Abstract
Background
Cyclooxygenase (COX) is the rate-limiting enzyme in the synthesis of prostaglandins. It exists in two isoforms: COX-1 which is constitutively expressed and COX-2 which is an inducible form activated by a variety of cytokines during inflammation.
Discussion
Interest in this enzyme arose in the early 1990s when, following epidemiological studies, aspirin (which is a COX inhibitor) was found to reduce the risk of colorectal cancer. Since then various studies to decipher the mechanisms by which COX reduces the development of colorectal cancer have been undertaken. One of the mechanisms being studied is its role in the angiogenesis of colorectal cancer. Angiogenesis of its own has been well established as a key factor in the development of tumours. Agents that specifically inhibit COX-2 are now in clinical development and have been licensed to be used in patients with familial adenomatosis polyposis.
Conclusion
What needs to be determined is whether the antiangiogenic effects of COX-2 inhibitors can be used in the prevention and/or treatment of colorectal cancer and its metastases.
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References
Huang A, McCall JM, Weston MD, Mathur P, Quinn H, Henderson DC, et al (2002) Phase I study of percutaneous cryotherapy for colorectal liver metastasis. Br J Surg 89:303–310
Fosslien E (2001) Review: Molecular pathology of cyclooxygenase-2 in cancer-induced angiogenesis. Ann Clin Lab Sci 31:325–348
Le Querrec A, Duval D, Tobelem G (1993) Tumour angiogenesis. Baillieres Clin Haematol 6:711–730
Eberhart CE, Coffey RJ, Radhika A, Giardiello FM, Ferrenbach S, DuBois RN (1994) Up-regulation of cyclooxygenase 2 gene expression in human colorectal adenomas and adenocarcinomas. Gastroenterology 107:1183–1188
Masunaga R, Kohno H, Dhar DK, Ohno S, Shibakita M, Kinugasa S, et al (2000) Cyclooxygenase-2 expression correlates with tumor neovascularization and prognosis in human colorectal carcinoma patients. Clin Cancer Res 6:4064–4068
Sawaoka H, Tsuji S, Tsujii M, Gunawan ES, Sasaki Y, Kawano S, et al (1999) Cyclooxygenase inhibitors suppress angiogenesis and reduce tumor growth in vivo. Lab Invest 79:1469–1477
Giovannucci E, Rimm EB, Stampfer MJ, Colditz GA, Ascherio A, Willett WC (1994) Aspirin use and the risk for colorectal cancer and adenoma in male health professionals. Ann Intern Med 121:241–2416
Giovannucci E, Egan KM, Hunter DJ, Stampfer MJ, Colditz GA, Willett WC, et al (1995) Aspirin and the risk of colorectal cancer in women. N Engl J Med 333:609–614
Smalley WE, DuBois RN (1997) Colorectal cancer and nonsteroidal anti-inflammatory drugs. Adv Pharmacol 39:1–20
Thun MJ, Namboodiri MM, Heath CW Jr (1991) Aspirin use and reduced risk of fatal colon cancer. N Engl J Med 325:1593–1596
Thun MJ, Namboodiri MM, Calle EE, Flanders WD, Heath CW Jr (1993) Aspirin use and risk of fatal cancer. Cancer Res 53:1322–1327
DuBois RN (2000) Review article: cyclooxygenase-a target for colon cancer prevention. Aliment Pharmacol Ther 14 [Suppl 1]:64–67
Chen WS, Wei SJ, Liu JM, Hsiao M, Kou-Lin J, Yang WK (2001) Tumor invasiveness and liver metastasis of colon cancer cells correlated with cyclooxygenase-2 (COX-2) expression and inhibited by a COX-2-selective inhibitor, etodolac. Int J Cancer 91:894–899
Reddy BS, Hirose Y, Lubet R, Steele V, Kelloff G, Paulson S, et al (2000) Chemoprevention of colon cancer by specific cyclooxygenase-2 inhibitor, celecoxib, administered during different stages of carcinogenesis. Cancer Res 60:293–297
Folkman J (1971) Tumor angiogenesis: therapeutic implications. N Engl J Med 285:1182–1186
Gately S (2000) The contributions of cyclooxygenase-2 to tumor angiogenesis. Cancer Metastasis Rev 19:19–27
Li Z, Shimada Y, Uchida S, Maeda M, Kawabe A, Mori A, et al (2000) TGF-alpha as well as VEGF, PD-ECGF and bFGF contribute to angiogenesis of esophageal squamous cell carcinoma. Int J Oncol 17:453–460
Matsushita M, Matsuzaki K, Date M, Watanabe T, Shibano K, Nakagawa T, et al (1999) Down-regulation of TGF-beta receptors in human colorectal cancer: implications for cancer development. Br J Cancer 80:194–205
Xiong B, Gong LL, Zhang F, Hu MB, Yuan HY (2002) TGF beta (1) expression and angiogenesis in colorectal cancer tissue. World J Gastroenterol 8:496–498
Schulze-Osthoff K, Risau W, Vollmer E, Sorg C (1990) In situ detection of basic fibroblast growth factor by highly specific antibodies. Am J Pathol 137:85–92
Lopez-Ocejo O, Viloria-Petit A, Bequet-Romero M, Mukhopadhyay D, Rak J, Kerbel RS (2000) Oncogenes and tumor angiogenesis: the HPV-16 E6 oncoprotein activates the vascular endothelial growth factor (VEGF) gene promoter in a p53 independent manner. Oncogene 19:4611–4620
Vane JR, Botting RMr (2001) Therapeutic roles of selective COX-2 inhibitors. Harvey, London
Trifan OC, Smith RM, Thompson BD, Hla T (1999) Overexpression of cyclooxygenase-2 induces cell cycle arrest. Evidence for a prostaglandin-independent mechanism. J Biol Chem 274:34141–34147
Luk GD (1996) Prevention of gastrointestinal cancer-the potential role of NSAIDs in colorectal cancer. Schweiz Med Wochenschr 126:801–812
Kutchera W, Jones DA, Matsunami N, Groden J, McIntyre TM, Zimmerman GA, et al (1996) Prostaglandin H synthase 2 is expressed abnormally in human colon cancer: evidence for a transcriptional effect. Proc Natl Acad Sci U S A 93:4816–8620
Gustafson-Svard C, Lilja I, Hallbook O, Sjodahl R (1996) Cyclooxygenase-1 and cyclooxygenase-2 gene expression in human colorectal adenocarcinomas and in azoxymethane induced colonic tumours in rats. Gut 38:79–84
DuBois RN, Shao J, Tsujii M, Sheng H, Beauchamp RD (1996) G1 delay in cells overexpressing prostaglandin endoperoxide synthase-2. Cancer Res 56:733–737
Sano H, Kawahito Y, Wilder RL, Hashiramoto A, Mukai S, Asai K, et al (1995) Expression of cyclooxygenase-1 and −2 in human colorectal cancer. Cancer Res 55:3785–9378
Sheng H, Shao J, Kirkland SC, Isakson P, Coffey RJ, Morrow J, et al (1997) Inhibition of human colon cancer cell growth by selective inhibition of cyclooxygenase-2. J Clin Invest 99:2254–2259
Tsujii M, DuBois RN (1995) Alterations in cellular adhesion and apoptosis in epithelial cells overexpressing prostaglandin endoperoxide synthase 2. Cell 83:493–501
Crew TE, Elder DJ, Paraskeva C (2000) A cyclooxygenase-2 (COX-2) selective non-steroidal anti-inflammatory drug enhances the growth inhibitory effect of butyrate in colorectal carcinoma cells expressing COX-2 protein: regulation of COX-2 by butyrate. Carcinogenesis 21:69–77
Sheng H, Shao J, Morrow JD, Beauchamp RD, DuBois RN (1998) Modulation of apoptosis and Bcl-2 expression by prostaglandin E2 in human colon cancer cells. Cancer Res 58:362–636
Li M, Wu X, Xu XC (2001) Induction of apoptosis in colon cancer cells by cyclooxygenase-2 inhibitor NS398 through a cytochrome c-dependent pathway. Clin Cancer Res 7:1010–1016
Elder DJ, Halton DE, Crew TE, Paraskeva C (2000) Apoptosis induction and cyclooxygenase-2 regulation in human colorectal adenoma and carcinoma cell lines by the cyclooxygenase-2-selective non-steroidal anti-inflammatory drug NS-398. Int J Cancer 86:553–560
Richter M, Weiss M, Weinberger I, Furstenberger G, Marian B (2001) Growth inhibition and induction of apoptosis in colorectal tumor cells by cyclooxygenase inhibitors. Carcinogenesis 22:17–25
Erickson BA, Longo WE, Panesar N, Mazuski JE, Kaminski DL (1999) The effect of selective cyclooxygenase inhibitors on intestinal epithelial cell mitogenesis. J Surg Res 81:101–107
Fukutake M, Nakatsugi S, Isoi T, Takahashi M, Ohta T, Mamiya S, et al (1998) Suppressive effects of nimesulide, a selective inhibitor of cyclooxygenase-2, on azoxymethane-induced colon carcinogenesis in mice. Carcinogenesis 19:1939–19342
Ichikawa Y, Ishikawa T, Tanaka K, Togo S, Shimada H (2001) [Extracellular matrix degradation enzymes: important factors in liver metastasis of colorectal cancer and good targets for anticancer metastatic therapy]. Nippon Geka Gakkai Zasshi 102:376–380
Tsujii M, Kawano S, DuBois RN (1997) Cyclooxygenase-2 expression in human colon cancer cells increases metastatic potential. Proc Natl Acad Sci U S A 94:3336–3340
Masferrer JL, Leahy KM, Koki AT, Zweifel BS, Settle SL, Woerner BM, et al (2000) Antiangiogenic and antitumor activities of cyclooxygenase-2 inhibitors. Cancer Res 60:1306–1311
Hao X, Bishop AE, Wallace M, Wang H, Willcocks TC, Maclouf J, et al (1999) Early expression of cyclooxygenase-2 during sporadic colorectal carcinogenesis. J Pathol 187:295–301
Zhang H, Sun XF (2002) Overexpression of cyclooxygenase-2 correlates with advanced stages of colorectal cancer. Am J Gastroenterol 97:1037–1041
Tsujii M, Kawano S, Tsuji S, Sawaoka H, Hori M, DuBois RN (1998) Cyclooxygenase regulates angiogenesis induced by colon cancer cells. Cell 93:705–716
Masferrer JL, Koki A, Seibert K (1999) COX-2 inhibitors. A new class of antiangiogenic agents. Ann N Y Acad Sci 889:84–86
Onn A, Tseng JE, Herbst RS (2001) Thalidomide, cyclooxygenase-2, and angiogenesis: potential for therapy. Clin Cancer Res 7:3311–3313
Sheehan KM, Sheahan K, O'Donoghue DP, MacSweeney F, Conroy RM, Fitzgerald DJ, et al (1999) The relationship between cyclooxygenase-2 expression and colorectal cancer. JAMA 282:1254–1257
Tomozawa S, Tsuno NH, Sunami E, Hatano K, Kitayama J, Osada T, et al (2000) Cyclooxygenase-2 overexpression correlates with tumour recurrence, especially haematogenous metastasis, of colorectal cancer. Br J Cancer 83:324–328
Fujita T, Matsui M, Takaku K, Uetake H, Ichikawa W, Taketo MM, et al (1998) Size- and invasion-dependent increase in cyclooxygenase 2 levels in human colorectal carcinomas. Cancer Res 58:4823–4826
Williams CS, Tsujii M, Reese J, Dey SK, DuBois RN (2000) Host cyclooxygenase-2 modulates carcinoma growth. J Clin Invest 105:1589–1594
Dormond O, Foletti A, Paroz C, Ruegg C (2001) NSAIDs inhibit alpha V beta 3 integrin-mediated and Cdc42/Rac-dependent endothelial-cell spreading, migration and angiogenesis. Nat Med 7:1041–1047
Cianchi F, Cortesini C, Bechi P, Fantappie O, Messerini L, Vannacci A, et al (2001) Up-regulation of cyclooxygenase 2 gene expression correlates with tumor angiogenesis in human colorectal cancer. Gastroenterology 121:1339–1347
Gallo O, Franchi A, Magnelli L, Sardi I, Vannacci A, Boddi V, et al (2001) Cyclooxygenase-2 pathway correlates with VEGF expression in head and neck cancer. Implications for tumor angiogenesis and metastasis. Neoplasia 3:53–61
Form DM, Auerbach R (1983) PGE2 and angiogenesis. Proc Soc Exp Biol Med 172:214–218
Kargman SL, O'Neill GP, Vickers PJ, Evans JF, Mancini JA, Jothy S (1995) Expression of prostaglandin G/H synthase-1 and −2 protein in human colon cancer. Cancer Res 55:2556–2559
Levy GN (1997) Prostaglandin H synthases, nonsteroidal anti-inflammatory drugs, and colon cancer. FASEB J 11:234–247
Bing RJ, Miyataka M, Rich KA, Hanson N, Wang X, Slosser HD, et al (2001) Nitric oxide, prostanoids, cyclooxygenase, and angiogenesis in colon and breast cancer. Clin Cancer Res 7:3385–3392
Daniel TO, Liu H, Morrow JD, Crews BC, Marnett LJ (1999) Thromboxane A2 is a mediator of cyclooxygenase-2-dependent endothelial migration and angiogenesis. Cancer Res 59:4574–4577
Jones MK, Wang H, Peskar BM, Levin E, Itani RM, Sarfeh IJ, et al (1999) Inhibition of angiogenesis by nonsteroidal anti-inflammatory drugs: insight into mechanisms and implications for cancer growth and ulcer healing. Nat Med 5:1418–1423
Thun MJ, Henley SJ, Patrono C (2002) Nonsteroidal anti-inflammatory drugs as anticancer agents: mechanistic, pharmacologic, and clinical issues. J Natl Cancer Inst 94:252–266
Prescott SM, Fitzpatrick FA (2000) Cyclooxygenase-2 and carcinogenesis. Biochim Biophys Acta 1470:M69–M78
Shao J, Sheng H, Inoue H, Morrow JD, DuBois RN (2000) Regulation of constitutive cyclooxygenase-2 expression in colon carcinoma cells. J Biol Chem 275:33951–3396
Dicker AP, Williams TL, Grant DS (2001) Targeting angiogenic processes by combination rofecoxib and ionizing radiation. Am J Clin Oncol 24:438–442
Leahy KM, Ornberg RL, Wang Y, Zweifel BS, Koki AT, Masferrer JL (2002) Cyclooxygenase-2 inhibition by celecoxib reduces proliferation and induces apoptosis in angiogenic endothelial cells in vivo. Cancer Res 62:625–631
Simmons DL, Botting RM, Robertson PM, Madsen ML, Vane JR (1999) Induction of an acetaminophen-sensitive cyclooxygenase with reduced sensitivity to nonsteroid antiinflammatory drugs. Proc Natl Acad Sci U S A 96:3275–3280
Barnes CJ, Cameron IL, Hardman WE, Lee M (1998) Non-steroidol anti-inflammatory drug effect on crypt cell proliferation and apoptosis during initiation of rat colon carcinogenesis. Br J Cancer 77:573–580
Goldman AP, Williams CS, Sheng H, Lamps LW, Williams VP, Pairet M, et al (1998) Meloxicam inhibits the growth of colorectal cancer cells. Carcinogenesis 19:2195–2199
Yu HG, Huang JA, Yang YN, Huang H, Luo HS, Yu JP, et al (2002) The effects of acetylsalicylic acid on proliferation, apoptosis, and invasion of cyclooxygenase-2 negative colon cancer cells. Eur J Clin Invest 32:838–846
Murphy VJ, Yang Z, Rorison KA, Baldwin GS (1998) Cyclooxygenase-2-selective antagonists do not inhibit growth of colorectal carcinoma cell lines. Cancer Lett 122:25–30
Williams CS, Watson AJ, Sheng H, Helou R, Shao J, DuBois RN (2000) Celecoxib prevents tumor growth in vivo without toxicity to normal gut: lack of correlation between in vitro and in vivo models. Cancer Res 60:6045–6051
McAdam BF, Catella-Lawson F, Mardini IA, Kapoor S, Lawson JA, FitzGerald GA (1999) Systemic biosynthesis of prostacyclin by cyclooxygenase (COX)-2: the human pharmacology of a selective inhibitor of COX-2. Proc Natl Acad Sci U S A 96:272–277
Whittle BJ (2000) COX-1 and COX-2 products in the gut: therapeutic impact of COX-2 inhibitors. Gut 47:320–325
Tomozawa S, Nagawa H, Tsuno N, Hatano K, Osada T, Kitayama J, et al (1999) Inhibition of haematogenous metastasis of colon cancer in mice by a selective COX-2 inhibitor, JTE-522. Br J Cancer 81:1274–1279
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Rao, M., Yang, W., Seifalian, A.M. et al. Role of cyclooxygenase-2 in the angiogenesis of colorectal cancer. Int J Colorectal Dis 19, 1–11 (2004). https://doi.org/10.1007/s00384-003-0511-2
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DOI: https://doi.org/10.1007/s00384-003-0511-2