Intracellular pathways in colorectal carcinogenesis

  • Sasa Badzek
  • Vesna Lesko Kelovic
  • Stjepko Plestina
  • Juraj Prejac
  • Mate Majerovic
  • Goran Augustin
Keywords: colorectal cancer, carcinogenesis


Colorectal cancer is a common and deadly malignant tumor, with 500 000 new cases detected worldwide each year. Colonoscopy with polipectomy is the golden standard for secondary prevention, with 30-40% colorectal cancer incidence reduction in high-risk population. First efforts in primary prevention with selective non-steroidal anti-inflammatory drugs are discouraged by their unexpected toxicity. Better understanding of intracellular signaling pathways responsible for colorectal cancer carcinogenesis, as reviewed in this article, leads to development of new methods for their selective switch off, and thereby prevention of tumor nascence.


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Ferro SA, Cosler LE, Wolff DA, et al. Variation in the cost of treatment for colorectal cancer. Journal of Clinical Oncology, 2006 ASCO Annual Meeting Proceedings Part I. Vol 24, No. 18S (June 20 Supplement), 2006: 3625.

Selby J, Friedman GD, Quesenberry CP, et al. A case-control study of screening sigmoidoscopy and mortality from colorectal cancer. N Engl J Med 1992;326:653-7.

Chan AT. Aspirin, non-steroidal antiinflamatory drugs, and colorectal neoplasia: future challenges in chemoprevention. Cancer Causes Control 2003;14:413-8.

Baron JA, Cole BF, Sandler RS, et al. A randomized trial od aspirin to prevent colorectal adenomas. N Engl J Med 2003;348:891-9.

Sandler RS, Halabi S, Baron JA, et al. A randomized trial of aspirin to prevent colorectal adenomas in patients with previous colorectal cancer. N Engl J Med 2003;348:883-90. (Erratum, N Engl J Med 2003;348:1939.)

Benamouzig R, Deyra J, Martin A, et al. Daily soluble aspirin and prevention of colorectal adenoma recurrence: one-year results of the APACC trial. Gastroenterology 2003;125:328-36.

Brown JR, DuBois RN. COX-2: a molecular target for colorectal cancer prevention. J Clin Oncol 2005;23:2840-55.

Eberhart CE, Coffey RJ, Radhika A, et al. Up-regulation of cyclooxygenase-2 gene expression in human colorectal adenomas and adenocarcinomas. Gastroenterology 1994;107:1183-8.

Zhang H, Sun XF. Overexpression of cyclooxygenase-2 correlates with advanced stages of colorectal cancer. Am J Gastroenterol 2002;97:1037-41.

Soumaoro LT, Uetake H, Higuchi T, et al. Cyclooxygenase-2 expression: a significant prognostic indicator for patients with colorectal cancer. Clin Cancer Res 2004;10:8465-71.

Bertagnoli MM, Eagle CJ, Zauber AG, et al. Celecoxib for the prevention of sporadic colorectal adenomas. N Engl J Med 2006;355:873-4.

Arber N, Eagle CJ, Spicak J, et al. Celecoxib for the prevention of colorectal adenomatous polyps. N Engl J Med 2006;355:885-95.

Baron JA, Sandler RS, Bresalier RS, et al. A randomized trial of rofecoxib for the chemoprevention of colorectal adenomas. Gastroenterology 2006;131:1674-82.

Kopp E, Ghosh S. Inhibition of NF-kappa B by sodium salicylate and aspirin. Science 1994;265:956-9.

Schwenger P, Bellosta P, Vietor I, et al. Sodium salicylate induces apoptosis via p38 mitogen-activated protein kinase but inhibits tumor necrosis factor-induced c-Jun N-terminal kinase/stressactivated protein kinase activation. Proc Natl Acad Sci USA 1997;94:2869-73.

Martinez ME, O'Brien TG, Fultz KE, et al. Pronounced reduction in adenoma recurrence associated with aspirin use and a polymorphism in the ornithine decarboxylase gene. Proc Natl Ac Sci USA 2003;100:7859-64.

Chan AT, Ogino S, Fuchs CS. Aspirin and the risk of colorectal cancer in relation to the expression of COX-2. N Engl J Med 2007;356:2131-42.

Petersen C, Petersen S, Milas L, et al. Enhancement of intrinsic tumor cell radiosensitivity induced by a selective cyclooxygenase-2 inhibitor. Clin Cancer Res 2000;6(6):2513-20.

Nishimura G, Yanoma S, Mizuno H, et al. A selective cyclooxygenase-2 inhibitor supresses tumor growth in nude mouse xenografted with human head and neck squamous carcinoma cells. Jpn J Cancer Res 1999;90(10):1152-62.

Yao R, Rioux N, Castonguay A, et al. Inhibition of COX-2 and induction of apoptosis: two determinants of nonsteroidal anti-inflammatory drugs' chemopreventive afficacies in mouse lung tumorigenesis. Exp Lung Res 2000;26(8):731-42.

Li M, Lotan R, Levin B, et al. Aspirin induction of apoptosis in esophageal cancer: a potential for chemoprevention. Cancer Epidemiol Biomarkers Prev 2000;9(6):545-9.

Grossman EM, Longo WE, Panesar N, et al. The role of cyclooxygenase enzymes in the growth of human gall bladder cancer cells. Carcinogenesis 2000;21(7):1403-9.

Yip-Schneider MT, Sweeney CJ, Jung SH, et al. Cell cycle effects of nonsteroidal anti-inflammatory drugs and enhanced growth inhibition in combination with gemcitabine in pancreatic carcinoma cells. J Pharmacol Exp Ther 2001;298(3):976-85.

Richter M, Weiss M, Weinberger I, et al. Growth inhibition and induction of apoptosis in colorectal tumor cells by cyclooxygenase inhibitors. Carcinogenesis 2001;22(1):17-25.

Nagy JA, Vasile E, Feng D, et al. Vascular permeability factor/vascular endothelial growth factor induces lymphangiogenesis as well as angiogenesis. J Exp Med 2002;196(11):1497-506.

Brehmer B, Biesterfeld S, Jakse G. Expression of matrix metalloproteinases (MMP-2 and -9) and their inhibitors (TIMP-1 and-2) in prostate cancer tissue. Prostate Cancer Prostatic Dis 2003;6(3):217-22.

Fodde R, Smiths R, Clevers H. APC, signal transduction and genetic instability in colorectal cancer. Nat Rev Cancer 2001;1:55-67.

Fearon ER, Vogelstein B. A genetic model for colorectal tumorigenesis. Cell 1990;61:759-67.

Hisamuddin IM, Yang VW. Molecular genetics of colorectal cancer: an overview. Cur Colorectal Cancer Rep 2006;2:53-9.

Lynch HT, de la Chapelle A. Hereditary colorectal cancer. N Engl J Med 2003;348:919-32.

L oeb LA. A mutator phenotype in cancer. Cancer Res 2001;61:3230-9.

Kondo Y, Issa J-PJ. Epigenetic changes in colorectal cancer. Cancer Metastasis Rev 2004;23:29-39.

Shen L, Issa J-PJ. Epigenetics in colorectal cancer. Curr Opin Gastroenterol 2002;18:68-73.

Clevers H. Wnt breakers in colon cancer. Cancer Cell 2004;5:5-6.

Doble BW, Woodget JR. GSK-3: tricks of the trade for a multi-tasking kinase. J Cell Sci 2003;116:1175-86.

Ilyas M. Wnt signaling and the mechanistic basis of tumour developement. J Pathol 2005;205:130-44.

Shtutman M, Zhurinsky J, Simcha I, et al. The cyclin D1 gene is a target of the β-catenin/LEF-1 pathway. Proc Natl Acad Sci USA 1999;96:5522–7.

Wong NACS, Pignatelli M. β-catenin-A linchpin in colorectal carcinogenesis? Am J Pathol 2002;160:389-401.

Howe LR, Subbaramaiah K, Chung WJ, et al. Transcriptional activation of cyclooxygenase-2 in Wnt-1-transformed mouse mammary epithelial cells. Cancer Res 1999;59:1572-7.

Levy L, Neuveut C, Renard CA, et al. Transcriptional activation of interleukin-8 by betacatenin-Tcf4. J Biol Chem 2002;277:42386-93.

Rockman SP, Currie SA, Ciavarella M, et al. Id2 is a target of the β-catenin/T cell factor pathway in colon carcinoma. J Biol Chem 2001;276:45113-9.

Mann B, Gelos M, Siedow A, et al. Target genes of β-catenin/T cellfactor/lymphoid-enhancer-factor signalling in human colorectal carcinomas. Proc Natl Acad Sci USA 1999;96:1603–8.

Willert J, Epping M, Pollack JR, et al. A transcriptional response to Wnt protein in human embryonic carcinoma cells. BMC Dev Biol 2002;2:8.

Dihlmann S, Kloor M, Fallsehr C, et al. Regulation of AKT1 expression by beta-catenin/Tcf/Lef signaling in colorectal cancer cells. Carcinogenesis 2005;26:1503-12.

He T-C, Chan TA,Vogelstein B, et al. PPARγ is an APC-regulated target of Non-steroidal antiinflammatory drugs. Cell 1999;99:335-45.

Conacci-Sorrell ME, Ben-Yedidia T, Shtutman M, et al. Nr-CAM is a target gene of the β-catenin/LEF-1 pathway in melanoma and colon cancer and its expression enhances motility and confers tumorigenesis. Genes Dev 2002;16:2058-72.

Gavert N, Conacci-Sorrell M, Gast D, et al. L1, a novel target of β-catenin signaling, transforms cells and is expressed at the invasive front of colon cancers. J Cell Biol 2005;168:633-42.

Lustig B, Jerchow B, Sachs M, et al. Negative feedback loop of wnt signaling through upregulation of conductin/axin2 in colorectal and liver tumors. Mol Cell Biol 2002;22:1184-93.

Boon EMJ, van der Neut R, van de Wetering M, et al. Wnt signaling regulates expression of the receptor tyrosine kinase Met in colorectal cancer. Cancer Res 2002;62:5126-8.

Battle E, Henderson JT, Beghtel H, et al. β-catenin and TCF mediate cell positioning in the intestinal epithelium by controlling the expression of EphB/Ephrin B. Cell 2002;111:251-63.

Shtutman M, Zhurinsky J, Oren M, et al. PML is a target gene of betacatenin and plakoglobin, and coactivates β-catenin-mediated transcription. Cancer Res 2002;62:5947-54.

Steigerwald K, Behbehani GK, Combs KA, et al. The APC tumor suppressor promotes transcription-independent apoptosis in vitro. Mol Cancer Res 2005;3:78-89.

Roura S, Miravet S, Piedra J, et al. Regulation of E-cadherin/catenin association by tyrosine phosphorylation. J Biol Chem 1999;274:36734-40.

Deng J, Miller SA, Wang H-Y, et al. β-catenin interacts with and inhibits NF-κB in human colon and breast cancer. Cancer Cell 2002;2:323-34.

Kerkhoff E, Rapp UR. Cell cycle targets of Ras/Raf signalling. Oncogene 1998;17:1457-62.

Fujita T, Washio K, Takabatake D, et al. Proteasome inhibitors can alter the signaling pathways and attenuate the P-glycoproteinmediated multidrug resistance. Int J Cancer 2005;117:670-82.

Cardone MH, Roy N, Stennicke HR, et al. Regulation of cell death protease caspase-9 by phosphorylation. Science 1998;282:1318-21.

Aoki M, Jiang H,Vogt PK. Proteasomal degradation of the FoxO1 transcriptional regulator in cells transformed by the P3k and Akt oncoproteins. Proc Natl Acad Sci USA 2004;101:13613-7.

Thomas GV. mTOR and cancer: reason for dancing at the crossroads? Cur Opin Genet Dev 2006;16:78-84.

Cullen PJ, Lockyer PJ. Integration of calcium and Ras signalling. Nature Rev Mol Cell Biol 2002;3:339-48.

Wakefield LM, Roberts AB. TGF-β signaling: positive and negative effects on tumorigenesis. Cur Opin Genet Dev 2002;12: 22-9.

Iglesias M, Frontelo P, Gamallo C, et al. Blockade of Smad4 in transformed keratinocytes containing a Ras oncogene leads to hyperactivation of the Ras-dependent Erk signalling pathway associated with progression to undifferentiated carcinomas. Oncogene 2000;19:4134-45.

Furuhashi M, Yagi K, Yamamoto H, et al. Axin facilitates Smad3 activation in the transforming growth factor β signaling pathway. Mol Cell Biol 2001;21:5132-41.

Labbe E, Letamendia A, Attiasano L. Association of Smads with lymphoid enhancer binding factor 1/T cell-specific factor mediates cooperative signalling by the transforming growth factor-beta and wnt pathways. Proc Natl Acad Sci USA 2000;97:8358-63.

Miyaki M, Iijima T, Konishi M, et al. Higher frequency of Smad4 gene mutation in human colorectal cancer with distant metastasis. Oncogene 1999;18: 3098-103.

Parsons R, Myeroff LL, Liu B, et al. Microsatellite instability and mutations of the transforming growth factor beta type II receptor gene in colorectal cancer. Cancer Res 1995;55:5548-50.

Takaku K, Oshima M, Miyoshi H, et al. Intestinal tumorigenesis in compound mutant mice of both DPC4 (Smad4) and Apc genes. Cell 1998;92:645-56.

Yu J, Zhang L. The transcriptional targets of p53 in apoptosis control. Biochem Biophys Res Com 2005;331:851-8.

Yu J, Zhang L, Hwang PM, et al. Identification and classification of p53-regulated genes. Proc Natl Acad Sci USA 1999;96:14517-22.

Roperch J-P, Lethrone F, Prieur S, et al. SIAH-1 promotes apoptosis and tumor suppression through a network involving the regulation of protein folding, unfolding, and trafficking: identification of common effectors with p53 and p21Waf1. Proc Natl Acad Sci USA 1999;96:8070-3.

Amson RB, Nemani M, Roperch JP, et al. Isolation of 10 differentially expressed cDNAs in p53-induced apoptosis: activation of the vertebrate homologue of the drosophila seven in absentia gene. Proc Natl Acad Sci USA 1996;93:3953-7.

Kohn KW, Pommier Y. Molecular interaction map of the p53 and mdm2 logic elements, which control the off-on switch of p53 in response to DNA damage. Biochem Biophys Res Com 2005;331:816-27.

Liu J, Stevens J, Rote CA, et al. Siah-1 mediates a novel β-catenin degradation pathway linking p53 to the adenomatous polyposis coli protein. Mol Cell 2001;7:927-36.

Nakayama K, Ronai Z. Siah new players in the cellular response to hypoxia. Cell Cycle 2004:3:1345-7.

Vaupel P. The role of hypoxia-induced factors in tumor progression. Oncologist 2004;9(Suppl 5):10-7.

Janne PA, Mayer RJ. Chemoprevention of colorectal cancer. N Engl J Med 2000;342:1960-8.

Hoeller D, Hecker C-M, Dikic I. Ubiquitin and ubiquitin-like proteins in cancer pathogenesis. Nat Rev Cancer 2006;6:776-88.

Amerik AY, Hochstrasser M. Mechanism and function of deubiquitinating enzymes. Biochim Biophys Acta 2004;1695:189-207.

Mani A, Gelmann EP. The ubiquitin-proteasome pathway and its role in cancer. J Clin Oncol 2005;23:4776-89.

Almond JB, Cohen GM. The proteasome: a novel target for cancer chemotherapy. Leukemia 2002;16:433-43.

Ougolkov A, Zhang B, Yamashita K, et al. Associations among β-TrCP, an E3 ubiquitin ligase receptor, β-catenin, and NF-κB in colorectal cancer. J Natl Cancer Inst 2004;96:1161-70.

Ni T, Li W, Zou F. The ubiquitin ligase ability of IAPs regulates apoptosis. IUBMB Life 2005;57:779-85.

Zhu Z, Ramos J, Kampa K, et al. Control of ASPP2/53BP2L protein levels by proteasomal degradation modulates p53 apoptotic function. J Biol Chem 2005;280:34473-80.

Friedman J, Xue D. To live or die by the sword: the regulation of apoptosis by the proteasome. Dev Cell 2004;7:460-1.

Jackson PK. Linking tumor suppression, DNA damage and the anaphase-promoting complex. Trends Cell Biol 2004;14:331-4.

Araki Y, Okamura S, Perwez Hussain S, et al. Regulation of cyclooxygenase-2 expression by the Wnt and Ras pathways. Cancer Res 2003;63:728-34.

Chun K-S, Surh Y-J. Signal transduction pathways regulating cyclooxygenase-2 expression: potential molecular targets for chemoprevention. Biochem Pharmacol 2004;68:1089-100.

Brown JR, DuBois RN. COX-2: a molecular target for colorectal cancer prevention. J Clin Oncol 2005;23:2840-55.

Castellone MD, Teramoto H, Gutkind JS. Cyclooxygenase-2 and colorectal cancer chemoprevention: the beta-catenin connection. Cancer Res 2006;66:11085-8.

Syeda F, Grosjean J, Houliston RA, et al. Cyclooxygenase-2 induction and prostacyclin release by protease-activated receptors in endothelial cells requires co-operation between mitogen-activated protein kinase and NF-κB pathways. J Biol Chem 2006;281:11792-804.

Matsuura H, Sakaue M, Subbaramaiah K, et al. Regulation of Cyclooxygenase-2 by interferon γ and transforming growth factor α in normal human epidermal keratinocytes and squamous carcinoma cells. J BiolChem 1999;274:29138-48.

Yan Z, Subbaramaiah K, Camilli T, et al. Benzo[α]pyrene induces the transcription of cyclooxygenase-2 in vascular smooth muscle cells. J Biol Chem 2000;275:4949-55.

Duque J, Diaz-Munoz MD, Fresno M, et al. Up-regulation of cyclooxygenase-2 by interleukin-1β in colon carcinoma cells. Cell Signal 2006;18:1262-9.

Yamaguchi K, Lantowski A, Dannenberg AJ, et al. Histone deacetylase inhibitors suppress the induction of c-Jun and its target genes including Cox-2. J Biol Chem 2005;280:32569-77.

Howe LR, Crawford HC, Subbaramaiah K, et al. PEA3 is up-regulated in response to Wnt1 and activates the expression of cyclooxygenase-2. J Biol Chem 2001;276:20108-15.

Meade EA, McIntyre TM, Zimmerman GA, et al. Peroxisome Proliferators enhance Cyclooxygenase-2 expression in epithelial cells. J Biol Chem 1999;274:8328-34.

Dixon DA, Balch GC, Kedersha N, et al. Regulation of cyclooxygenase-2 expression by the translational silencer TIA-1. J Exp Med 2003;198:475-81.

Dixon DA, Kaplan CD, McIntyre TM, et al. Post-transcriptional control of cyclooxygenase-2 gene expression. J Biol Chem.. 2000;275:11750-7.

Duque J, Fresno M, Iniguez MA. Expression and function of the Nuclear Factor of Activated T cells in colon carcinoma cells. J Biol Chem 2005;280:8686-93.

Smith WL, Garavito RM, DeWitt DL. Prostaglandin endoperoxide H synthases (Cyclooxygenases)-1 and -2. J Biol Chem 1996;271:33157-60.

Warner TD, Mitchell JA. Nonsteroidal anti-inflammatory drugs inhibiting prostanoid efflux: as easy as ABC? Proc Natl Acad Sci USA 2003;100:9108-10.

Cutler NS, Graves-Deal R, LaFleur BJ, et al. Stromal production of prostacyclin confers an antiapoptotic effect to colonic epithelial cells. Cancer Res 2003;63:1748-51.

Ko SC, Chapple KS, Hawcroft G, et al. Paracrine cyclooxygenase-2-mediated signalling by macrophages promotes tumorigenic progression of intestinal epithelial cells. Oncogene 2002:21:7175-86.

Narumiya S, FitzGerald GA. Genetic and pharmacological analysis of prostanoid receptor function. J Clin Invest 2001;108:25-30.

Sheng H, Shao J, Washington MK, et al. Prostaglandin E2 increases growth and motility of colorectal carcinoma cells. J Biol Chem 2001;276:18075-81.

Buchanan FG,Wang D, Bargiacchi F, et al. Prostaglandin E2 regulates cell migration via the intracellular activation of the epidermal growth factor receptor. J Biol Chem 2003;278:35451-7.

Pai R, Soreghan B, Szabo I, et al. Prostaglandin E2 transactivates EGF receptor: a novel mechanism for promoting colon cancer growth and gastrointestinal hypertrophy. Nat Med 2002;8:289-93.

Castellone MD, Teramoto H, Williams BO, et al. Prostaglandin E2 promotes colon cancer cell growth through a Gs-axin-beta-catenin signalling axis. Science 2005;310:1504-10.

Clevers H. Colon cancer- Understanding how NSAIDs work. N Engl J Med 2006;354:761-3.

Beyer M, Schultze JL. Regulatory T cells in cancer. Blood 2006;108:804-11.

Hirabayashi T, Murayama T, Shimizu T. Regulatory mechanism and physiological role of cytosolic phospholipase A2. Biol Pharm Bull 2004;27:1168-73.

Taketo MM, Sonoshita M. Phospholipase A2 and apoptosis. Biochim Biophys Acta 2002;1585:72-6.

Jayadev S, Hayter HL, Andrieu N, et al. Phospholipase A2 is necessary for Tumor Necrosis Factor α-induced ceramide generation in L929 cells. J Biol Chem 1997;272:17196-203.

Cao Y, Dave KB, Doan TP, et al. Fatty acid CoA ligase 4 is up-regulated in colon adenocarcinoma. Cancer Res 2001;61:8429-34.

Sung YK, Hwang SY, Park MK, et al. Fatty acid-CoA ligase 4 is overexpressed in human hepatocellular carcinoma. Cancer Sci 2003;94:421-4.

Ikawa H, Kamitani H, Calvo BF, et al. Expression of 15-lipoxygenase-1 in human colorectal cancer. Cancer Res. 1999;59:360-6.

How to Cite
Badzek S, Lesko Kelovic V, Plestina S, Prejac J, Majerovic M, Augustin G. Intracellular pathways in colorectal carcinogenesis. Acta Chir. Croat. [Internet]. 2012Mar.15 [cited 2021Jan.24];9(1):25-4. Available from:

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