Skip to main content
Log in

Cyclooxygenase-2 expression correlates with uPAR levels and is responsible for poor prognosis of colorectal cancer

  • Published:
Clinical & Experimental Metastasis Aims and scope Submit manuscript

Abstract

Considering recent findings that cyclooxygensase-2 (COX-2) is involved in the progression of colorectal carcinoma (CRC), the role of COX-2 in promoting invasion and angiogenesis was investigated by evaluating the relationship of COX-2 expression to various clinicopathological variables, including plasminogen activating system (PA system) and vascular endothelial growth factor (VEGF). Tumor tissues from 71 patients with CRC were assayed to determine the antigen levels of urokinase-type plasminogen activator (uPA), uPA receptor (uPAR), and plasminogen activator inhibitor-1 and -2 (PAI-1 and PAI-2), as well as immunohistochemical expression of VEGF. COX-2 was assayed immunohistochemically in 56 patients. COX-2 expression was detected in cancer cells and it was also expressed by stromal cells in some patients. Fourteen patients (25%) were COX-2 positive, whereas 42 were negative. COX-2 expression was significantly related to lymphatic invasion (P=0.0317), but was not related to microvessel density or VEGF expression. In the PA system, uPAR antigen levels were significantly higher in tumors with COX-2 expression than in tumors without (P=0.0233). Univariate analysis showed that significant prognostic variables for survival were tumor size, lymph node involvement, lymphatic invasion, vascular invasion, liver metastasis, high uPAR level, and COX-2 expression, but only liver metastasis was an independent prognostic factor (P=0.0065) in multivariate analysis. COX-2 expression was a more important prognostic indicator than any other factor except liver metastasis (P=0.0526). The significant relationship between the presence of COX-2 protein and uPAR antigen levels contributed to the enhancement of tumor invasion and the poor outcome in patients with CRC.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Sano H, Kawahito Y, Wilder RL et al. Expression of cyclooxygenase-1, and-2 in human colorectal cancer Cancer Res 1995; 55: 3785–9.

    PubMed  CAS  Google Scholar 

  2. Wolff H, Saukkonen K, Anttila S et al. Expression of cyclooxygenase-2 in human lung carcinoma. Cancer Res 1998; 15: 4997–5001.

    Google Scholar 

  3. Tucker ON, Dannenberg AJ, Yang EK et al. Cyclooxygenase-2 expression is upregulated in human pancreatic cancer. Cancer Res 1999; 59: 987–90.

    PubMed  CAS  Google Scholar 

  4. Boolbol SK, Dannenberg AJ, Chadburn DA et al. Cyclooxygenase-2 overexpression and tumor formation are blocked by sulindac in a murine model of familial adenomatous polyposis. Cancer Res 1996; 56: 2556–60.

    PubMed  CAS  Google Scholar 

  5. Sawaoka H, Kawano S, Tsuji S et al. Cyclooxygenase-2 inhibitors suppress the growth of gastric cancer xenografts via induction of apoptosis in nude mice. Am J Physiol 1998; 274: G1061–7.

    PubMed  CAS  Google Scholar 

  6. Tsujii M, Kawano S, Tsujii S et al. Cyclooxygenase regulates angiogenesis induced by colon cancer cells. Cell 1998; 93: 705–16.

    Article  PubMed  CAS  Google Scholar 

  7. Fujita T, Minoru M, Takaku K et al. Size-and invasion-dependent increase in cyclooxygenase 2 levels in human colorectal carcinomas. Cancer Res 1998; 58: 4823–6.

    PubMed  CAS  Google Scholar 

  8. Shirahama T, Arima J, Akiba S et al. Relation between cyclooxygenase-2 expression and tumor invasiveness and patient survival in transitional cell carcinoma of the urinary bladder. Cancer 2001; 92: 188–93.

    Article  PubMed  CAS  Google Scholar 

  9. Takahashi Y, Kawahara F, Noguchi M et al. Activation of matrix metalloprotease-2 in human breast cancer cell line overexpressing cyclooxygenase-1 or-2. FEBS Lett 1999; 460: 145–8.

    Article  PubMed  CAS  Google Scholar 

  10. Dano K, Andreasen PA, Grondahl HJ et al. Plasminogen activators, tissue degradation, and cancer. Adv Cancer Res 1985; 44: 139–266.

    Article  PubMed  CAS  Google Scholar 

  11. Mazzieri R, Masiero L, Zanetta et al. Control of type IV collagenase activity by components of the urokinase-plasmin system: A regulatory meehanism with cell-bound reactants. EMBO J 1997; 16: 2319–32.

    Article  PubMed  CAS  Google Scholar 

  12. Rao JS, Steck PA, Tofilon P et al. Role of plasminogen activator and of 92-KDa type IV collagenase in glioblastoma invasion using an in vitro matrigel model. J Neurooncol 1994; 18: 129–38.

    Article  PubMed  CAS  Google Scholar 

  13. Keski-Oja J, Lohi J, Tuuttila A et al. Proteolytic processing of the 72,000-Da type IV collagenase by urokinase plasminogen activator. Exp Cell Res 1992; 202: 471–6.

    Article  PubMed  CAS  Google Scholar 

  14. Duffy MJ, Reilly D, O'Sullivan C et al. Urokinase-plasminogen activator, a new and independent prognostic marker in breast cancer. Cancer Res 1990; 50: 6827–9.

    PubMed  CAS  Google Scholar 

  15. Sumiyoshi K, Serizawa K, Urano T et al. Plasminogen activator system in human breast cancer. Int J Cancer 1992; 50: 345–8.

    PubMed  CAS  Google Scholar 

  16. Sprengers ED, Kluft C. Plasminogen activator inhibitors. Blood 1987; 69: 381–7.

    PubMed  CAS  Google Scholar 

  17. Tsuji M, Kawano S, Sawaoka H et al. Evidence for involvement of cyclooxygenase-2 in proliferation of two gastrointestinal cancer cell lines. Prostaglandins Leukot & Essent Fatty Acids 1996; 55: 179–83.

    Article  CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

  19. Hara A, Yoshimi N, Niwa M et al. Apoptosis induced by NS-398, a selective cyclooxygenase-2 inhibitor, in human colorectal cancer cell lines. Jpn J Cancer Res 1997; 88: 600–4.

    PubMed  CAS  Google Scholar 

  20. Elder DJ, Halton DE, Hague A et al. Induction of apoptotic cell death in human colorectal carcinoma cell lines by a cyclooxygenase-2(COX-2)-selective nonsteroidal anti-inflammatory drug: independence from COX-2 protein expression. Clin Cancer Res 1997; 3: 1679–83.

    PubMed  CAS  Google Scholar 

  21. Elder DJ, Halton DE, Crew TE et al. 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 2000; 86: 553–60.

    Article  PubMed  CAS  Google Scholar 

  22. Huang M, Stolina M, Sharma S et al. Non-small cell lung cancer cyclooxygenase-2-dependent regulation of cytokine balance in lymphocytes and macrophages: Up-regulation of interleukin 10 and down-regulation of interleukin 12 production. Cancer Res 1998; 58: 1208–16.

    PubMed  CAS  Google Scholar 

  23. Dohadwala M, Luo J, Zhu L et al. Non-small cell lung cancer cyclooxygenase-2-dependent invasion is mediated by CD44. J Biol Chem 2001; 276: 20809–12.

    Article  PubMed  CAS  Google Scholar 

  24. Chen WS, Wei SJ, Liu JM et al. Tumor invasiveness and liver metastasis of colon cancer cells correlated with cyclooxygenase-2 (COX-2) expression and inhibited by a COX-2-selective inhibitor, etodlac. Int J Cancer 2001; 91: 894–9.

    Article  PubMed  CAS  Google Scholar 

  25. Ohno R, Yoshinaga K, Fujita T et al. Depth of invasion parallels increased cyclooxygenase-2 levels in patients with gastric carcinoma. Cancer 2001; 91: 1876–81.

    Article  PubMed  CAS  Google Scholar 

  26. Masferrer JL, Leahy KM, Koki AT et al. Antiangiogenine and antitumor activities of cyclooxygenase-2 inhibitors. Cancer Res 2000; 60: 1306–11.

    PubMed  CAS  Google Scholar 

  27. Sawaoka H, Tsuji S, Tsujii M et al. Cyclooxygenase inhibitors suppress angiogenesis and reduce tumor growth in vivo. Lab Invest 1999; 79: 1469–77.

    PubMed  CAS  Google Scholar 

  28. Liu XH, Kirschenbaum A, Yao S et al. Inhibition of cyclooxygenase-2 suppresses angiogenesis and the growth of prostate cancer in vivo. J Urol 2000; 164: 820–5.

    Article  PubMed  CAS  Google Scholar 

  29. Abe J, Urano T, Konno H et al. Larger and more invasive colorectal carcinoma contains larger amounts of plasminogen activator inhibitor type 1 and its relative ratio over urokinase receptor correlates well with tumor size. Cancer 1999; 86: 2602–11.

    Article  PubMed  CAS  Google Scholar 

  30. Duffy MJ. The role of proteolytic enzymes in cancer invasion and metastasis. Clin Exp Metastasis 1992; 10: 145–55.

    Article  PubMed  CAS  Google Scholar 

  31. Costantini V, Sidoni A, Deveglia R et al. Combined overexpression of urokinase, urokinase receptor, and plasminogen activator inhibitor-1 is associated with breast cancer progression: An immunohistochemical comparison of normal, benign, and malignant breast tissues. Cancer 1996; 77: 1079–88.

    Article  PubMed  CAS  Google Scholar 

  32. McCabe NP, Angwafo FF 3rd, Zaher A et al. Expression of soluble urokinase plasminogen activator receptor may be related to outcome in prostate cancer patients. Oncol Rep 2000; 7: 879–82.

    PubMed  CAS  Google Scholar 

  33. de Witte JH, Foekens JA, Brunner N et al. Prognostic impact of urokinase-type plasminogen activator receptor (uPAR) in cytosols and pellet extracts derived from primary breast tumors. Br J Cancer 2001; 85: 85–92.

    Article  PubMed  CAS  Google Scholar 

  34. Nekarda H, Schmitt M, Ulm K et al. Prognostic impact of urokinasetype plasminogen activator and its inhibitor PAI-1 in completely resected gastric cancer. Cancer Res 1994; 54: 2900–7.

    PubMed  CAS  Google Scholar 

  35. Chambers SK, Ivins CM, Carcangiu ML. Plasminogen activator inhibitor-1 is an independent poor prognostic factor for survival in advanced stage epithelial ovarian cancer patients. Int J Cancer 1998; 79: 449–54.

    Article  PubMed  CAS  Google Scholar 

  36. Deng G, Curriden SA, Wang S et al. Is plasminogen activator inhibitor-1 the molecular switch that governs urokinase receptor-mediated cell adhesion and release? J Cell Biol 1996; 134: 1563–71.

    Article  PubMed  CAS  Google Scholar 

  37. Stefansson S, Lawrence DA. The serpin PAI-1 inhibits cell migration by blocking integrinaVb3 binding to vitronectin. Nature 1996; 383: 441–3.

    Article  PubMed  CAS  Google Scholar 

  38. Kjoller L, Kanse SM, Kirkegaard T et al. Plasminogen activator inhibitor-1 represses integrin-and vitronectin-mediated cell migration independently of its function as an inhibitor of plasminogen activation. Exp Cell Res 1997; 232: 420–9.

    Article  PubMed  CAS  Google Scholar 

  39. Hapke S, Kessler H, Arroyo de Prada N et al. Integrin alpha(v)beta(3)/vitronectin interaction affects expression of the urokinase system in human ovarian cancer cells. J Biol Chem 2001; 276: 26340–8.

    Article  PubMed  CAS  Google Scholar 

  40. Khatib AM, Nip J, Fallavollita L et al. Regulation of urokinase plasminogen activator/plasmin-mediated invasion of melanoma cells by the integrin vitronectin receptor alphaVbeta3. Int J Cancer 2001; 91: 300–8.

    Article  PubMed  CAS  Google Scholar 

  41. Dimberg J, Hugander A, Sirsjo A et al. Enhanced expression of cyclooxygensa-2 and nuclear beta-catenin are related to mutations in the APC gene in human colorectal cancer. Anticancer Res 2001; 21: 911–5.

    PubMed  CAS  Google Scholar 

  42. Pan MR, Chuang LY, Hung WC. Non-steroidal anti-inflammatory drugs inhibit matrix metalloproteinase-2 expression via repression of transcription in lung cancer cells. FEBS Lett 2001; 508: 365–8.

    Article  PubMed  CAS  Google Scholar 

  43. Attiga FA, Fernandez PM, Weeraratna AT et al. Inhibitors of prostaglandin synthesis inhibit human prostate tumor cell invasiveness and reduce the release of matrix metalloproteases. Cancer Res 2000; 60: 4629–37.

    PubMed  CAS  Google Scholar 

  44. Masunaga R, Kohno H, Dhar DK et al. Cyclooxygenase-2 expression correlates with tumor neovascularization and prognosis in human colorectal carcinoma patients. Clin Cancer Res 2000; 6: 4064–8.

    PubMed  CAS  Google Scholar 

  45. Majima M, Hayashi I, Muramatsu M et al. Cyclo-oxygenase-2 enhances basic fibroblast growth factor-induced angiogenesis through induction of vascular endothelial growth factor in rat sponge implants. Br J Pharmacol 2000; 130: 641–9.

    Article  PubMed  CAS  Google Scholar 

  46. Cianchi F, Cortesini C, Bechi P et al. Up-regulation of cyclooxygenase 2 gene expression correlates with tumor angiogenesis in human colorectal cancer. Gastroenterology 2001; 121: 1339–47.

    Article  PubMed  CAS  Google Scholar 

  47. Dempke W, Rie C, Grothey A et al. Cyclooxygenase-2: A novel target for cancer chemotherapy? J Cancer Res Clin Oncol 2001; 127: 411–7.

    Article  PubMed  CAS  Google Scholar 

  48. Gallo O, Franchi A, Magnelli L et al. Cyclooxygenase-2 pathway correlates with VEGF expression in head and neck cancer. Implications for tumor angiogenesis and metastasis. Neoplasia 2001; 3: 53–61.

    Article  PubMed  CAS  Google Scholar 

  49. Mazar AP. The urokinase plasminogen activator receptor (uPAR) as a target for the diagnosis and therapy of cancer. Anticancer Drugs 2001; 12: 387–400.

    Article  PubMed  CAS  Google Scholar 

  50. Konno H, Abe J, Kaneko T et al. Urokinase receptor and vascular endothelial growth factor are synergistically associated with the liver metastasis of colorectal cancer. Jpn J Cancer Res 2001; 92: 516–23.

    PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Rights and permissions

Reprints and permissions

About this article

Cite this article

Konno, H., Baba, M., Shoji, T. et al. Cyclooxygenase-2 expression correlates with uPAR levels and is responsible for poor prognosis of colorectal cancer. Clin Exp Metastasis 19, 527–534 (2002). https://doi.org/10.1023/A:1020392309715

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1023/A:1020392309715

Navigation