Endocrine Pathology

, Volume 16, Issue 4, pp 253–277 | Cite as

Cyclooxygenase-2 and thromboxane synthase in non-endocrine and endocrine tumors: A review

  • Onder Onguru
  • Mary B. Casey
  • Sabine Kajita
  • Nobuki Nakamura
  • Ricardo V. Lloyd


Prostaglandins (PG) are members of a large group of hormonally active fatty acids derived from free fatty acids. They are formed from arachidonic acid—the major PG precursor. Cyclooxygenase (COX)-1 and -2 are the rate-limiting steps in PG synthesis. COX-2 is overexpressed in many human non-endocrine and endocrine tumors including colon, breast, prostate, brain, thyroid, and pituitary. COX-2 has an important role in angiogenesis and tumor growth. Thromboxane synthase (TS) catalyzes the synthesis of thromboxane A2 (TXA2), which is derived from arachidonic acid and prostaglandin H2 and is a vasoconstrictor and inducer of platelet aggregation. TXA2 stimulates tumor growth and spread of some tumors and TS appears to have a critical role in tumorigenesis in some organ systems.

In this review, we examine the role of COX-2 and TS in various non-endocrine tumors, especially colon, breast, prostate, and brain as well as in endocrine tumors. The accumulating evidence points to an increasingly important role of COX-2 and TS in tumor progression and metastasis.

Key Words

Cyclooxygenase-2 thromboxane synthase colon tumor breast tumor prostate tumor brain tumor thyroid tumor pituitary tumor 


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Thun MJ, Namboodiri MM, Heath CW, Jr. Aspirin use and reduced risk of fatal colon cancer. N Engl J Med 325:1593–1596, 1991.PubMedCrossRefGoogle Scholar
  2. 2.
    Giovannucci E, Egan KM, Hunter DJ, et al. Aspirin and the risk of colorectal cancer in women. N Engl J Med 333:609–614, 1995.PubMedCrossRefGoogle Scholar
  3. 3.
    Sandler RS, Galanko JC, Murray SC, Helm JF, Woosley JT. Aspirin and nonsteroidal anti-inflammatory agents and risk for colorectal adenomas. Gastroenterology 114:441–447, 1998.PubMedCrossRefGoogle Scholar
  4. 4.
    Logan RF, Little J, Hawtin PG, Hardcastle JD. Effect of aspirin and non-steroidal anti-inflammatory drugs on colorectal adenomas: case-control study of subjects participating in the Nottingham faecal occult blood screening programme. BMJ 307:285–289, 1993.PubMedGoogle Scholar
  5. 5.
    Smith WL, DeWitt DL, Garavito RM. Cyclooxygenases: structural, cellular, and molecular biology. Annu Rev Biochem 69:145–182, 2000.PubMedCrossRefGoogle Scholar
  6. 6.
    Hamberg M, Samuelsson B. Detection and isolation of an endoperoxide intermediate in prostaglandin biosynthesis. Proc Natl Acad Sci USA 70:899–903, 1973.PubMedCrossRefGoogle Scholar
  7. 7.
    Ihara H, Yokoyama C, Miyata A, et al. Induction of thromboxane synthase and protaglandin endoperoxide synthase mRNAs in human erythroleukemia cells by phorbol ester. FEBS Lett 306:161–164, 1992.PubMedCrossRefGoogle Scholar
  8. 8.
    McDonough W, Tran N, Giese A, Norman SA, Berens ME. Altered gene expression in human astrocytoma cells selected for migration: I. Thromboxane synthase. J Neuropathol Exp Neurol 57:449–455, 1998.PubMedGoogle Scholar
  9. 9.
    Giese A, Hagel C, Kim EL, et al. Thromboxane synthase regulates the migratory phenotype of human glioma cells. Neuro-oncol 1:3–13, 1999.PubMedCrossRefGoogle Scholar
  10. 10.
    Pradono P, Tazawa R, Maemondo M, et al. Gene transfer of thromboxane A(2) synthase and prostaglandin I(2) synthase antithetically altered tumor angiogenesis and tumor growth. Cancer Res 62:63–66, 2002.PubMedGoogle Scholar
  11. 11.
    Daniel TO, Liu H, Morrow JD, Crews BC, Marnett LJ. Thromboxane A2 is a mediator of cyclooxygenase-2-dependent endothelial migration and angiogenesis. Cancer Res 59:4574–4577, 1999.PubMedGoogle Scholar
  12. 12.
    Vane JR, Bakhle YS, Botting RM. Cyclo-oxygenase 1 and 2. Annu Rev Pharmacol Toxicol 38:97–120, 1998.PubMedCrossRefGoogle Scholar
  13. 13.
    Chan BS, Satriano JA, Pucci M, Schuster VL. Mechanism of prostaglandin E2 transport across the plasma membrane of HeLa cells and Xenopus oocytes expressing the prostaglandin transporter “PGT.” J Biol Chem 273:6689–6697, 1998.PubMedCrossRefGoogle Scholar
  14. 14.
    Ushikubi F, Segi E, Sugimoto Y, et al. Impaired febrile response in mice lacking the prostaglandin E receptor subtype EP3. Nature 395:281–284, 1998.PubMedCrossRefGoogle Scholar
  15. 15.
    Murata T, Ushikubi F, Matsuoka T, et al. Altered pain perception and inflammatory response in mice lacking prostacyclin receptor. Nature 388:678–682, 1997.PubMedCrossRefGoogle Scholar
  16. 16.
    Lim H, Gupta RA, Ma WG, et al. Cyclo-oxygenase-2-derived prostacyclin mediates embryo implantation in the mouse via PPARdelta. Genes Dev 13:1561–1574, 1999.PubMedGoogle Scholar
  17. 17.
    Funk CD. Prostaglandins and leukotrienes: advances in eicosanoid biology. Science 294:1871–1875, 2001.PubMedCrossRefGoogle Scholar
  18. 18.
    Bjorkman DJ. The effect of aspirin and non-steroidal anti-inflammatory drugs on prostaglandins. Am J Med 105:8S-12S, 1998.PubMedCrossRefGoogle Scholar
  19. 19.
    Hla T, Neilson K. Human cyclooxygenase-2 cDNA. Proc Natl Acad Sci USA 89:7384–7388, 1992.PubMedCrossRefGoogle Scholar
  20. 20.
    Williams CS, DuBois RN. Prostaglandin endoperoxide synthase: why two isoforms? Am J Physiol 270:G393–400, 1996.PubMedGoogle Scholar
  21. 21.
    Morita I, Schindler M, Regier MK, et al. Different intracellular locations for prostaglandin endoperoxide H synthase-1 and -2. J Biol Chem 270:10902–10908, 1995.PubMedCrossRefGoogle Scholar
  22. 22.
    Kujubu DA, Fletcher BS, Varnum BC, Lim RW, Herschman HR. TIS10, a phorbol ester tumor promoter-inducible mRNA from Swiss 3T3 cells, encodes a novel prostaglandin synthase/cyclooxygenase homologue. J Biol Chem 266:12866–12872, 1991.PubMedGoogle Scholar
  23. 23.
    Smith WL, DeWitt DL. Biochemistry of prostaglandin endoperoxide H synthase-1 and synthase-2 and their differential susceptibility to nonsteroidal anti-inflammatory drugs. Semin Nephrol 15:179–194, 1995.PubMedGoogle Scholar
  24. 24.
    Sheng H, Williams CS, Shao J, Liang P, DuBois RN, Beauchamp RD. Induction of cyclooxygenase-2 by activated Ha-ras oncogene in Rat-1 fibroblasts and the role of mitogen-activated protein kinase pathway. J Biol Chem 273:22120–22127, 1998.PubMedCrossRefGoogle Scholar
  25. 25.
    Sheng H, Shao J, Dixon DA, et al. Transforming growth factor-betal enhances Ha-ras-induced expression of cyclooxygenase-2 in intestinal epithelial cells via stabilization of mRNA. J Biol Chem 275:6628–6635, 2000.PubMedCrossRefGoogle Scholar
  26. 26.
    Sheng H, Shao J, Dubois RN. K-Ras-mediated increase in cyclooxygenase 2 mRNA stability involves activation of the protein kinase B1. Cancer Res 61:2670–2675, 2001.PubMedGoogle Scholar
  27. 27.
    Ristimaki A, Sivula A, Lundin J, et al. Prognostic significance of elevated cyclooxygenase-2 expression in breast cancer. Cancer Res 62:632–635, 2002.PubMedGoogle Scholar
  28. 28.
    Araki Y, Okamura S, Hussain SP, et al. Regulation of cyclooxygenase-2 expression by the Wnt and ras pathways. Cancer Res 63:728–734, 2003.PubMedGoogle Scholar
  29. 29.
    Jones MK, Wang H, Peskar BM, et al. Inhibition of angiogenesis by nonsteroidal anti-inflammatory drugs: insight into mechanisms and implications for cancer growth and ulcer healing. Nat Med 5:1418–1423, 1999.PubMedCrossRefGoogle Scholar
  30. 30.
    Tsujii M, Kawano S, Tsuji S, Sawaoka H, Hori M, DuBois RN. Cyclooxygenase regulates angiogenesis induced by colon cancer cells. Cell 93:705–716, 1998.PubMedCrossRefGoogle Scholar
  31. 31.
    Masferrer JL, Leahy KM, Koki AT, et al. Antiangiogenic and antitumor activities of cyclooxygenase-2 inhibitors. Cancer Res 60:1306–1311, 2000.PubMedGoogle Scholar
  32. 32.
    Williams CS, Tsujii M, Reese J, Dey SK, DuBois RN. Host cyclooxygenase-2 modulates carcinoma growth. J Clin Invest 105:1589–1594, 2000.PubMedGoogle Scholar
  33. 33.
    Leung WK, To KF, Go MY, et al. Cyclooxygenase-2 upregulates vascular endothelial growth factor expression and angiogenesis in human gastric carcinoma. Int J Oncol 23:1317–1322, 2003.PubMedGoogle Scholar
  34. 34.
    Tsujii M, Kawano S, DuBois RN. Cyclooxygenase-2 expression in human colon cancer cells increases metastatic potential. Proc Natl Acad Sci USA 94:3336–3340, 1997.PubMedCrossRefGoogle Scholar
  35. 35.
    Tsujii M, DuBois RN. Alterations in cellular adhesion and apoptosis in epithelial cells overexpressing prostaglandin endoperoxide synthase 2. Cell 83:493–501, 1995.PubMedCrossRefGoogle Scholar
  36. 36.
    Gupta RA, Dubois RN. Colorectal cancer prevention and treatment by inhibition of cyclooxygenase-2. Nat Rev Cancer 1:11–21, 2001.PubMedCrossRefGoogle Scholar
  37. 37.
    Oshima M, Dinchuk JE, Kargman SL, et al. Suppression of intestinal polyposis in Apc delta716 knockout mice by inhibition of cyclooxygenase 2 (COX-2). Cell 87:803–809, 1996.PubMedCrossRefGoogle Scholar
  38. 38.
    Liu CH, Chang SH, Narko K, et al. Overexpression of cyclooxygenase-2 is sufficient to induce tumorigenesis in transgenic mice. J Biol Chem 276:18563–18569, 2001.PubMedCrossRefGoogle Scholar
  39. 39.
    Neufang G, Furstenberger G, Heidt M, Marks F, Muller-Decker K. Abnormal differentiation of epidermis in transgenic mice constitutively expressing cyclooxygenase-2 in skin. Proc Natl Acad Sci USA 98:7629–7634, 2001.PubMedCrossRefGoogle Scholar
  40. 40.
    Dannenberg AJ, Howe LR. The role of COX-2 in breast and cervical cancer. Prog Exp Tumor Res 37:90–106, 2003.PubMedGoogle Scholar
  41. 41.
    Jones DA, Fitzpatrick FA. “Suicide” inactivation of thromboxane A2 synthase. Characteristics of mechanism-based inactivation with isolated enzyme and intact platelets. J Biol Chem 265:20166–20171, 1990.PubMedGoogle Scholar
  42. 42.
    Needleman P, Turk J, Jakschik BA, Morrison AR, Lefkowith JB. Arachidonic acid metabolism. Annu Rev Biochem 55:69–102, 1986.PubMedCrossRefGoogle Scholar
  43. 43.
    Hirata M, Hayashi Y, Ushikubi F, et al. Cloning and expression of cDNA for a human thromboxane A2 receptor. Nature 349:617–620, 1991.PubMedCrossRefGoogle Scholar
  44. 44.
    Ogletree ML. Overview of physiological and pathophysiological effects of thromboxane A2. Fed Proc 46:133–138, 1987.PubMedGoogle Scholar
  45. 45.
    Tone Y, Miyata A, Hara S, Yukawa S, Tanabe T. Abundant expression of thromboxane synthase in rat macrophages. FEBS Lett 340:241–244, 1994.PubMedCrossRefGoogle Scholar
  46. 46.
    Nie D, Lamberti M, Zacharek A, et al. Thromboxane A(2) regulation of endothelial cell migration, angiogenesis, and tumor metastasis. Biochem Biophys Res Commun 267:245–251, 2000.PubMedCrossRefGoogle Scholar
  47. 47.
    Giardiello FM, Hamilton SR, Krush AJ, et al. Treatment of colonic and rectal adenomas with sulindac in familial adenomatous polyposis. N Engl J Med 328:1313–1316, 1993.PubMedCrossRefGoogle Scholar
  48. 48.
    Labayle D, Fischer D, Vielh P, et al. Sulindac causes regression of rectal polyps in familial adenomatous polyposis. Gastroenterology 101:635–639, 1991.PubMedGoogle Scholar
  49. 49.
    Nugent KP, Farmer KC, Spigelman AD, Williams CB, Phillips RK. Randomized controlled trial of the effect of sulindac on duodenal and rectal polyposis and cell proliferation in patients with familial adenomatous polyposis. Br J Surg 80:1618–1619, 1993.PubMedCrossRefGoogle Scholar
  50. 50.
    Steinbach G, Lynch PM, Phillips RK, et al. The effect of celecoxib, a cyclooxygenase-2 inhibitor, in familial adenomatous polyposis. N Engl J Med 342:1946–1952, 2000.PubMedCrossRefGoogle Scholar
  51. 51.
    Higuchi T, Iwama T, Yoshinaga K, Toyooka M, Taketo MM, Sugihara K. A randomized, double-blind, placebo-controlled trial of the effects of rofecoxib, a selective cyclooxygenase-2 inhibitor, on rectal polyps in familial adenomatous polyposis patients. Clin Cancer Res 9:4756–4760, 2003.PubMedGoogle Scholar
  52. 52.
    Eberhart CE, Coffey RJ, Radhika A, Giardiello FM, Ferrenbach S, DuBois RN. Up-regulation of cyclooxygenase 2 gene expression in human colorectal adenomas and adenocarcinomas. Gastroenterology 107:1183–1188, 1994.PubMedGoogle Scholar
  53. 53.
    Sano H, Kawahito Y, Wilder RL, et al. Expression of cyclooxygenase-1 and -2 in human colorectal cancer. Cancer Res 55:3785–3789, 1995.PubMedGoogle Scholar
  54. 54.
    DuBois RN, Giardiello FM, Smalley WE. Nonsteroidal anti-inflammatory drugs, eicosanoids, and colorectal cancer prevention. Gastroenterol Clin North Am 25:773–791, 1996.PubMedCrossRefGoogle Scholar
  55. 55.
    Williams CS, Luongo C, Radhika A, et al. Elevated cyclooxygenase-2 levels in Min mouse adenomas. Gastroenterology 111:1134–1140, 1996.PubMedCrossRefGoogle Scholar
  56. 56.
    Chapple KS, Cartwright EJ, Hawcroft G, et al. Localization of cyclooxygenase-2 in human sporadic colorectal adenomas. Am J Pathol 156:545–553, 2000.PubMedGoogle Scholar
  57. 57.
    Muller-Decker K, Albert C, Lukanov T, Winde G, Marks F, Furstenberger G. Cellular localization of cyclo-oxygenase isozymes in Crohn’s disease and colorectal cancer. Int J Colorectal Dis 14:212–218, 1999.PubMedCrossRefGoogle Scholar
  58. 58.
    Khan KN, Masferrer JL, Woerner BM, Soslow R, Koki AT. Enhanced cyclooxygenase-2 expression in sporadic and familial adenomatous polyposis of the human colon. Scand J Gastroenterol 36:865–869, 2001.PubMedCrossRefGoogle Scholar
  59. 59.
    Sheehan KM, Sheahan K, O’Donoghue DP, et al. The relationship between cyclooxygenase-2 expression and colorectal cancer. JAMA 282:1254–1257, 1999.PubMedCrossRefGoogle Scholar
  60. 60.
    Kutchera W, Jones DA, Matsunami N, et al. Prostaglandin H synthase 2 is expressed abnormally in human colon cancer: evidence for a transcriptional effect. Proc Natl Acad Sci USA 93:4816–4820, 1996.PubMedCrossRefGoogle Scholar
  61. 61.
    Nakajima T, Hamanaka K, Fukuda T, Oyama T, Kashiwabara K, Sano T. Why is cyclooxygenase-2 expressed in neuroendocrine cells of the human alimentary tract? Pathol Int 47:889–891, 1997.PubMedCrossRefGoogle Scholar
  62. 62.
    Hasegawa K, Ichikawa W, Fujita T, et al. Expression of cyclooxygenase-2 (COX-2) mRNA in human colorectal adenomas. Eur J Cancer 37:1469–1474, 2001.PubMedCrossRefGoogle Scholar
  63. 63.
    Yang VW, Shields JM, Hamilton SR, et al. Size-dependent increase in prostanoid levels in adenomas of patients with familial adenomatous polyposis. Cancer Res 58:1750–1753, 1998.PubMedGoogle Scholar
  64. 64.
    Sheehan KM, O’Connell F, O’Grady A, et al. The relationship between cyclooxygenase-2 expression and characteristics of malignant transformation in human colorectal adenomas. Eur J Gastroenterol Hepatol 16:619–625, 2004.PubMedCrossRefGoogle Scholar
  65. 65.
    Arao J, Sano Y, Fujii T, et al. Cyclooxygenase-2 is overexpressed in serrated adenoma of the colorectum. Dis Colon Rectum 44:1319–1323, 2001.PubMedCrossRefGoogle Scholar
  66. 66.
    Fujita T, Matsui M, Takaku K, et al. Size- and invasion-dependent increase in cyclooxygenase 2 levels in human colorectal carcinomas. Cancer Res 58:4823–4826, 1998.PubMedGoogle Scholar
  67. 67.
    Moorghen M, Ince P, Finney KJ, Sunter JP, Appleton DR, Watson AJ. A protective effect of sulindac against chemically-induced primary colonic tumours in mice. J Pathol 156:341–347, 1988.PubMedCrossRefGoogle Scholar
  68. 68.
    Jacob RF, Marshall DJ, Newton MA, et al. Chemoprevention of spontaneous intestinal adenomas in the Apc Min mouse model by the nonsteroidal anti-inflammatory drug piroxicam. Cancer Res 56:710–714, 1996.Google Scholar
  69. 69.
    Barnes CJ, Lee M. Chemoprevention of spontaneous intestinal adenomas in the adenomatous polyposis coli Min mouse model with aspirin. Gastroenterology 114:873–877, 1998.PubMedCrossRefGoogle Scholar
  70. 70.
    Rahme E, Barkun AN, Toubouti Y, Bardou M. The cyclooxygenase-2-selective inhibitors rofecoxib and celecoxib prevent colorectal neoplasia occurrence and recurrence. Gastroenterology 125:404–412, 2003.PubMedCrossRefGoogle Scholar
  71. 71.
    Waskewich C, Blumenthal RD, Li H, Stein R, Goldenberg DM, Burton J. Celecoxib exhibits the greatest potency amongst cyclooxygenase (COX) inhibitors for growth inhibition of COX-2-negative hematopoietic and epithelial cell lines. Cancer Res 62:2029–2033, 2002.PubMedGoogle Scholar
  72. 72.
    Shiff SJ, Qiao L, Tsai LL, Rigas B. Sulindac sulfide, an aspirin-like compound, inhibits proliferation, causes cell cycle quiescence, and induces apoptosis in HT-29 colon adenocarcinoma cells. J Clin Invest 96:491–503, 1995.PubMedCrossRefGoogle Scholar
  73. 73.
    Subbaramaiah K, Altorki N, Chung WJ, Mestre JR, Sampat A, Dannenberg AJ. Inhibition of cyclooxygenase-2 gene expression by p53. J Biol Chem 274:10911–10915, 1999.PubMedCrossRefGoogle Scholar
  74. 74.
    Sheng GG, Shao J, Sheng H, et al. A selective cyclooxygenase 2 inhibitor suppresses the growth of H-ras-transformed rat intestinal epithelial cells. Gastroenterology 113:1883–1891, 1997.PubMedCrossRefGoogle Scholar
  75. 75.
    Fujita M, Fukui H, Kusaka T, et al. Relationship between cyclooxygenase-2 expression and K-ras gene mutation in colorectal adenomas. J Gastroenterol Hepatol 15:1277–1281, 2000.PubMedCrossRefGoogle Scholar
  76. 76.
    Liang JT, Huang KC, Jeng YM, Lee PH, Lai HS, Hsu HC. Microvessel density, cyclooxygenase 2 expression, K-ras mutation and p53 overexpression in colonic cancer. Br J Surg 91:355–361, 2004.PubMedCrossRefGoogle Scholar
  77. 77.
    Karnes WE, Jr., Shattuck-Brandt R, Burgart LJ, et al. Reduced COX-2 protein in colorectal cancer with defective mismatch repair. Cancer Res 58:5473–5477, 1998.PubMedGoogle Scholar
  78. 78.
    Sinicrope FA, Lemoine M, Xi L, et al. Reduced expression of cyclooxygenase 2 proteins in hereditary nonpolyposis colorectal cancers relative to sporadic cancers. Gastroenterology 117:350–358, 1999.PubMedCrossRefGoogle Scholar
  79. 79.
    Marnett LJ. Aspirin and the potential role of prostaglandins in colon cancer. Cancer Res 52:5575–5589, 1992.PubMedGoogle Scholar
  80. 80.
    Coogan PF, Rao SR, Rosenberg L, et al. The relationship of nonsteroidal anti-inflammatory drug use to the risk of breast cancer. Prev Med 29:72–76, 1999.PubMedCrossRefGoogle Scholar
  81. 81.
    Harris RE, Namboodiri KK, Farrar WB. Nonsteroidal antiinflammatory drugs and breast cancer. Epidemiology 7:203–205, 1996.PubMedCrossRefGoogle Scholar
  82. 82.
    Egan KM, Stampfer MJ, Giovannucci E, Rosner BA, Colditz GA. Prospective study of regular aspirin use and the risk of breast cancer. J Natl Cancer Inst 88:988–993, 1996.PubMedCrossRefGoogle Scholar
  83. 83.
    Nakatsugi S, Ohta T, Kawamori T, et al. Chemoprevention by nimesulide, a selective cyclooxygenase-2 inhibitor, of 2-amino-1-methyl-6-phenylimidazo[4,5-b] pyridine (PhIP)-induced mammary gland carcinogenesis in rats. Jpn J Cancer Res 91:886–892, 2000.PubMedGoogle Scholar
  84. 84.
    Robertson FM, Parrett ML, Joarder FS, et al. Ibuprofen-induced inhibition of cyclooxygenase isoform gene expression and regression of rat mammary carcinomas. Cancer Lett 122:165–175, 1998.PubMedCrossRefGoogle Scholar
  85. 85.
    Harris RE, Alshafie GA, Abou-Issa H, Seibert K. Chemoprevention of breast cancer in rats by celecoxib, a cyclooxygenase 2 inhibitor. Cancer Res 60:2101–2103, 2000.PubMedGoogle Scholar
  86. 86.
    Rozic JG, Chakraborty C, Lala PK. Cyclooxygenase inhibitors retard murine mammary tumor progression by reducing tumor cell migration, invasiveness and angiogenesis. Int J Cancer 93:497–506, 2001.PubMedCrossRefGoogle Scholar
  87. 87.
    Kundu N, Yang Q, Dorsey R, Fulton AM. Increased cyclooxygenase-2 (cox-2) expression and activity in a murine model of metastatic breast cancer. Int J Cancer 93:681–686, 2001.PubMedCrossRefGoogle Scholar
  88. 88.
    Liu XH, Rose DP. Differential expression and regulation of cyclooxygenase-1 and -2 in two human breast cancer cell lines. Cancer Res 56:5125–5127, 1996.PubMedGoogle Scholar
  89. 89.
    Kundu N, Fulton AM. Selective cyclooxygenase (COX)-1 or COX-2 inhibitors control metastatic disease in a murine model of breast cancer. Cancer Res 62:2343–2346, 2002.PubMedGoogle Scholar
  90. 90.
    Yoshimura N, Sano H, Okamoto M, et al. Expression of cyclooxygenase-1 and -2 in human breast cancer. Surg Today 33:805–811, 2003.PubMedCrossRefGoogle Scholar
  91. 91.
    Watanabe O, Shimizu T, Imamura H, et al. Expression of cyclooxygenase-2 in malignant and benign breast tumors. Anticancer Res 23:3215–3221, 2003.PubMedGoogle Scholar
  92. 92.
    Soslow RA, Dannenberg AJ, Rush D, et al. COX-2 is expressed in human pulmonary, colonic, and mammary tumors. Cancer 89:2637–2645, 2000.PubMedCrossRefGoogle Scholar
  93. 93.
    Subbaramaiah K, Norton L, Gerald W. Increased expression of cyclooxygenase-2 in HER-2-overexpressing human breast cancer cells. NCI 7th SPORE Investigators Workshop. 1999.Google Scholar
  94. 94.
    Bennett A, Berstock DA, Raja B, Stamford IF. Survival time after surgery is inversely related to the amounts of prostaglandins extracted from human breast cancers [proceedings]. Br J Pharmacol 66:451P, 1979.Google Scholar
  95. 95.
    Rolland PH, Martin PM, Jacquemier J, Rolland AM, Toga M. Prostaglandin in human breast cancer: evidence suggesting that an elevated prostaglandin production is a marker of high metastatic potential for neoplastic cells. J Natl Cancer Inst 64:1061–1070, 1980.PubMedGoogle Scholar
  96. 96.
    Brueggemeier RW, Quinn AL, Parrett ML, Joarder FS, Harris RE, Robertson FM. Correlation of aromatase and cyclooxygenase gene expression in human breast cancer specimens. Cancer Lett 140:27–35, 1999.PubMedCrossRefGoogle Scholar
  97. 97.
    Shim JY, An HJ, Lee YH, Kim SK, Lee KP, Lee KS. Overexpression of cyclooxygenase-2 is associated with breast carcinoma and its poor prognostic factors. Mod Pathol 16:1199–1204, 2003.PubMedCrossRefGoogle Scholar
  98. 98.
    Denkert C, Winzer KJ, Muller BM, et al. Elevated expression of cyclooxygenase-2 is a negative prognostic factor for disease free survival and overall survival in patients with breast carcinoma. Cancer 97:2978–2987, 2003.PubMedCrossRefGoogle Scholar
  99. 99.
    Wulfing P, Diallo R, Muller C, et al. Analysis of cyclooxygenase-2 expression in human breast cancer: high throughput tissue microarray analysis. J Cancer Res Clin Oncol 129:375–382, 2003.PubMedCrossRefGoogle Scholar
  100. 100.
    Subbaramaiah K, Norton L, Gerald W, Dannenberg AJ. Cyclooxygenase-2 is over-expressed in HER-2/neu-positive breast cancer: evidence for involvement of AP-1 and PEA3. J Biol Chem 277:18649–18657, 2002.PubMedCrossRefGoogle Scholar
  101. 101.
    Howe LR, Subbaramaiah K, Patel J, et al. Celecoxib, a selective cyclooxygenase 2 inhibitor, protects against human epidermal growth factor receptor 2 (HER-2)/neu-induced breast cancer. Cancer Res 62:5405–5407, 2002.PubMedGoogle Scholar
  102. 102.
    Half E, Tang XM, Gwyn K, Sahin A, Wathen K, Sinicrope FA. Cyclooxygenase-2 expression in human breast cancers and adjacent ductal carcinoma in situ. Cancer Res 62:1676–1681, 2002.PubMedGoogle Scholar
  103. 103.
    Simeone AM, Li YJ, Broemeling LD, Johnson MM, Tuna M, Tari AM. Cyclooxygenase-2 is essential for HER2/neu to suppress N-(4-hydroxyphenyl)retinamide apoptotic effects in breast cancer cells. Cancer Res 64:1224–1228, 2004.PubMedCrossRefGoogle Scholar
  104. 104.
    Chang SH, Liu CH, Conway R, et al. Role of prostaglandin E2-dependent angiogenic switch in cyclooxygenase 2-induced breast cancer progression. Proc Natl Acad Sci USA 101:591–596, 2004.PubMedCrossRefGoogle Scholar
  105. 105.
    Davies G, Salter J, Hills M, Martin LA, Sacks N, Dowsett M. Correlation between cyclooxygenase-2 expression and angiogenesis in human breast cancer. Clin Cancer Res 9:2651–2656, 2003.PubMedGoogle Scholar
  106. 106.
    Nelson JE, Harris RE. Inverse association of prostate cancer and non-steroidal anti-inflammatory drugs (NSAIDs): results of a case-control study. Oncol Rep 7:169–170, 2000.PubMedGoogle Scholar
  107. 107.
    Langman MJ, Cheng KK, Gilman EA, Lancashire RJ. Effect of anti-inflammatory drugs on overall risk of common cancer: case-control study in general practice research database. BMJ 320:1642–1646, 2000.PubMedCrossRefGoogle Scholar
  108. 108.
    Basler JW, Piazza GA. Nonsteroidal anti-inflammatory drugs and cyclooxygenase-2 selective inhibitors for prostate cancer chemoprevention. J Urol 171:S59–62; discussion S62-53, 2004.PubMedCrossRefGoogle Scholar
  109. 109.
    Kirschenbaum A, Klausner AP, Lee R, et al. Expression of cyclooxygenase-1 and cyclooxygenase-2 in the human prostate. Urology 56:671–676, 2000.PubMedCrossRefGoogle Scholar
  110. 110.
    Gupta S, Srivastava M, Ahmad N. Bostwick DG, Mukhtar H. Over-expression of cyclooxygenase-2 in human prostate adenocarcinoma. Prostate 42:73–78, 2000.PubMedCrossRefGoogle Scholar
  111. 111.
    Madaan S, Abel PD, Chaudhary KS, et al. Cytoplasmic induction and over-expression of cyclooxygenase-2 in human prostate cancer: implications for prevention and treatment. BJU Int 86:736–741, 2000.PubMedCrossRefGoogle Scholar
  112. 112.
    Yoshimura R, Sano H, Masuda C, et al. Expression of cyclooxygenase-2 in prostate carcinoma. Cancer 89:589–596, 2000.PubMedCrossRefGoogle Scholar
  113. 113.
    Lee LM, Pan CC, Cheng CJ, Chi CW, Liu TY. Expression of cyclooxygenase-2 in prostate adenocarcinoma and benign prostatic hyperplasia. Anticancer Res 21:1291–1294, 2001.PubMedGoogle Scholar
  114. 114.
    Uotila P, Valve E, Martikainen P, Nevalainen M, Nurmi M, Harkonen P. Increased expression of cyclooxygenase-2 and nitric oxide synthase-2 in human prostate cancer. Urol Res 29:23–28, 2001.PubMedCrossRefGoogle Scholar
  115. 115.
    Subbarayan V, Sabichi AL, Llansa N, Lippman SM, Menter DG. Differential expression of cyclooxygenase-2 and its regulation by tumor necrosis factor-alpha in normal and malignant prostate cells. Cancer Res 61:2720–2726, 2001.PubMedGoogle Scholar
  116. 116.
    Barqawi A, Thompson IM, Crawford ED. Prostate cancer chemoprevention: an overview of United States trials. J Urol 171:S5–8; discussion S9, 2004.PubMedCrossRefGoogle Scholar
  117. 117.
    Liu XH, Yao S, Kirschenbaum A, Levine AC. NS398, a selective cyclooxygenase-2 inhibitor, induces apoptosis and down-regulates bcl-2 expression in LNCaP cells. Cancer Res 58:4245–4249, 1998.PubMedGoogle Scholar
  118. 118.
    Liu XH, Kirschenbaum A, Yao S, Lee R, Holland JF, Levine AC. Inhibition of cyclooxygenase-2 suppresses angiogenesis and the growth of prostate cancer in vivo. J Urol 164:820–825, 2000.PubMedCrossRefGoogle Scholar
  119. 119.
    Kulp SK, Yang YT, Hung CC, et al. 3-phosphoinositide-dependent protein kinase-1/Akt signaling represents a major cyclooxygenase-2-independent target for celecoxib in prostate cancer cells. Cancer Res 64:1444–1451, 2004.PubMedCrossRefGoogle Scholar
  120. 120.
    Zha S, Gage WR, Sauvageot J, et al. Cyclooxygenase-2 is up-regulated in proliferative inflammatory atrophy of the prostate, but not in prostate carcinoma. Cancer Res 61:8617–8623, 2001.PubMedGoogle Scholar
  121. 121.
    Deininger MH, Weller M, Streffer J, Mittelbronn M, Meyermann R. Patterns of cyclooxygenase-1 and -2 expression in human gliomas in vivo. Acta Neuropathol (Berl) 98:240–244, 1999.CrossRefGoogle Scholar
  122. 122.
    Prayson RA, Castilla EA, Vogelbaum MA, Barnett GH. Cyclooxygenase-2 (COX-2) expression by immunohistochemistry in glioblastoma multiforme. Ann Diagn Pathol 6:148–153, 2002.PubMedCrossRefGoogle Scholar
  123. 123.
    Shono T, Tofilon PJ, Bruner JM, Owolabi O, Lang FF. Cyclooxygenase-2 expression in human gliomas: prognostic significance and molecular correlations. Cancer Res 61:4375–4381, 2001.PubMedGoogle Scholar
  124. 124.
    Joki T, Heese O, Nikas DC, et al. Expression of cyclooxygenase 2 (COX-2) in human glioma and in vitro inhibition by a specific COX-2 inhibitor, NS-398. Cancer Res 60:4926–4931, 2000.PubMedGoogle Scholar
  125. 125.
    Matsuo M, Yonemitsu N, Zaitsu M, et al. Expression of prostaglandin H synthase-2 in human brain tumors. Acta Neuropathol (Berl) 102:181–187, 2001.Google Scholar
  126. 126.
    Castilla EA, Prayson RA, Kanner AA, et al. Cyclooxygenase-2 in oligodendroglial neoplasms. Cancer 98:1465–1472, 2003.PubMedCrossRefGoogle Scholar
  127. 127.
    Deininger MH, Meyermann R, Trautmann K, et al. Cyclooxygenase (COX)-1 expressing macrophages/microglial cells and COX-2 expressing astrocytes accumulate during oligodendroglial godendroglioma progression. Brain Res 885:111–116, 2000.PubMedCrossRefGoogle Scholar
  128. 128.
    Prayson RA, Cyclooxygenase-2, Bcl-2, and chromosome 1p analysis in protoplasmic astrocytomas. Hum Pathol 35:317–321, 2004.PubMedCrossRefGoogle Scholar
  129. 129.
    Patti R, Gumired K, Reddanna P, Sutton LN, Phillips PC, Reddy CD. Overexpression of cyclooxygenase-2 (COX-2) in human primitive neuroectodermal tumors: effect of celecoxib and rofecoxib. Cancer Lett 180:13–21, 2002.PubMedCrossRefGoogle Scholar
  130. 130.
    Matsuo M, Yoshida N, Zaitsu M, Ishii K, Hamasaki Y. Inhibition of human glioma cell growth by a PHS-2 inhibitor, NS398, and a prostaglandin E receptor subtype EP1-selective antagonist, SC51089. J Neurooncol 66:285–292, 2004.PubMedCrossRefGoogle Scholar
  131. 131.
    King JG, Jr, Khalili K. Inhibition of human brain tumor cell growth by the anti-inflammatory drug, flurbiprofen. Oncogene 20:6864–6870, 2001.PubMedCrossRefGoogle Scholar
  132. 132.
    Petersen C, Petersen S, Milas L, Lang FF, Tofilon PJ. Enhancement of intrinsic tumor cell radiosensitivity induced by a selective cyclooxygenase-2 inhibitor. Clin Cancer Res 6:2513–2520, 2000.PubMedGoogle Scholar
  133. 133.
    Badie B, Schartner JM, Hagar AR, et al. Microglia cyclooxygenase-2 activity in experimental gliomas: possible role in cerebral edema formation. Clin Cancer Res 9:872–877, 2003.PubMedGoogle Scholar
  134. 134.
    Portnow J, Suleman S, Grossman SA, Eller S, Carson K. A cyclooxygenase-2 (COX-2) inhibitor compared with dexamethasone in a survival study of rats with intracerebral 9L gliosarcomas. Neurooncol 4:22–25, 2002.Google Scholar
  135. 135.
    Ito Y, Yoshida H, Nakano K, et al. Cyclooxy-genase-2 expression in thyroid neoplasms. Histopathology 42:492–497, 2003.PubMedCrossRefGoogle Scholar
  136. 136.
    Nose F, Ichikawa T, Fujiwara M, Okayasu I. Up-regulation of cyclooxygenase-2 expression in lymphocytic thyroiditis and thyroid tumors: significant correlation with inducible nitric oxide synthase. Am J Clin Pathol 117:546–551, 2002.PubMedCrossRefGoogle Scholar
  137. 137.
    Cornetta AJ, Russell JP, Cunnane M, Keane WM, Rothstein JL. Cyclooxygenase-2 expression in human thyroid carcinoma and Hashimoto’s thyroiditis. Laryngoscope 112:238–242, 2002.PubMedCrossRefGoogle Scholar
  138. 138.
    Specht MC, Tucker ON, Hocever M, Gonzalez D, Teng L, Fahey TJ, 3rd. Cyclooxygenase-2 expression in thyroid nodules. J Clin Endocrinol Metab 87:358–363, 2002.PubMedCrossRefGoogle Scholar
  139. 139.
    Kim SJ, Lee JH, Yoon JS, et al. Immunohistochemical expression of COX-2 in thyroid nodules. Korean J Intern Med 18:225–229, 2003.PubMedGoogle Scholar
  140. 140.
    Berg J, Stocher M, Bogner S, Wolfl S, Pichler R, Stekel H. Inducible cyclooxygenase-2 gene expression in the human thyroid epithelial cell line Nthy-ori3-1. Inflamm Res 49:139–143, 2000.PubMedCrossRefGoogle Scholar
  141. 141.
    Siironen P, Ristimaki A, Nordling S, Louhimo J, Haapiainen R, Haglund C. Expression of COX-2 is increased with age in papillary thyroid cancer. Histopathology 44:490–497, 2004.PubMedCrossRefGoogle Scholar
  142. 142.
    Casey MB, Zhang S, Jin L, Kajita S, Lloyd RV. Expression of cyclooxygenase-2 and thromboxane synthase in non-neoplastic and neoplastic thyroid lesions. Endocr Pathol 15:107–116, 2004.PubMedCrossRefGoogle Scholar
  143. 143.
    Kajita S, Ruebel KH, Casey MB, Nakamura N, Lloyd RV. Role of COX-2, thromboxane A(2) synthase, and prostaglandin I(2) synthase in papillary thyroid carcinoma growth. Mod Pathol 18:221–227, 2005.PubMedCrossRefGoogle Scholar
  144. 144.
    Bell CD, Vidal S, Kovacs K, Horvath E, Rotondo F. An immunohistochemical survey of nine cases of medullary carcinoma of thyroid including reactivity for Cox-1 and Cox-2 enzymes. Endocr Pathol 13:331–340, 2002.PubMedCrossRefGoogle Scholar
  145. 145.
    Vidal S, Kovacs K, Bell D, Horvath E, Scheithauer BW, Lloyd RV. Cyclooxygenase-2 expression in human pituitary tumors. Cancer 97:2814–2821, 2003.PubMedCrossRefGoogle Scholar
  146. 146.
    Bloomer CW, Kenyon L, Hammond E, et al. Cyclooxygenase-2 (COX-2) and epidermal growth factor receptor (EGFR) expression in human pituitary macroadenomas. Am J Clin Oncol 26:S75–80, 2003.PubMedGoogle Scholar
  147. 147.
    Onguru O, Scheithauer BW, Kovacs K, et al. Analysis of Cox-2 and thromboxane synthase expression in pituitary adenomas and carcinomas. Endocr Pathol 15:17–27, 2004.PubMedCrossRefGoogle Scholar
  148. 148.
    Ohike N, Morohoshi T. Immunohistochemical analysis of cyclooxygenase (COX)-2 expression in pancreatic endocrine tumors: association with tumor progression and proliferation. Pathol Int 51:770–777, 2001.PubMedCrossRefGoogle Scholar
  149. 149.
    Salmenkivi K, Haglund C, Ristimaki A, Arola J, Heikkila P. Increased expression of cyclooxygenase-2 in malignant pheochromocytomas. J Clin Endocrinol Metab 86:5615–5619, 2001.PubMedCrossRefGoogle Scholar
  150. 150.
    Johnsen JI, Lindskog M, Ponthan F, et al. Cyclooxygenase-2 is expressed in neuroblastoma, and nonsteroidal anti-inflammatory drugs induce apoptosis and inhibit tumor growth in vivo. Cancer Res 64:7210–7215, 2004.PubMedCrossRefGoogle Scholar
  151. 151.
    Bing RJ, Miyataka M, Rich KA, et al. Nitric oxide, prostanoids, cyclooxygenase, and angiogenesis in colon and breast cancer. Clin Cancer Res 7:3385–3392, 2001.PubMedGoogle Scholar
  152. 152.
    Nie D, Che M, Zacharek A, et al. Differential expression of thromboxane synthase in prostate carcinoma: role in tumor cell motility. Am J Pathol 164:429–439, 2004.PubMedGoogle Scholar
  153. 153.
    Drago JR, Al-Mondhiry HA. The effect of prostaglandin modulators on prostate tumor growth and metastasis. Anticancer Res 4:391–394, 1984.PubMedGoogle Scholar
  154. 154.
    Castelli MG, Chiabrando C, Fanelli R, et al. Prostaglandin and thromboxane synthesis by human intracranial tumors. Cancer Res 49:1505–1508, 1989.PubMedGoogle Scholar
  155. 155.
    Kurzel F, Hagel C, Zapf S, Meissner H, Westphal M, Giese A. Cyclo-oxygenase inhibitors and thromboxane synthase inhibitors differentially regulate migration arrest, growth inhibition and apoptosis in human glioma cells. Acta Neurochir (Wien) 144:71–87, 2002.CrossRefGoogle Scholar
  156. 156.
    Yoshizato K, Zapf S, Westphal M, Berens ME, Giese A. Thromboxane synthase inhibitors induce apoptosis in migration-arrested glioma cells. Neurosurgery 50:343–354, 2002.PubMedCrossRefGoogle Scholar

Copyright information

© Humana Press Inc 2005

Authors and Affiliations

  • Onder Onguru
    • 1
  • Mary B. Casey
    • 1
  • Sabine Kajita
    • 1
  • Nobuki Nakamura
    • 1
  • Ricardo V. Lloyd
    • 1
  1. 1.Department of Laboratory Medicine and PathologyMayo Clinic College of MedicineRochester

Personalised recommendations