetic/genetic “crosstalk” during CRC tumorigenesis is the finding of genetic mutations in genes encoding epigenetic modifiers. For example, in a study of the genetic landscape of CRC, it was found that 50% of mutation-driver genes were those encoding epigenetic modifiers (e.g., DNMT3b, EZH2, etc.) (). Another genome-wide association study revealed mutations in the gene encoding the Tet methylcytosine dioxygenase 2, an enzyme involved in DNA demethylation (). These (and many other studies) demonstrate the complex interplay between genetics and epigenetics (), thus increasing the challenges of designing targeted CRC therapies.
Epigenetics likely also contributes to the wide degree of heterogeneity of CRC tumors. Recently, an international consortium recognized four CRC consensus molecular subtypes, including: (1) CMS1 (microsatellite instable, hypermutated); (2) CMS2 (activated canonical WNT and MYC signaling; (3) CMS3, with metabolic dysregulation; and (4) CMS4, having activated TGF-β signaling, with stromal invasion and angiogenesis. Each of these subtypes was found to have their own distinctive epigenomes (). Moreover, CRC tumors with relative epigenomic homogeneity associated with short relapse-free and overall survival ().
Epithelial-to-Mesenchymal Transition
The importance of epigenomics to cancer is further supported by studies in melanoma, in which plating of melanoma cells onto an extracellular matrix derived from embryonic stem cells, could reverse the malignant phenotype (). Such malignant reversion was later found to associate with epigenetic remodeling by microenvironmental paracrine release of the cytokine Lefty, which is silenced by DNA methylation, and also by the microRNA miRNA-302, in melanoma cells. Analogously, Lefty is inhibited by the oncoprotein Nodal, and the embryonic transcription factor Notch4 (; ). Other studies showed that the epithelial-to-mesenchymal transition (EMT)-opposing microRNAs miR-34 and the miR-200 family are silenced by DNA methylation in CRC metastatic cells and tissues. Re-expression of these miRNA genes, by DNA methylation inhibitors, inhibited the synthesis of the EMT modulators TWIST, SNAIL, and ZEB1 (; ; ). Moreover, a p53/miR-34 axis has been reported to stabilize the β-catenin antagonist GSK-3β within the nucleus, resulting in repression of Wnt and Snail pathway transcriptional targets ().
Consequently, we posit that an additional aspect of CRC neoplastic epigenomic alterations is their intimate role in regulating EMT (), which has further been linked to the cancer “stemness” phenotype (). The EMT transition involves massive, genome-wide epigenomic changes that underlie phenotypic plasticity, such as the loss of tight junctions, loss of cell-to-cell adherence, loss of cell polarity, changes in cell morphology to an elongated shape (allowing traverse between endothelial cells), and the formation of lamellapodia and cytoskeletal remodeling, thus facilitating motility and invasion (Figure 1) ().
FIGURE 1
Epigenomic Reactivation of Embryonic Developmental Pathways
In addition to EMT, most cancers are now known to reactivate embryonic self-renewal pathways, including Hedgehog, Notch, and TGFβ/Stat3. As described above, most CRCs are reliant on the Wnt (Wingless) developmental pathway. It is possible that direct targeting of embryonic pathways might be more effective against both stem and dedifferentiating tumor cells (; ; ), and cancers “addicted to” upregulated embryonic pathway activity (e.g., Wnt in CRC and PIK3CA in metastatic breast cancer), combined with high tumor heterogeneity, might be more vulnerable to such therapies (; ; ). Another “master regulator” of chromatin remodeling to an undifferentiated phenotype is the Polycomb oncoprotein EZH2, which represses transcription by trimethylation of histone H3, lysine 27 (H3K27me3) ().
Current and Potential CRC Therapeutic Approaches
In Figure 1, we present a model for the genesis and progression of CRC, via canonical or non-canonical Wnt signaling. Here, the simplest means of carcinogenesis would be genetic or epigenetic anomalies in colonic crypt stem cells, particularly those expressing the Wnt signaling component LGR5 (; ). However, epigenomic alterations also allow for dedifferentiation of villi cells (transient-amplifying or even fully differentiated, polarized colonocytes), particularly in response to inflammation (and activity of the oncogenic pathway NF-κB (), and various environmental agents (). As >95% of CRCs are believed to involve overactive Wnt signaling, this may occur via numerous mechanisms, including APC mutation, DNA methylation silencing of SFRP (secreted frizzled receptor protein), activating mutations in beta-catenin, loss of AXIN2 degradation by silencing of the E3 ligase gene tankyrase (TNKS2), and upregulated signaling of the hepatocyte growth factor (HGF) pathway (; ; ; ).
In this scenario, reactivation of embryonic signaling pathways (possibly via aberrant paracrine interactions with a pericryptal myofibroblast “stem cell niche”) () and CRC upregulation of Wnt signaling, in conjunction with the loss of gatekeeper genes (SFRP, APC, DKK, etc.) upregulate EMT and other promalignant processes (; ). Additional activating mutations in CRC driver genes/pathways may also “crosstalk” (e.g., HGF, PI3K/AKT, TNKS2) with Wnt signaling to facilitate rapid proliferation into a fully malignant tumor (via β-catenin stabilization, nuclear translocation, and cotransactivation of TEF/LEF-occupied gene promoters). These events then initiate a cascade that eventually results in EMT and a cancer stem-like phenotype, involving highly plastic phenotypes, such as cell shape distortion (extravasation between endothelial cells), motility to reach the circulatory system, and suppression of immunosurveillence by downregulating specific HLA, and other antigenic cell surface immunophenotypes ().
Possible Epigenome-Targeting Therapeutic Approaches for CRC
Wnt Inhibitors
As mentioned above, APC and/or CTNNB1 (β-catenin) mutation(s) are present in >90% of CRC cases, thus singling out the Wnt pathway as predominant in this cancer type (). Moreover, Wnt ligands can stimulate various non-canonical and non-frizzled related pathways, and Wnt signaling has been found to “crosstalk” with several other signal cascades (e.g., KRAS, BRAF, etc.) (Figure 1). In particular, tyrosine (not serine/threonine) phosphorylation of β-catenin (and loss of its degradation), leads to its nuclear translocation and oncogene transactivation (). Consequently, a number of Wnt inhibitors have now been developed, including those targeting tankarases 1 and 2 (affecting AXIN2 degradation), porcupine, and disheveled (). Thus, while inhibitors of canonical Wnt signaling may well be beneficial, even more ideal therapeutics might target the downstream effectors that act as convergence points for several pathways (e.g., TCF/LEF, TWIST, MYC, etc.) ().
Epigenome-Modulating Agents
In addition to Wnt inhibitors, we posit that epigenetic transcriptional derepressors might be a complimentary means of enhancing the efficacy of embryonic pathway-targeting therapies. For example, DNA methylation specifically silences a number of tumor suppressor genes (e.g., miR-34, miR-200 family, SFRP, etc.), while global epigenomic alterations underlie the phenotypic plasticity of EMT/stemness. Such dedifferentiating phenotypic alterations correlate with widespread trimethylation of histone H3, lysine 27 (H3K27me3), a transcriptionally repressive modification catalyzed by the Polycomb group protein, and histone methyltransferase, EZH2 (; ; ) (Figure 1). Most recently, the retinoblastoma-binding protein-2, RBP2 (JARED1A, KDM5a), a histone H3 lysine 4 (H3K4, an activating modification) demethylase, was discovered in various other cancers as complexed with EZH2 (; ), and is now the subject of intense investigation for inhibitors (; ).
Interestingly, one study in YB5 CRC cells comprised of a screen of FDA-approved drugs that could synergize with the DNA methylation inhibitor decitabine to derepress a silenced reporter gene (). This screen revealed, in particular, that the antiarrhythmic proscillaridin, paired with decitabine, effected widespread epigenomic reprogramming, including silencing of two CRC oncogenes, SYMD3 and KDM8 ().
Several other recent studies support our hypothesis. In one study of chemoresistant CRC and other cell lines, histone deacetylase inhibitors (HDACIs) reversed EMT and cancer stem cell phenotypes (), while one specific HDACI, resminostat, has now completed a Phase I clinical trial (Clinicaltrials.gov, NCT01277406) for patients with advanced CRC (). Another Phase II trial of the HDACI entinostat, combined with the demethylating agent azacitidine proved tolerable, but unfortunately, poorly efficacious (). Other HDACIs, however, in Phase I or II trials, include CUDC-907 (Curis, Inc., Lexington, MA, USA) and CXD101 (Celleron Therapeutics, Oxford, UK). Thus, while HDACIs have yet only shown efficacy against specific lymphomas, it is likely that well-designed clinical trials will validate their promise against solid tumors (particularly as adjuvant therapies).
Summary
Much progress has been made in the treatment of CRC, including a tripling of the 5-year survival for stage IV disease, from 11 to 30 months. Nonetheless, following most first-line therapies, secondary approaches remain only minimally life-extending. Due to the essential and complex involvement of epigenetics, in CRC and most cancers, approaches to reverse the various DNA and histone modifications related to self-renewal of cancer stem cells, hold promise for more effective treatment of CRC and other malignant diseases.
Statements
Author contributions
CB and AT: idea generation, literature review. AT: supervised the outline, designed the figure in collaboration with CB and JR. CB, JR, and AT contributed to the writing and proofing of the manuscript. All the authors read and approved the final version of this manuscript.
Funding
This work was supported by start-up funds (F- 110760) to Dr. Tiwari from the University of Toledo.
Acknowledgments
We thank Mr. Kyle McIntosh (UT) and Ms. Haneen Amawi (UT) for polishing the figure. We thank Ms. Charisse Montgomery (UT) for critical review of this manuscript.
Conflict of interest
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The reviewer KM and handling Editor declared their shared affiliation, and the handling Editor states that the process nevertheless met the standards of a fair and objective review.
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Summary
Keywords
colorectal cancer, embryonic signaling pathways, epigenomics, epithelial-to-mesenchymal transition, tumor progression
Citation
Balch C, Ramapuram JB and Tiwari AK (2017) The Epigenomics of Embryonic Pathway Signaling in Colorectal Cancer. Front. Pharmacol. 8:267. doi: 10.3389/fphar.2017.00267
Received
21 February 2017
Accepted
28 April 2017
Published
19 May 2017
Volume
8 - 2017
Edited by
Brion William Murray, Pfizer (United States), USA
Reviewed by
Karen Maegley, Pfizer (United States), USA; Maitri Yogen Shah, University of Texas MD Anderson Cancer Center, USA
Updates
Copyright
© 2017 Balch, Ramapuram and Tiwari.
This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
*Correspondence: Amit K. Tiwari, amit.tiwari@utoledo.edu
This article was submitted to Pharmacology of Anti-Cancer Drugs, a section of the journal Frontiers in Pharmacology
Disclaimer
All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.