Portal de Periódicos da CAPES

Diet, Microbiota, and Colorectal Cancer

2019; Cell Press; Volume: 21; Linguagem: Inglês

10.1016/j.isci.2019.10.011

2589-0042

Tatiana P. Grazioso, Marta Brandt, Nabil Djouder,

Digestive system and related health

The intestinal epithelium is a very dynamic tissue under a high regenerative pressure, which makes it susceptible to malignant transformation. Proper integration of various cell signaling pathways and a balanced cross talk between different cell types composing the organ are required to maintain intestinal homeostasis. Dysregulation of this balance can lead to colorectal cancer (CRC). Here, we review important insights into molecular and cellular mechanisms of CRC. We discuss how perturbation in complex regulatory networks, including the Wnt, Notch, BMP, and Hedgehog pathways; and how variations in inflammatory signaling, nutrients, and microbiota can affect intestinal homeostasis contributing to the malignant transformation of intestinal cells. The intestinal epithelium is a very dynamic tissue under a high regenerative pressure, which makes it susceptible to malignant transformation. Proper integration of various cell signaling pathways and a balanced cross talk between different cell types composing the organ are required to maintain intestinal homeostasis. Dysregulation of this balance can lead to colorectal cancer (CRC). Here, we review important insights into molecular and cellular mechanisms of CRC. We discuss how perturbation in complex regulatory networks, including the Wnt, Notch, BMP, and Hedgehog pathways; and how variations in inflammatory signaling, nutrients, and microbiota can affect intestinal homeostasis contributing to the malignant transformation of intestinal cells. The intestine is the last part of the gastrointestinal tract, and is divided into two anatomically and functionally different sections: the small intestine and the large intestine, whose main functions are food digestion, stool compaction, and absorption of water, nutrients, and salts. Both the small and large intestines present an outer layer of smooth muscle with enteric nervous system; a middle layer composed of connective tissue, nerves, and lymphatic vessels; and an inner epithelial layer called the mucosa. The small intestine presents epithelial folds resembling finger-like protrusions called villi, which face the lumen and aim to maximize the available absorptive area. Villi are surrounded by epithelial invaginations that form the crypts of Lieberkühn (Figure 1). In contrast, the colonic epithelium lacks villi and consists of a plane surface with multiple epithelial invaginations forming the crypts (Clevers, 2013Clevers H. The intestinal crypt, a prototype stem cell compartment.Cell. 2013; 154: 274-284Abstract Full Text Full Text PDF PubMed Scopus (470) Google Scholar, Lieberkuhn, 1745Lieberkuhn J.N. Dissertatio anatomico-physiologica de fabrica et actione villorum intestinorum tenuium hominis. Lugduni Batavorum, 1745Google Scholar, Potten, 1995Potten C. Structure, function and proliferative organisation of the mammalian gut (Radiation and gut). Lugduni Batavorum, 1995Google Scholar, Simons and Clevers, 2011Simons B.D. Clevers H. Stem cell self-renewal in intestinal crypt.Exp. Cell Res. 2011; 317: 2719-2724Crossref PubMed Scopus (96) Google Scholar). The intestinal epithelium is one of the most rapidly renewing tissues in humans (Potten et al., 1997Potten C.S. Booth C. Pritchard D.M. The intestinal epithelial stem cell: the mucosal governor.Int. J. Exp. Pathol. 1997; 78: 219-243Crossref PubMed Google Scholar). Self-renewal is controlled by intestinal stem cells (ISCs) present at the bottom of the crypt. ISCs are +4 leucine-rich repeat-containing G-protein-coupled receptor 5-positive (Lgr5+ or Lgr5high). Upon division, ISCs migrate upward to the crypts' upper part and undergo four to five replication cycles to become Lgr5- (Lgr5low) progenitors or transit-amplifying (TA) cells committed to differentiation. TA cells differentiate and migrate toward the luminal surface until they become terminally differentiated intestinal epithelial cells belonging to two lineages: the absorptive and the secretory. The absorptive lineage includes enterocytes responsible for the absorption of nutrients in the intestinal lumen (Noah et al., 2011Noah T.K. Donahue B. Shroyera N.F. Intestinal development and differentiation.Experimental Cell Researc. 2011; 317: 2702-2710Crossref PubMed Scopus (0) Google Scholar). The secretory lineage includes: gobletcells, which secrete protective mucins, and enteroendocrine cells that secrete mucus and hormones such as serotonin and secretin (Barker et al., 2012Barker N. Van Oudenaarden A. Clevers H. Identifying the stem cell of the intestinal crypt: strategies and pitfalls.Cell Stem Cell. 2012; 11: 452-460Abstract Full Text Full Text PDF PubMed Scopus (182) Google Scholar, Clevers, 2013Clevers H. The intestinal crypt, a prototype stem cell compartment.Cell. 2013; 154: 274-284Abstract Full Text Full Text PDF PubMed Scopus (470) Google Scholar). Differentiated intestinal epithelial cells continue moving upward to the villus tip, and upon reaching the surface they undergo apoptosis (Simons and Clevers, 2011Simons B.D. Clevers H. Stem cell self-renewal in intestinal crypt.Exp. Cell Res. 2011; 317: 2719-2724Crossref PubMed Scopus (96) Google Scholar), allowing the renewal of all the cells in the crypt villus axis (Figure 1). Importantly, an exception to this upward migration occurs in the Paneth cells, which migrate downward to the bottom of the crypt, where they contribute to the stem cell niche (Simons and Clevers, 2011Simons B.D. Clevers H. Stem cell self-renewal in intestinal crypt.Exp. Cell Res. 2011; 317: 2719-2724Crossref PubMed Scopus (96) Google Scholar). Paneth cells are the main source of Wnt3 and EGF signals, necessary for maintaining crypt cells' proliferative capacity, and for the secretion of antimicrobial peptides (i.e., defensins) and hydrolytic enzymes, such as lysozymes, to maintain a sterile environment in the crypts (Figure 1) (Barker et al., 2012Barker N. Van Oudenaarden A. Clevers H. Identifying the stem cell of the intestinal crypt: strategies and pitfalls.Cell Stem Cell. 2012; 11: 452-460Abstract Full Text Full Text PDF PubMed Scopus (182) Google Scholar, Clevers, 2013Clevers H. The intestinal crypt, a prototype stem cell compartment.Cell. 2013; 154: 274-284Abstract Full Text Full Text PDF PubMed Scopus (470) Google Scholar, Kim et al., 2005Kim K.A. Kakitani M. Zhao J. Oshima T. Tang T. Binnerts M. Liu Y. Boyle B. Park E. Emtage P. et al.Medicine: mitogenic influence of human R-spondin1 on the intestinal epithelium.Science. 2005; 309: 1256-1259Crossref PubMed Scopus (0) Google Scholar, Sato et al., 2011Sato T. 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Identifying the stem cell of the intestinal crypt: strategies and pitfalls.Cell Stem Cell. 2012; 11: 452-460Abstract Full Text Full Text PDF PubMed Scopus (182) Google Scholar, Chaves-Pérez et al., 2019Chaves-Pérez A. Yilmaz M. Perna C. de la Rosa S. Djouder N. URI is required to maintain intestinal architecture during ionizing radiation.Science. 2019; 364: eaaq1165Crossref PubMed Scopus (0) Google Scholar, Clevers, 2013Clevers H. The intestinal crypt, a prototype stem cell compartment.Cell. 2013; 154: 274-284Abstract Full Text Full Text PDF PubMed Scopus (470) Google Scholar). The intestinal epithelium is a very dynamic tissue, where ISCs are under a high regenerative pressure. Thus, a proper homeostatic regulation by a strict balance between cell proliferation, differentiation, and apoptosis is needed (Kitisin and Mishra, 2006Kitisin K. Mishra L. Molecular biology of colorectal cancer: new targets.Semin. Oncol. 2006; 33: 14-23Crossref PubMed Scopus (0) Google Scholar). This complex regulatory network involves the Wnt, Notch, BMP, and Hedgehog signaling pathways, which depend on the spatial organization of signals from surrounding mesenchymal cells and the stem cell niche (Medema and Vermeulen, 2011Medema J.P. Vermeulen L. Microenvironmental regulation of stem cells in intestinal homeostasis and cancer.Nature. 2011; 474: 318-326Crossref PubMed Scopus (313) Google Scholar). Deregulation of these main signaling pathways leads to intestinal homeostasis disruption, which contributes to colorectal cancer (CRC) development. The Wnt signaling was one of the first pathways described to be implicated in regulating intestinal homeostasis. Current evidence shows that it plays a key role in maintaining crypt stem cell population in proliferating and undifferentiated states (Crosnier et al., 2006Crosnier C. Stamataki D. Lewis J. Organizing cell renewal in the intestine: stem cells, signals and combinatorial control.Nat. Rev. Genet. 2006; 7: 349-359Crossref PubMed Scopus (486) Google Scholar). Activation of the Wnt pathway is controlled by the binding of Wnt ligands to LRP5/6 receptors and to receptors from the Fizzled family. The oncoprotein β-catenin is inhibited when bound to the adenomatous polyposis coli (APC). The destruction complex composed by APC, Axin, and two kinases, the casein kinase I (CKI) and the glycogen synthase kinase 3 (GSK3), targets β-catenin for phosphorylation-mediated proteosomal degradation. Wnt binding to LRP5/6 inhibits APC leading to β-catenin stabilization and translocation to the nucleus, where it binds to TCF transcription factors and activates the transcription of Wnt/TCF target genes (Clevers, 2013Clevers H. The intestinal crypt, a prototype stem cell compartment.Cell. 2013; 154: 274-284Abstract Full Text Full Text PDF PubMed Scopus (470) Google Scholar, Radtke and Clevers, 2005Radtke F. Clevers H. Self-renewal and cancer of the gut: two sides of a coin.Science. 2005; 307: 1904-1909Crossref PubMed Scopus (543) Google Scholar). The Notch signaling pathway plays an essential role in controlling intestinal homeostasis. Notch and its ligands are transmembrane protein receptors that mediate cell-to-cell contact. In the intestinal epithelium, Notch signaling plays a crucial role by regulating cell differentiation, determining the lineage fate of TA cells. Activation of the Notch pathway relies on the interaction of five ligands (Jagged1/2 and Delta like-1/3/4) and four receptors (Notch1/2/3/4) (Rallis et al., 2019Rallis G. Koletsa T. Saridaki Z. Manousou K. Koliou G.-A. Kostopoulos I. Kotoula V. Makatsoris T. Kourea H.P. Raptou G. et al.Association of notch and hedgehog pathway activation with prognosis in early-stage colorectal cancer.Anticancer Res. 2019; 39: 2129-2138Crossref PubMed Scopus (1) Google Scholar). Mechanistically, the interactions of Notch receptors with its cell-bound ligands induce the activation of a proteolytic cascade with three sequential cleavage steps. Upon ligand binding, the S1 site of the Notch receptor is cleaved by a Furin-like convertase forming a Notch extracellular domain, non-covalently bound to a transmembrane fragment (Logeat et al., 1998Logeat F. Bessia C. Brou C. LeBail O. Jarriault S. Seidah N.G. Israël A. The Notch1 receptor is cleaved constitutively by a furin-like convertase.Proc. Natl. Acad. Sci. U S A. 1998; 95: 8108-8112Crossref PubMed Scopus (0) Google Scholar). A second cleavage occurs at the S2 site by the action of a metalloprotease from the ADAM family, which gives rise to a transient intermediate peptide that acts as substrate for y-secretase-like protease catalyzing the intramembranous cleavage of the Notch intracellular domain (NICD) at the S3 site (Brou et al., 2000Brou C. Logeat F. Gupta N. Bessia C. LeBail O. Doedens J.R. Cumano A. Roux P. 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Ray W.J. et al.A presenilin-1-dependent γ-secretase-like protease mediates release of notch intracellular domain.Nature. 1999; 398: 518-522Crossref PubMed Scopus (1657) Google Scholar). Upon its release, NICD translocates to the nucleus, where it binds to the transcription factor CSL. This complex stimulates the transcription of Notch target genes (Clevers, 2013Clevers H. The intestinal crypt, a prototype stem cell compartment.Cell. 2013; 154: 274-284Abstract Full Text Full Text PDF PubMed Scopus (470) Google Scholar, Struhl and Adachi, 1998Struhl G. Adachi A. Nuclear access and action of Notch in vivo.Cell. 1998; 93: 649-660Abstract Full Text Full Text PDF PubMed Scopus (607) Google Scholar) involved in cell growth, differentiation, angiogenesis, and apoptosis (Al-Hussaini et al., 2011Al-Hussaini H. Subramanyam D. Reedijk M. Sridhar S.S. Notch signaling pathway as a therapeutic target in breast cancer.Mol. Cancer Ther. 2011; 10: 9-15Crossref PubMed Scopus (97) Google Scholar). The role and functions of Notch signaling in CRC has been previously reviewed (Vinson et al., 2016Vinson K.E. George D.C. Fender A.W. Bertrand F.E. Sigounas G. The Notch pathway in colorectal cancer.Int. J. Cancer. 2016; 138: 1835-1842Crossref PubMed Scopus (51) Google Scholar), supporting the role of Notch dysregulation in aberrant cell division, proliferation, and apoptosis resistance, leading to tumorigenesis and metastasis. The bone morphogenic protein (BMP) belongs to the TGF-β superfamily of ligands that control intracellular signaling through SMAD proteins (Medema and Vermeulen, 2011Medema J.P. Vermeulen L. Microenvironmental regulation of stem cells in intestinal homeostasis and cancer.Nature. 2011; 474: 318-326Crossref PubMed Scopus (313) Google Scholar). In the intestine, BMP2 and BMP4 are expressed in mesenchymal cells, and are responsible for counteracting Wnt signaling and halting proliferation at the crypt-villus border. Importantly, BMPs are active only at the top of the crypt, where they counteract proliferation, and promote cell differentiation. Mechanistically, BMPs bind to their type II receptor, which leads to the phosphorylation and activation of type I BMP receptor, and subsequently to the activation of SMAD (Gehart and Clevers, 2018Gehart H. Clevers H. Tales from the crypt: new insights into intestinal stem cells.Nat. Rev. Gastroenterol. Hepatol. 2018; 1: 19-34Google Scholar). SMAD translocates to the nucleus where it acts either as a co-activator, or as a co-repressor for transcription (Radtke and Clevers, 2005Radtke F. Clevers H. Self-renewal and cancer of the gut: two sides of a coin.Science. 2005; 307: 1904-1909Crossref PubMed Scopus (543) Google Scholar). The Hedgehog signaling pathway involves Hedgehog proteins controlling epithelial and mesenchymal cell interaction, as well as BMP production. The constitutive activation of this pathway leads to an increase in the activation of BMP signaling pathway and, therefore, to a reduction in the TA compartment (Van Dop et al., 2009Van Dop W. Uhmann A. Wijgerde M. Sleddens–Linkels E. Heijmans J. Offerhaus G.J. Weerman M.A.V.D.B. Boeckxstaens G.E. Hommes D.W. Hardwick J.C. et al.Depletion of the colonic epithelial precursor cell compartment upon conditional activation of the hedgehog pathway.Gastroenterology. 2009; 136: 2195-2203Abstract Full Text Full Text PDF PubMed Scopus (68) Google Scholar). On the other hand, reduction in the Hedgehog signaling leads to an improper intestinal differentiation and hyperplasia through enhancement of the Wnt signaling pathway (Madison et al., 2005Madison B.B. Braunstein K. Kuizon E. Portman K. Qiao X.T. Gumucio D.L. Epithelial hedgehog signals pattern the intestinal crypt-villus axis.Development. 2005; 132: 279-289Crossref PubMed Scopus (262) Google Scholar). Cancer is a multifactorial neoplastic disease, in which both genetic and environmental factors interact affecting proliferation, differentiation, survival, and metabolism of the cells in the organism. The high regenerative pressure, and the constant contact with nutrients and microbiota, makes the intestinal epithelia highly susceptible to malignant transformation. CRC is one of the most common cancer types. Worldwide, it is currently the third most frequently diagnosed cancer in men and the second in woman. An estimate of 1.7 million cases was reported in 2015, worldwide. In addition, CRC represents the third leading cause of cancer-related deaths, accounting for 9.2% of total cancer deaths worldwide and causing approximately 832,000 deaths in 2015 (Fitzmaurice, 2018Fitzmaurice C. Global, regional, and National cancer incidence, mortality, years of life lost, years lived with disability, and disability-adjusted life-years for 32 cancer groups, 1990 to 2015.JAMA Oncol. 2018; 3: 524-548Google Scholar). Many risk factors have been associated with CRC, and both genetic and environmental factors play a mutual role in tumor development. CRC can have an hereditary or sporadic background, but because CRC has been described as a multi-hit neoplasia, the tumor arises from the accumulation of multiple mutations overtime. For instance, mutations in the tumor suppressor gene APC can occur somatically initiating tumor formation, or be a germ line mutation, thus predisposing to tumor development (Vogelstein and Kinzler, 1993Vogelstein B. Kinzler K.W. The multistep nature of cancer.Trends Genet. 1993; 9: 138-141Abstract Full Text PDF PubMed Scopus (1411) Google Scholar). Hereditary CRC accounts for approximately 5%-10% of all CRC cases and involves inherited mutations in high-risk cancer susceptibility genes (APC, DNA MMR genes, p53 mutations, KRAS, BRAF, among others) (Markowitz and Bertagnolli, 2009Markowitz S.D. Bertagnolli M.M. Molecular basis of colorectal cancer.N. Engl. J. Med. 2009; 361: 2449-2460Crossref PubMed Scopus (1094) Google Scholar). Studies have reported that having one affected first-degree relative increases the risk of developing CRC by 2-fold. This association increases to even 4-fold for individuals with three or more affected first-degree relatives (Kuipers et al., 2015Kuipers E.J. Grady W.M. Lieberman D. Seufferlein T. Sung J.J. Boelens P.G. van de Velde C.J.H. Watanabe T. Colorectal cancer.Nat. Rev. 2015; 1: 109-113Google Scholar, Taylor et al., 2010Taylor D.P. Burt R.W. Williams M.S. Haug P.J. Cannon-Albright L.A. Population-based family history-specific risks for colorectal cancer: a constellation approach.Gastroenterology. 2010; 138: 877-885Abstract Full Text Full Text PDF PubMed Scopus (130) Google Scholar). Most common forms of hereditary CRC are linked to familiar CRC syndromes, including hereditary non-polyposis colon cancer (HNPCC, or Lynch syndrome). These diseases are associated with mutations in the DNA repair pathway, mostly in MLH1 and MSH2, which trigger microsatellite instability (Haggar and Boushey, 2008Haggar F.A. Boushey R.P. Colorectal cancer epidemiology: incidence, mortality, survival, and risk factors.Clin. Colon Rectal Surg. 2008; 22: 191-197Crossref Scopus (933) Google Scholar), and familial adenomatous polyposis (FAP) caused by mutations in APC (Nishisho et al., 1991Nishisho I. Nakamura Y. Miyoshi Y. Miki Y. Ando H. Horii A. Koyama K. Utsunomiya J. Baba S. Hedge P. et al.Mutations of chromosome 5q21 genes in FAP and colorectal cancer patients.Science. 1991; 371: 665-669Crossref Scopus (1479) Google Scholar). The majority of CRC are sporadic and occur due to the accumulation of mutational changes, such as chromosomal and microsatellite instability, that drive the neoplastic process (Kitisin and Mishra, 2006Kitisin K. Mishra L. Molecular biology of colorectal cancer: new targets.Semin. Oncol. 2006; 33: 14-23Crossref PubMed Scopus (0) Google Scholar, Vogelstein and Kinzler, 1993Vogelstein B. Kinzler K.W. The multistep nature of cancer.Trends Genet. 1993; 9: 138-141Abstract Full Text PDF PubMed Scopus (1411) Google Scholar). Importantly, many environmental factors have been shown to influence the risk of developing somatic mutations favoring tumor formation (Kuipers et al., 2015Kuipers E.J. Grady W.M. Lieberman D. Seufferlein T. Sung J.J. Boelens P.G. van de Velde C.J.H. Watanabe T. Colorectal cancer.Nat. 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Moreover, age has been shown to have an influence in CRC incidence as it strongly increases with age, having an estimated median age of diagnosis of 70 years old in developed countries. Recently, chronic inflammation and inflammatory bowel disease (IBD) have been linked to CRC development. IBD encompasses two inflammation-related conditions of the intestines: ulcerative colitis (UC) and Crohn disease (CD). IBD is characterized by the interaction of different factors such as genetic predisposition, altered microbiota, and environmental factors that trigger an aberrant immune response, leading to impaired intestinal homeostasis. UC is characterized by inflammation of the mucosa of the colon and rectum, whereas CD presents inflammation spread through all the thickness of the bowel wall, affecting all parts of the digestive tract (Haggar and Boushey, 2008Haggar F.A. Boushey R.P. Colorectal cancer epidemiology: incidence, mortality, survival, and risk factors.Clin. Colon Rectal Surg. 2008; 22: 191-197Crossref Scopus (933) Google Scholar). CRC development is characterized by the progressive accumulation of multiple genetic and epigenetic aberrations within cells (Fearon and Vogelstein, 1990Fearon E.F. Vogelstein B. A genetic model for colorectal tumorigenesis.Cell. 1990; 61: 759-767Abstract Full Text PDF PubMed Scopus (8996) Google Scholar, Nguyen and Duong, 2018Nguyen H.T. Duong H.Q. The molecular characteristics of colorectal cancer: implications for diagnosis and therapy (review).Oncol. Lett. 2018; 16: 9-18PubMed Google Scholar). In 1990, Fearon and Vogelstein proposed a model for CRC tumorigenesis describing that the total accumulation of genetic and epigenetic mutations was responsible for tumor formation, and its biological properties. In this regard, tumors arise as the result of gradual accumulation of mutations in multiple genes, such as those leading to oncogene activation, or inhibition of tumor suppressor genes (Fearon and Vogelstein, 1990Fearon E.F. Vogelstein B. A genetic model for colorectal tumorigenesis.Cell. 1990; 61: 759-767Abstract Full Text PDF PubMed Scopus (8996) Google Scholar). However, recent evidences have shown that the progression from polyp to cancer involves not only the accumulation of multiple mutations, but also alteration at different molecular events (Lao and Grady, 2011Lao V.V. Grady W.M. Epigenetics and colorectal cancer.Nat. Rev. Gastroenterol. Hepatol. 2011; 8: 686-700Crossref PubMed Scopus (338) Google Scholar), and even though the genomic and molecular basis may differ, the conventional pathway for CRC begins as a benign adenomatous polyp that progressively develops into an advanced adenoma with high-grade dysplasia and eventually into an invasive tumor that leads to the loss of the epithelial structure and function. ISCs have been proposed to be at the origin of CRC (Barker et al., 2009Barker N. Ridgway R.A. Van Es J.H. Van De Wetering M. Begthel H. Van Den Born M. Danenberg E. Clarke A.R. Sansom O.J. Clevers H. Crypt stem cells as the cells-of-origin of intestinal cancer.Nature. 2009; 457: 608-611Crossref PubMed Scopus (1325) Google Scholar, Markowitz and Bertagnolli, 2009Markowitz S.D. Bertagnolli M.M. Molecular basis of colorectal cancer.N. Engl. J. Med. 2009; 361: 2449-2460Crossref PubMed Scopus (1094) Google Scholar) with the significant contribution of micro-environmental factors that support tumor development. Although the sequence of sporadic events that leads to CRC is still poorly understood, it has been well described that the initiating event in CRC is the activation of the Wnt signaling pathway, mainly by mutations in β-catenin, or loss in the APC gene, promoting cellular activation and proliferation (Medema and Vermeulen, 2011Medema J.P. Vermeulen L. Microenvironmental regulation of stem cells in intestinal homeostasis and cancer.Nature. 2011; 474: 318-326Crossref PubMed Scopus (313) Google Scholar). Additionally, as further discussed, throughout tumor evolution, adenomas increase microsatellite instability (MSI) and chromosomal instability (CIN), and as adenomas grow, they acquire mutations in the small GTPase KRAS, followed by loss of SMAD4, inactivating mutations in TP53, and loss of PTEN, which together lead to the malignant transformation of the intestinal epithelium (Walther et al., 2009Walther A. Johnstone E. Swanton C. Midgley R. Tomlinson I. Kerr D. Genetic prognostic and predictive markers in colorectal cancer.Nat. Rev. Cancer. 2009; 9: 489-499Crossref PubMed Scopus (467) Google Scholar). Even though generally the malignant transformation occurs from adenoma to CRC, an additional class of premalignant polyps called serrated polyps, with high potential for malignant transformation, is now recognized (Lao and Grady, 2011Lao V.V. Grady W.M. Epigenetics and colorectal cancer.Nat. Rev. Gastroenterol. Hepatol. 2011; 8: 686-700Crossref PubMed Scopus (338) Google Scholar). In this regard, about 15%–30% of CRCs follow an alternative route of carcinogenesis, called the serrated colorectal carcinogenesis (Yamane et al., 2014Yamane L. Scapulatempo-Neto C. Reis R.M. Guimarães D.P. Serrated pathway in colorectal carcinogenesis.World J. Gastroenterol. 2014; 20: 2634-2640Crossref PubMed Scopus (42) Google Scholar). In this model, serrated polyps replace the adenoma as the precursor lesion progressing to CRC. Serrated polyps originate upon BRAF mutations, and hypermethylations in the promoter area of the CpG islands of tumor suppressor genes (Villanacci et al., 2019Villanacci V. Baronchelli C. Manenti S. Bassotti G. Salviato T. Serrated lesions of the colon A window on a more clear classification.Annals of Diagnostic Pathology. 2019; 41: 8-13Crossref PubMed Scopus (1) Google Scholar). Importantly, in the serrated pathway the methylation and inactivation o