Ulcerative Colitis–Associated Carcinoma: Epithelial SMAD4-Mediated Signaling Is a Key Guardian

Patients affected by long-lasting and relapsing intestinal inflammation such as ulcerative colitis are at high risk of progressing to colitis-associated cancer (CAC).1Low D. Mino-Kenudson M. Mizoguchi E. Recent advancement in understanding colitis-associated tumorigenesis.Inflamm Bowel Dis. 2014; 20: 2115-2123Crossref PubMed Scopus (20) Google Scholar CAC is a multifactorial disease and involves genetic predisposition, environmental triggers, dysbiosis, as well as an impaired immune system. Chronic inflammation also causes DNA damage and genomic mutations in the epithelium as a result of its requirement to go through numerous regenerative cycles. The sporadic colorectal cancer adenoma–carcinoma sequence involves sequential mutations of key tumor-suppressor genes or oncogenes such as APC, KRAS, and TP53,2Fearon E.R. Vogelstein B. A genetic model for colorectal tumorigenesis.Cell. 1990; 61: 759-767Abstract Full Text PDF PubMed Scopus (10012) Google Scholar whereas colitis-associated colorectal cancer instead follows a multistep process called inflammation dysplasia sequence, with TP53 mutations being an early detrimental genetic event.1Low D. Mino-Kenudson M. Mizoguchi E. Recent advancement in understanding colitis-associated tumorigenesis.Inflamm Bowel Dis. 2014; 20: 2115-2123Crossref PubMed Scopus (20) Google Scholar Transforming growth factor β (TGFβ) superfamily proteins regulate a variety of cellular functions as well as pathologic processes. TGFβ superfamily members include TGFβ, activins, and bone morphogenetic proteins (BMPs), among others. TGFβ superfamily ligands signal through serine/threonine kinase–receptor subtypes I and II, where the type I receptor is activated upon ligand binding and then associates with the type II receptor. This activated receptor complex leads to the transphosphorylation of the receptor-associated SMAD (R-SMAD) proteins, which include SMAD1, 5, and 8 for the BMPs, and SMAD 2 and 3 for the activins and TGFβ. These phosphorylated R-SMADs associate with SMAD4, a shared partner of the TGFβ superfamily. This SMAD trimer complex (phosphorylated R-Smads-SMAD4)s then translocates to the nucleus where it activates transcription of specific target genes. Over the years, impairments of the TGFβ superfamily signaling pathway in inflammatory bowel disease (IBD) pathogenesis and wound healing process have been studied in experimental models as well as in patients.3Allaire J.M. Darsigny M. Marcoux S.S. Roy S.A. Schmouth J.F. Umans L. Zwijsen A. Boudreau F. Perreault N. Loss of Smad5 leads to the disassembly of the apical junctional complex and increased susceptibility to experimental colitis.Am J Physiol Gastrointest Liver Physiol. 2011; 300: G586-G597Crossref PubMed Scopus (22) Google Scholar, 4Ihara S. Hirata Y. Koike K. TGF-beta in inflammatory bowel disease: a key regulator of immune cells, epithelium, and the intestinal microbiota.J Gastroenterol. 2017; 52: 777-787Crossref PubMed Scopus (146) Google Scholar, 5Sedda S. Marafini I. Dinallo V. Di Fusco D. Monteleone G. The TGF-beta/Smad system in IBD pathogenesis.Inflamm Bowel Dis. 2015; 21: 2921-2925Crossref PubMed Scopus (43) Google Scholar However, the relationship between CAC and specific elements of the TGFβ superfamily signaling, such as the SMADs effectors, has not been studied extensively, with one study investigating the specific role of SMAD7 in lamina propria mononuclear cells as a protective role for CAC in murine models.6Chandrasinghe P. Cereser B. Moorghen M. Al Bakir I. Tabassum N. Hart A. Stebbing J. Warusavitarne J. Role of SMAD proteins in colitis-associated cancer: from known to the unknown.Oncogene. 2018; 37: 1-7Crossref PubMed Scopus (20) Google Scholar To date, there has been limited attention directed toward the role played by SMAD effectors within the epithelial compartment in CAC pathogenesis. In this issue of Cellular and Molecular Gastroenterology and Hepatology, Means et al7Means A.L. Freeman T.J. Zhu J. Woodbury L.G. Marincola-Smith P. Wu C. Meyer A.R. Weaver C.J. Padmanabhan C. An H. Zi J. Wessinger B.C. Chaturvedi R. Brown T.D. Deane N.G. Coffey R.J. Wilson K.T. Smith J.J. Sawyers C.L. Goldenring J.R. Novitskiy S.V. Washington M.K. Shi C. Beauchamp R.D. Epithelial Smad4 deletion up-regulates inflammation and promotes inflammation-associated cancer.Cell Mol Gastroenterol Hepatol. 2018; 6: 257-276Abstract Full Text Full Text PDF PubMed Scopus (33) Google Scholar used a conditional knockout mouse model with an intestinal epithelial deletion of SMAD4 to characterize the homeostatic role of this important TGFβ superfamily intracellular effector during experimental colitis. The investigators showed that mice with epithelial deletion of Smad4 presented macroscopic invasive adenocarcinomas of the distal colon and rectum, 3 months after the completion of 3 rounds of treatment with the colonic irritant dextran sulfate sodium. Surprisingly, chronic dextran sulfate sodium treatment alone was sufficient to drive carcinogenesis in mutant mice and the histopathologic analysis of the tumors showed a strong similarity from those derived from human CAC. Lesions found in mice with epithelial deletion of Smad4 followed the inflammation dysplasia sequence1Low D. Mino-Kenudson M. Mizoguchi E. Recent advancement in understanding colitis-associated tumorigenesis.Inflamm Bowel Dis. 2014; 20: 2115-2123Crossref PubMed Scopus (20) Google Scholar because the WNT/β–catenin pathway was not up-regulated and tumors appeared flat or slightly elevated at the mucosal surface with extensive invasion of glands into the submucosa and muscularis mucosa. The development of CAC in these mutant mice was shown to be an early event because colonic carcinomas invading the submucosa already were observed after 2 months in some mice. By using RNA sequencing analysis, Means et al7Means A.L. Freeman T.J. Zhu J. Woodbury L.G. Marincola-Smith P. Wu C. Meyer A.R. Weaver C.J. Padmanabhan C. An H. Zi J. Wessinger B.C. Chaturvedi R. Brown T.D. Deane N.G. Coffey R.J. Wilson K.T. Smith J.J. Sawyers C.L. Goldenring J.R. Novitskiy S.V. Washington M.K. Shi C. Beauchamp R.D. Epithelial Smad4 deletion up-regulates inflammation and promotes inflammation-associated cancer.Cell Mol Gastroenterol Hepatol. 2018; 6: 257-276Abstract Full Text Full Text PDF PubMed Scopus (33) Google Scholar showed a strong inflammatory signature after loss of epithelial Smad4, with deregulated expression of numerous chemokines and cytokines as well as their receptors. From the group of deregulated molecules, C-C motif chemokine 20 (CCL20) was of particular interest because it is known to play a role in IBD as well as in colon cancer. Means et al7Means A.L. Freeman T.J. Zhu J. Woodbury L.G. Marincola-Smith P. Wu C. Meyer A.R. Weaver C.J. Padmanabhan C. An H. Zi J. Wessinger B.C. Chaturvedi R. Brown T.D. Deane N.G. Coffey R.J. Wilson K.T. Smith J.J. Sawyers C.L. Goldenring J.R. Novitskiy S.V. Washington M.K. Shi C. Beauchamp R.D. Epithelial Smad4 deletion up-regulates inflammation and promotes inflammation-associated cancer.Cell Mol Gastroenterol Hepatol. 2018; 6: 257-276Abstract Full Text Full Text PDF PubMed Scopus (33) Google Scholar then used elegant in vitro studies involving conditionally immortalized Smad4fl/fl cell lines as well as rectal cancer–derived human tumoroids to confirm the central role played by SMAD4 in repression of CCL20 gene expression in colonic epithelial cells. In addition, they explored mechanisms by which epithelial colonic TGFβ/BMP signaling, through the SMAD4 intracellular effector, interacts with cytokine and chemokine expression. Again using in vitro models, Means et al7Means A.L. Freeman T.J. Zhu J. Woodbury L.G. Marincola-Smith P. Wu C. Meyer A.R. Weaver C.J. Padmanabhan C. An H. Zi J. Wessinger B.C. Chaturvedi R. Brown T.D. Deane N.G. Coffey R.J. Wilson K.T. Smith J.J. Sawyers C.L. Goldenring J.R. Novitskiy S.V. Washington M.K. Shi C. Beauchamp R.D. Epithelial Smad4 deletion up-regulates inflammation and promotes inflammation-associated cancer.Cell Mol Gastroenterol Hepatol. 2018; 6: 257-276Abstract Full Text Full Text PDF PubMed Scopus (33) Google Scholar showed that TGFβ signaling, as well as BMP signaling, could block the induction of CCL20 in a cell-autonomous manner when used as a prophylactic treatment or after an inflammatory trigger such as tumor necrosis factor, interleukin 1β, or lipopolysaccharides. This study by Means et al7Means A.L. Freeman T.J. Zhu J. Woodbury L.G. Marincola-Smith P. Wu C. Meyer A.R. Weaver C.J. Padmanabhan C. An H. Zi J. Wessinger B.C. Chaturvedi R. Brown T.D. Deane N.G. Coffey R.J. Wilson K.T. Smith J.J. Sawyers C.L. Goldenring J.R. Novitskiy S.V. Washington M.K. Shi C. Beauchamp R.D. Epithelial Smad4 deletion up-regulates inflammation and promotes inflammation-associated cancer.Cell Mol Gastroenterol Hepatol. 2018; 6: 257-276Abstract Full Text Full Text PDF PubMed Scopus (33) Google Scholar provides new insight into the importance of the TGFβ/BMP signaling pathways within the colonic epithelium and its relevance regarding gastrointestinal pathologies such as IBD and CAC. As Means et al7Means A.L. Freeman T.J. Zhu J. Woodbury L.G. Marincola-Smith P. Wu C. Meyer A.R. Weaver C.J. Padmanabhan C. An H. Zi J. Wessinger B.C. Chaturvedi R. Brown T.D. Deane N.G. Coffey R.J. Wilson K.T. Smith J.J. Sawyers C.L. Goldenring J.R. Novitskiy S.V. Washington M.K. Shi C. Beauchamp R.D. Epithelial Smad4 deletion up-regulates inflammation and promotes inflammation-associated cancer.Cell Mol Gastroenterol Hepatol. 2018; 6: 257-276Abstract Full Text Full Text PDF PubMed Scopus (33) Google Scholar showed, loss of Smad4 in the colonic epithelium implicates an important deregulation of cytokine and chemokine expression, thus leading to an increase of professional immune cell infiltration in the colonic submucosa, inevitably modifying the subepithelial microenvironment. How this dysfunctional microenvironment impacts the development of CAC in the long run will need to be investigated in future studies and could lead to translational insight involving regulation of these morphogenetic pathways for the treatment of the disease. Epithelial Smad4 Deletion Up-Regulates Inflammation and Promotes Inflammation-Associated CancerCellular and Molecular Gastroenterology and HepatologyVol. 6Issue 3PreviewChronic inflammation is a predisposing condition for colorectal cancer. Many studies to date have focused on proinflammatory signaling pathways in the colon. Understanding the mechanisms that suppress inflammation, particularly in epithelial cells, is critical for developing therapeutic interventions. Here, we explored the roles of transforming growth factor β (TGFβ) family signaling through SMAD4 in colonic epithelial cells. Full-Text PDF Open Access

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