Understanding and Targeting the Colon Cancer Pathogenesis
A Molecular Perspective
DOI:
https://doi.org/10.1590/s2175-97902022e20354Keywords:
Hedgehog, WNT/β-catenin, Notch, Colon cancer, Molecular targetsAbstract
Colorectal cancer (CRC) one of the leading cause of cancer-related deaths worldwide. With the presently available knowledge on CRC, it is understood that the underlying is a complex process. The complexity of CRC lies in aberrant activation of several cellular signaling pathways that lead to activation and progression of CRC. In this context, recent studies have pointed towards the role of developmental pathways like; hedgehog (HH), wingless-related integration site (WNT/β-catenin) and Notch pathways that play a crucial role in maintenance and homeostasis of colon epithelium. Moreover, the deregulation of these signaling pathways has also been associated with the pathogenesis of CRC. Therefore, in the search for better therapeutic options, these pathways have emerged as potential targets. The present review attempts to highlight the role of HH, WNT/β-catenin and Notch pathways in colon carcinogenesis.
Downloads
References
Alteri R, Bandi P, Brooks D, Cokkinides V, Doroshenk M, Gansler T, et al. Colorectal cancer facts & figures 2011-2013. Atlanta: American Cancer Society. 2011.
Alvarez-Medina R, Cayuso J, Okubo T, Takada S, Martí E. Wnt canonical pathway restricts graded Shh/Gli patterning activity through the regulation of Gli3 expression. Development. 2008;135(2):237-247.
Arnold M, Sierra MS, Laversanne M, Soerjomataram I, Jemal A, Bray F. Global patterns and trends in colorectal cancer incidence and mortality. Gut. 2017;66(4):683-691.
Axelrod JD, Matsuno K, Artavanis-Tsakonas S, Perrimon N. Interaction between Wingless and Notch signaling pathways mediated by dishevelled. Science. 1996;271(5257):1826-1832.
Bertrand FE. The cross-talk of NOTCH and GSK-3 signaling in colon and other cancers. Biochimica et Biophysica Acta (BBA) - Molecular Cell Research. 2020;1867(9):118738.
Bertrand FE, Angus CW, Partis WJ, Sigounas G. Development al pathways in colon cancer: crosstalk between WNT, BMP, Hedgehog and Notch. Cell cycle (Georgetown, Tex.). 2012;11(23):4344-4351.
Bertrand FE, Angus CW, Partis WJ, Sigounas G. Development al pathways in colon cancer: crosstalk between WNT, BMP, Hedgehog and Notch. Cell Cycle. 2012;11(23):4344-4351.
Bienz M, Clevers H. Linking colorectal cancer to Wnt signaling. Cell. 2000;103(2):311-320.
Burgess AW, Faux MC, Layton MJ, Ramsay RG. Wnt signaling and colon tumorigenesis--a view from the periphery. Exp Cell Res. 2011;317(19):2748-2758.
Carpenter D, Stone DM, Brush J, Ryan A, Armanini M, Frantz G, et al. Characterization of two patched receptors for the vertebrate hedgehog protein family. Proc Natl Acad Sci U S A. 1998;95(23):13630-13634.
Cavallo RA, Cox RT, Moline MM, Roose J, Polevoy GA, Clevers H, et al. Drosophila Tcf and Groucho interact to repress Wingless signalling activity. Nature. 1998;395(6702):604-608.
Chen X, Stoeck A, Lee SJ, Shih Ie M, Wang MM, Wang TL. Jagged1 expression regulated by Notch3 and Wnt/β- catenin signaling pathways in ovarian cancer. Oncotarget. 2010;1(3):210-218.
Cheng SY, Bishop JM. Suppressor of Fused represses Gli-mediated transcription by recruiting the SAP18- mSin3 corepressor complex. Proc Natl Acad Sci U S A . 2002;99(8):5442-5447.
Clevers H. Wnt/β-Catenin Signaling in Development and Disease. Cell . 2006; 127(3): 469-480.
Clevers H, Nusse R. Wnt/β-catenin signaling and disease. Cell . 2012;149(6):1192-1205.
Das PK, Islam F, Lam AK. The Roles of Cancer Stem Cell s and Therapy Resistance in Colorectal Carcinoma. Cells. 2020;9(6):1392.
Deng W, Vanderbilt DB, Lin CC, Martin KH, Brundage KM, Ruppert JM. SOX9 inhibits β-TrCP-mediated protein degradation to promote nuclear GLI1 expression and cancer stem cell properties. J Cell Sci. 2015;128(6):1123-1138.
Ehtesham M, Sarangi A, Valadez JG, Chanthaphaychith S, Becher MW, Abel TW, et al. Ligand-dependent activation of the hedgehog pathway in glioma progenitor cells. Oncogene. 2007;26(39):5752-5761.
Espinosa L, Inglés-Esteve J, Aguilera C, Bigas A. Phosphorylation by glycogen synthase kinase-3 beta down- regulates Notch activity, a link for Notch and Wnt pathways. J Biol Chem. 2003;278(34):32227-32235.
Estrach S, Ambler CA, Lo Celso C, Hozumi K, Watt FM. Jagged 1 is a beta-catenin target gene required for ectopic hair follicle formation in adult epidermis. Development . 2006;133(22):4427-4438.
Favoriti P, Carbone G, Greco M, Pirozzi F, Pirozzi RE, Corcione F. Worldwide burden of colorectal cancer: a review. Updates Surg. 2016;68(1):7-11.
Ferlay J, Colombet M, Soerjomataram I, Mathers C, Parkin DM, Piñeros M, et al. Estimating the global cancer incidence and mortality in 2018: GLOBOCAN sources and methods. Int J Cancer. 2019;144(8):1941-1953.
Fiaschi M, Rozell B, Bergström A, Toftgård R. Development of mammary tumors by conditional expression of GLI1. Cancer Res. 2009;69(11):4810-4817.
Fodde R, Brabletz T. Wnt/beta-catenin signaling in cancer stemness and malignant behavior. Curr Opin Cell Biol. 2007;19(2):150-158.
Fre S, Pallavi SK, Huyghe M, Laé M, Janssen KP, Robine S, et al. Notch and Wnt signals cooperatively control cell proliferation and tumorigenesis in the intestine. Proc Natl Acad Sci U S A . 2009;106(15):6309-6314.
Geissler K, Zach O. Pathways involved in Drosophila and human cancer development: the Notch, Hedgehog, Wingless, Runt, and Trithorax pathway. Ann Hematol. 2012;91(5):645- 669.
Hall PA, Coates PJ, Ansari B, Hopwood D. Regulation of cell number in the mammalian gastrointestinal tract: the importance of apoptosis. J Cell Sci. 1994;107(Pt 12):3569- 3577.
Heath JP. Epithelial cell migration in the intestine. Cell Biol Int. 1996;20(2):139-146.
Heretsch P, Tzagkaroulaki L, Giannis A. Modulators of the hedgehog signaling pathway. Bioorg Med Chem. 2010;18(18):6613-6624.
Huang R, Wang G, Song Y, Tang Q, You Q, Liu Z, et al. Colorectal cancer stem cell and chemoresistant colorectal cancer cell phenotypes and increased sensitivity to Notch pathway inhibitor. Mol Med Rep. 2015;12(2):2417-2424.
Hui CC, Angers S. Gli proteins in development and disease. Annu Rev Cell Dev Biol. 2011;27:513-537.
Jin YH, Kim H, Oh M, Ki H, Kim K. Regulation of Notch1/ NICD and Hes1 expressions by GSK-3α/β. Mol Cells. 2009;27(1):15-19.
Joo WD, Visintin I, Mor G. Targeted cancer therapy--are the days of systemic chemotherapy numbered? Maturitas. 2013;76(4):308-314.
Kasper M, Regl G, Frischauf AM, Aberger F. GLI transcription factors: mediators of oncogenic Hedgehog signalling. Eur J Cancer. 2006;42(4):437-445.
Katoh Y, Katoh M. Hedgehog target genes: mechanisms of carcinogenesis induced by aberrant hedgehog signaling activation. Curr Mol Med. 2009;9(7):873-886.
Khan I, Mahfooz S, Saeed M, Ahmad I, Ansari IA. Andrographolide Inhibits Proliferation of Colon Cancer SW- 480 Cell s via Downregulating Notch Signaling Pathway. Anticancer Agents Med Chem. 2020.
Kim TG, Hwi KK, Hung CS. Morphological and biochemical changes of andrographolide-induced cell death in human prostatic adenocarcinoma PC-3 cells. In Vivo. 2005;19(3):551- 557.
Kogerman P, Grimm T, Kogerman L, Krause D, Undén AB, Sandstedt B, et al. Mammalian suppressor-of-fused modulates nuclear-cytoplasmic shuttling of Gli-1. Nat Cell Biol. 1999;1(5):312-319.
Kuhnert F, Davis CR, Wang HT, Chu P, Lee M, Yuan J, et al. Essential requirement for Wnt signaling in proliferation of adult small intestine and colon revealed by adenoviral expression of Dickkopf-1. Proc Natl Acad Sci U S A . 2004;101(1):266-271.
Kwon C, Cheng P, King IN, Andersen P, Shenje L, Nigam V, et al. Notch post-translationally regulates β-catenin protein in stem and progenitor cells. Nat Cell Biol. 2011;13(10):1244- 1251.
Lindemann RK. Stroma-Initiated Hedgehog Signaling Takes Center Stage in B-Cell Lymphoma. Cancer Res earch. 2008;68(4):961-964.
Liu H, Gu D, Xie J. Clinical implications of hedgehog signaling pathway inhibitors. Chin J Cancer. 2011;30(1):13-26.
Makinodan E, Marneros AG. Protein kinase A activation inhibits oncogenic Sonic hedgehog signalling and suppresses basal cell carcinoma of the skin. Exp Dermatol. 2012;21(11):847-852.
Malanchi I, Peinado H, Kassen D, Hussenet T, Metzger D, Chambon P, et al. Cutaneous cancer stem cell maintenance is dependent on beta-catenin signalling. Nature . 2008;452(7187):650-653.
Mao J, Maye P, Kogerman P, Tejedor FJ, Toftgard R, Xie W, et al. Regulation of Gli1 transcriptional activity in the nucleus by Dyrk1. J Biol Chem. 2002;277(38):35156-35161.
Mazumdar T, DeVecchio J, Shi T, Jones J, Agyeman A, Houghton JA. Hedgehog signaling drives cellular survival in human colon carcinoma cells. Cancer Res . 2011;71(3):1092- 1102.
Medema JP, Vermeulen L. Microenvironmental regulation of stem cells in intestinal homeostasis and cancer. Nature . 2011;474(7351):318-326.
Meng RD, Shelton CC, Li YM, Qin LX, Notterman D, Paty PB, et al. gamma-Secretase inhibitors abrogate oxaliplatin- induced activation of the Notch-1 signaling pathway in colon cancer cells resulting in enhanced chemosensitivity. Cancer Res . 2009;69(2):573-582.
Miyamoto S, Rosenberg DW. Role of Notch signaling in colon homeostasis and carcinogenesis. Cancer Sci. 2011;102(11):1938-1942.
Mohandas KM. Colorectal cancer in India: controversies, enigmas and primary prevention. Indian J Gastroenterol. 2011; 0(1):3-6.
Morin PJ, Sparks AB, Korinek V, Barker N, Clevers H, Vogelstein B, et al. Activation of beta-catenin-Tcf signaling in colon cancer by mutations in beta-catenin or APC. Science . 1997;275(5307):1787-1790.
Nguyen LH, Goel A, Chung DC. Pathways of Colorectal Carcinogenesis. Gastroenterology. 2020;158(2):291-302.
Palle K, Mani C, Tripathi K, Athar M. Aberrant GLI1 Activation in DNA Damage Response, Carcinogenesis and Chemoresistance. Cancers. 2015;7(4):2330-2351.
Pandurangan AK, Divya T, Kumar K, Dineshbabu V, Velavan B, Sudhandiran G. Colorectal carcinogenesis: Insights into the cell death and signal transduction pathways: A review. World J Gastrointest Oncol. 2018;10(9):244-259.
Park S, Jee SH (2018). Epidemiology of Colorectal Cancer in Asia-Pacific Region. Surgical Treatment of Colorectal Cancer: Asian Perspectives on Optimization and Standardization. N. K. Kim, K. Sugihara and J.-T. Liang. Singapore, Springer Singapore: 3-10.
Pelullo M, Zema S, Nardozza F, Checquolo S, Screpanti I, Bellavia D. Wnt, Notch, and TGF-β Pathways Impinge on Hedgehog Signaling Complexity: An Open Window on Cancer. Front Genet. 2019;10:711-711.
Pezzuto JM. Natural Compounds in Cancer Therapy. John Boik, Oregon Medical Press, Princeton, MN, 2001, $32.00 (ISBN 0-9648280-1-4). Pharm Biol. 2002;40(1):79-79.
Qiao L, Wong BC. Role of Notch signaling in colorectal cancer. Carcinogenesis. 2009;30(12):1979-1986.
Rahnama F, Toftgård R, Zaphiropoulos PG. Distinct roles of PTCH2 splice variants in Hedgehog signalling. Biochem J. 2004;378(Pt 2):325-334.
Rajurkar M, De Jesus-Monge WE, Driscoll DR, Appleman VA, Huang H, Cotton JL, et al. The activity of Gli transcription factors is essential for Kras-induced pancreatic tumorigenesis. Proc Natl Acad Sci U S A . 2012;109(17):E1038- 1047.
Reedijk M, Odorcic S, Zhang H, Chetty R, Tennert C, Dickson BC, et al. Activation of Notch signaling in human colon adenocarcinoma. Int J Oncol. 2008;33(6):1223-1229.
Ricci-Vitiani L, Pagliuca A, Palio E, Zeuner A, De Maria R. Colon cancer stem cells. Gut . 2008;57(4):538-548.
Riccio O, van Gijn ME, Bezdek AC, Pellegrinet L, van Es JH, Zimber-Strobl U, et al. Loss of intestinal crypt progenitor cells owing to inactivation of both Notch1 and Notch2 is accompanied by derepression of CDK inhibitors p27Kip1 and p57Kip2. EMBO Rep. 2008;9(4):377-383.
Roose J, Molenaar M, Peterson J, Hurenkamp J, Brantjes H, Moerer P, et al. The Xenopus Wnt effector XTcf-3 interacts with Groucho-related transcriptional repressors. Nature . 1998;395(6702):608-612.
Ruiz i Altaba A. Gli proteins encode context-dependent positive and negative functions: implications for development and disease. Development . 1999;126(14):3205-3216.
Sang L, Roberts JM, Coller HA. Hijacking HES1: how tumors co-opt the anti-differentiation strategies of quiescent cells. Trends Mol Med. 2010;16(1):17-26.
Sauer B. Inducible gene targeting in mice using the Cre/lox system. Methods. 1998;14(4):381-392.
Schröder N, Gossler A. Expression of Notch pathway components in fetal and adult mouse small intestine. Gene Expr Patterns. 2002;2(3-4):247-250.
Sheng T, Chi S, Zhang X, Xie J. Regulation of Gli1 localization by the cAMP/protein kinase A signaling axis through a site near the nuclear localization signal. J Biol Chem. 2006;281(1):9-12.
Shenoy AK, Fisher RC, Butterworth EA, Pi L, Chang LJ, Appelman HD, et al. Transition from colitis to cancer: high Wnt activity sustains the tumor-initiating potential of colon cancer stem cell precursors. Cancer Res . 2012;72(19):5091-5100.
Singh S, Mishra A, Bharti S, Tiwari V, Singh J, Parul, et al. Glycogen Synthase Kinase-3β Regulates Equilibrium Between Neurogenesis and Gliogenesis in Rat Model of Parkinson’s Disease: a Crosstalk with Wnt and Notch Signaling. Mol Neurobiol. 2018;55(8):6500-6517.
Stecca B, Ruiz i Altaba A. A GLI1-p53 inhibitory loop controls neural stem cell and tumour cell numbers. The EMBO journal. 2009;28(6):663-676.
Takebe N, Ivy SP. Controversies in cancer stem cells: targeting embryonic signaling pathways. Clin Cancer Res . 2010;16(12):3106-3112.
Usui T, Sakurai M, Umata K, Elbadawy M, Ohama T, Yamawaki H, et al. Hedgehog Signals Mediate Anti-Cancer Drug Resistance in Three-Dimensional Primary Colorectal Cancer Organoid Culture. Int J Mol Sci. 2018;19(4):1098.
van den Brink GR, Bleuming SA, Hardwick JC, Schepman BL, Offerhaus GJ, Keller JJ, et al. Indian Hedgehog is an antagonist of Wnt signaling in colonic epithelial cell differentiation. Nat Genet. 2004;36(3):277-282.
van Es JH, Jay P, Gregorieff A, van Gijn ME, Jonkheer S, Hatzis P, et al. Wnt signalling induces maturation of Paneth cells in intestinal crypts. Nat Cell Biol. 2005;7(4):381-386.
Varjosalo M, Taipale J. Hedgehog: functions and mechanisms. Genes Dev. 2008;22(18):2454-2472.
Varnat F, Zacchetti G, Ruiz i Altaba A. Hedgehog pathway activity is required for the lethality and intestinal phenotypes of mice with hyperactive Wnt signaling. Mech Dev. 2010;127(1):73-81.
Vieira NM, Elvers I, Alexander MS, Moreira YB, Eran A, Gomes JP, et al. Jagged 1 Rescues the Duchenne Muscular Dystrophy Phenotype. Cell . 2015;163(5):1204-1213.
Wall DS, Mears AJ, McNeill B, Mazerolle C, Thurig S, Wang Y, et al. Progenitor cell proliferation in the retina is dependent on Notch-independent Sonic hedgehog/Hes1 activity. J Cell Biol. 2009;184(1):101-112.
Wall DS, Wallace VA. Hedgehog to Hes1: The heist of a Notch target. Cell Cycle. 2009;8(9):1301-1302.
Watt FM. Unexpected Hedgehog-Wnt interactions in epithelial differentiation. Trends Mol Med . 2004;10(12):577- 580.
Yang L, Xie G, Fan Q, Xie J. Activation of the hedgehog- signaling pathway in human cancer and the clinical implications. Oncogene. 2010;29(4):469-481.
Yeung TM, Gandhi SC, Wilding JL, Muschel R, Bodmer WF. Cancer stem cells from colorectal cancer-derived cell lines. Proc Natl Acad Sci U S A . 2010;107(8):3722-3727.
Yoon JW, Lamm M, Iannaccone S, Higashiyama N, Leong KF, Iannaccone P, et al. p53 modulates the activity of the GLI1 oncogene through interactions with the shared coactivator TAF9. DNA Repair (Amst). 2015;34:9-17.
Yoshikawa K, Shimada M, Miyamoto H, Higashijima J, Miyatani T, Nishioka M, et al. Sonic hedgehog relates to colorectal carcinogenesis. J Gastroenterol. 2009;44(11):1113- 1117.
Zagouras P, Stifani S, Blaumueller CM, Carcangiu ML, Artavanis-Tsakonas S. Alterations in Notch signaling in neoplastic lesions of the human cervix. Proc Natl Acad Sci U S A . 1995;92(14):6414-6418.
Zheng L, Conner SD. Glycogen synthase kinase 3β inhibition enhances Notch1 recycling. Mol Biol Cell . 2018;29(4):389- 395.
Downloads
Published
Issue
Section
License
Copyright (c) 2022 Brazilian Journal of Pharmaceutical Sciences
This work is licensed under a Creative Commons Attribution 4.0 International License.
All content of the journal, except where identified, is licensed under a Creative Commons attribution-type BY.
The on line journal has open and free access.
