[en] OBJECTIVE: We investigated the potential involvement of the thromboxane A(2) (TXA(2)) pathway in human prostate cancer (PCa). METHODS: Expression of cyclooxygenase-2 (COX-2), TXA(2) synthase (TXS), and TXA(2) receptors (TPRs), the main actors of the TXA(2) pathway, was analyzed on serial tissue sections from 46 human PCa specimens. RESULTS: The expression levels of COX-2, TXS, and TPRs were significantly higher in malignant than in corresponding nontumoral prostatic epithelial cells. Increased immunoreactivity for these antigens was also observed in high-grade prostate intraepithelial neoplasia (HGPIN) glands. COX-2, TXS, and TPR proteins usually displayed a coordinated overexpression pattern in PCa lesions, as assessed in serial tissue sections. Increased levels of these proteins in the tumors were all significantly associated with higher Gleason scores and pathologic stages. CONCLUSIONS: Proteins specifically involved in the TXA(2) pathway are up-regulated in human PCa and their level of expression is associated with tumor extraprostatic extension and loss of differentiation. Our study is the first to examine simultaneously all key proteins involved in this pathway including TXA(2) receptors and results suggest that the TXA(2) pathway may be a potential target for PCa prevention/therapy.
Disciplines :
Urology & nephrology
Author, co-author :
Dassesse, Thibaut
de Leval, Xavier
de Leval, Laurence ; Université de Liège - ULiège > Département des sciences biomédicales et précliniques > Anatomie et cytologie pathologiques
Pirotte, Bernard ; Université de Liège - ULiège > Chimie pharmaceutique
Castronovo, Vincenzo ; Université de Liège - ULiège > Département des sciences biomédicales et précliniques > Biologie générale et cellulaire
Waltregny, David ; Université de Liège - ULiège > Département des sciences biomédicales et précliniques > Labo de recherche sur les métastases
Language :
English
Title :
Activation of the thromboxane A2 pathway in human prostate cancer correlates with tumor Gleason score and pathologic stage
Harris R.E., Beebe-Donk J., Doss H., and Burr Doss D. Aspirin, ibuprofen, and other non-steroidal anti-inflammatory drugs in cancer prevention: a critical review of non-selective COX-2 blockade (review). Oncol Rep 13 (2005) 559-583
Koehne C.H., and Dubois R.N. COX-2 inhibition and colorectal cancer. Semin Oncol 31 (2004) 12-21
Nelson J.E., and Harris R.E. Inverse association of PCa and non-steroidal anti-inflammatory drugs (NSAIDs): results of a case-control study. Oncol Rep 7 (2000) 169-170
Terry M.B., Gammon M.D., Zhang F.F., et al. Association of frequency and duration of aspirin use and hormone receptor status with breast cancer risk. JAMA 291 (2004) 2433-2440
Rodrigues S., Bruyneel E., Rodrigue C.M., Shahin E., and Gespach C. Cyclooxygenase 2 and carcinogenesis. Bull Cancer 91 (2004) S61-S76
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 (2002) 63-66
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 (2000) 245-251
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 (2004) 429-439
Nanji A.A. Thromboxane synthase and organ preference for metastases. N Engl J Med 329 (1993) 138-139
Daniel T.O., Liu H., Morrow J.D., Crews B.C., and Marnett L.J. Thromboxane A2 is a mediator of cyclooxygenase-2-dependent endothelial migration and angiogenesis. Cancer Res 59 (1999) 4574-4577
Jurasz P., Alonso-Escolano D., and Radomski M.W. Platele-cancer interactions: mechanisms and pharmacology of tumour cell-induced platelet aggregation. Br J Pharmacol 143 (2004) 819-826
Atkinson S., and Fox S.B. Vascular endothelial growth factor (VEGF)-A and platelet-derived growth factor (PDGF) play a central role in the pathogenesis of digital clubbing. J Pathol 203 (2004) 721-728
Rhee J.S., Black M., Schubert U., et al. The functional role of blood platelet components in angiogenesis. Thromb Haemost 92 (2004) 394-402
Ross J.A., Potter J.D., and Severson R.K. Platelet-derived growth factor and risk factors for colorectal cancer. Eur J Cancer Prev 2 (1993) 197-210
Liu X.H., Kirschenbaum A., Yao S., Lee R., Holland J.F., and Levine A.C. Inhibition of cyclooxygenase-2 suppresses angiogenesis and the growth of PCa in vivo. J Urol 164 (2000) 820-825
Yoshimura R., Sano H., Masuda C., et al. Expression of cyclooxygenase-2 in prostate carcinoma. Cancer 89 (2000) 589-596
Kirschenbaum A., Liu X., Yao S., and Levine A.C. The role of cyclooxygenase-2 in PCa. Urology 58 (2001) 127-131
Lee L.M., Pan C.C., Cheng C.J., Chi C.W., and Liu T.Y. Expression of cyclooxygenase-2 in prostate adenocarcinoma and benign prostatic hyperplasia. Anticancer Res 21 (2001) 1291-1294
Zha S., Gage W.R., Sauvageot J., et al. Cyclooxygenase-2 is up-regulated in proliferative inflammatory atrophy of the prostate, but not in prostate carcinoma. Cancer Res 61 (2001) 8617-8623
Rubio J., Ramos D., Lopez-Guerrero J.A., et al. Immunohistochemical expression of Ki-67 antigen, Cox-2 and Bax/Bcl-2 in PCa: prognostic value in biopsies and radical prostatectomy specimens. Eur Urol 48 (2005) 745-751
Zang T., Sun F., and Li Y. Expression of COX-2 in prostatic cancer and benign prostatic hyperplasia. Zhonghua Wai Ke Za Zhi 39 (2001) 702-703
Uotila P., Valve E., Martikainen P., Nevalainen M., Nurmi M., and Harkonen P. Increased expression of cyclooxygenase-2 and nitric oxide synthase-2 in human PCa. Urol Res 29 (2001) 23-28
Madaan S., Abel P.D., Chaudhary K.S., et al. Cytoplasmic induction and over-expression of cyclooxygenase-2 in human PCa: implications for prevention and treatment. BJU Int 86 (2000) 736-741
Gupta S., Srivastava M., Ahmad N., Bostwick D.G., and Mukhtar H. Over-expression of cyclooxygenase-2 in human prostate adenocarcinoma. Prostate 42 (2000) 73-78
Wang W., Bergh A., and Damber J.E. Cyclooxygenase-2 expression correlates with local chronic inflammation and tumor neovascularization in human PCa. Clin Cancer Res 11 (2005) 3250-3256
Edwards J., Mukherjee R., Munro A.F., Wells A.C., Almushatat A., and Bartlett J.M. HER2 and COX2 expression in human PCa. Eur J Cancer 40 (2004) 50-55
Shappell S.B., Manning S., Boeglin W.E., et al. Alterations in lipoxygenase and cyclooxygenase-2 catalytic activity and mRNA expression in prostate carcinoma. Neoplasia 3 (2001) 287-303
Tanji N., Kikugawa T., and Yokoyama M. Immunohistochemical study of cyclooxygenases in prostatic adenocarcinoma; relationship to apoptosis and Bcl-2 protein expression. Anticancer Res 20 (2000) 2313-2319
Kinsella B.T. Thromboxane A2 signalling in humans: a 'Tail' of two receptors. Biochem Soc Trans 29 (2001) 641-654
Laroche G., Lepine M.C., Theriault C., et al. Oligomerization of the alpha and beta isoforms of the thromboxane A2 receptor: relevance to receptor signaling and endocytosis. Cell Signal 17 (2005) 1373-1383
Bostwick D.G., and Montironi R. Evaluating radical prostatectomy specimens: therapeutic and prognostic importance. Virchows Arch 430 (1997) 1-16
Waltregny D., Bellahcene A., Van Riet I., et al. Prognostic value of bone sialoprotein expression in clinically localized human PCa. J Natl Cancer Inst 90 (1998) 1000-1008
van den Brule F.A., Waltregny D., Liu F.T., and Castronovo V. Alteration of the cytoplasmic/nuclear expression pattern of galectin-3 correlates with prostate carcinoma progression. Int J Cancer 89 (2000) 361-367
Chaplet M., Waltregny D., Detry C., Fisher L.W., Castronovo V., and Bellahcene A. Expression of dentin sialophosphoprotein in human PCa and its correlation with tumor aggressiveness. Int J Cancer 118 (2006) 850-856
Sjogren S., Inganas M., Norberg T., et al. The p53 gene in breast cancer: prognostic value of complementary DNA sequencing versus immunohistochemistry. J Natl Cancer Inst 88 (1996) 173-182
Taketo M.M. Cyclooxygenase-2 inhibitors in tumorigenesis (part I). J Natl Cancer Inst 90 (1998) 1529-1536
Vane J.R., Bakhle Y.S., and Botting R.M. Cyclooxygenases 1 and 2. Annu Rev Pharmacol Toxicol 38 (1998) 97-120
Gately S., and Li W.W. Multiple roles of COX-2 in tumor angiogenesis: a target for antiangiogenic therapy. Semin Oncol 31 (2004) 2-11
Wei D., Wang L., He Y., Xiong H.Q., Abbruzzese J.L., and Xie K. Celecoxib inhibits vascular endothelial growth factor expression in and reduces angiogenesis and metastasis of human pancreatic cancer via suppression of Sp1 transcription factor activity. Cancer Res 64 (2004) 2030-2038
Rao C.V., and Reddy B.S. NSAIDs and chemoprevention. Curr Cancer Drug Targets 4 (2004) 29-42
Fortun P.J., and Hawkey C.J. Nonsteroidal antiinflammatory drugs and the small intestine. Curr Opin Gastroenterol 21 (2005) 169-175
Bannwarth B. Do selective cyclo-oxygenase-2 inhibitors have a future?. Drug Saf 28 (2005) 183-189
Bresalier R.S., Sandler R.S., Quan H., et al. Cardiovascular events associated with rofecoxib in a colorectal adenoma chemoprevention trial. N Engl J Med 352 (2005) 1092-1102
Levesque L.E., Brophy J.M., and Zhang B. The risk for myocardial infarction with cyclooxygenase-2 inhibitors: a population study of elderly adults. Ann Intern Med 142 (2005) 481-489
Vanchieri C. Vioxx withdrawal alarms cancer prevention researchers. J Natl Cancer Inst 96 (2004) 1734-1735
Walsh M.T., Foley J.F., and Kinsella B.T. The alpha, but not the beta, isoform of the human thromboxane A2 receptor is a target for prostacyclin-mediated desensitization. J Biol Chem 275 (2000) 20412-20423
Walsh M., Foley J.F., and Kinsella B.T. Investigation of the role of the carboxyl-terminal tails of the alpha and beta isoforms of the human thromboxane A(2) receptor (TP) in mediating receptor:effector coupling. Biochim Biophys Acta 1496 (2000) 164-182
Breyer R.M., Bagdassarian C.K., Myers S.A., and Breyer M.D. Prostanoid receptors: subtypes and signaling. Annu Rev Pharmacol Toxicol 41 (2001) 661-690
Valentin F., Field M.C., and Tippins J.R. The mechanism of oxidative stress stabilization of the thromboxane receptor in COS-7 cells. J Biol Chem 279 (2004) 8316-8324
Theriault C., Rochdi M.D., and Parent J.L. Role of the Rab11-associated intracellular pool of receptors formed by constitutive endocytosis of the beta isoform of the thromboxane A2 receptor (TP beta). Biochemistry 43 (2004) 5600-5607
Tsujii M., and DuBois R.N. Alterations in cellular adhesion and apoptosis in epithelial cells overexpressing prostaglandin endoperoxide synthase 2. Cell 83 (1995) 493-501
Tsujii M., Kawano S., Tsuji S., Sawaoka H., Hori M., and DuBois R.N. Cyclooxygenase regulates angiogenesis induced by colon cancer cells. Cell 93 (1998) 705-716
Sawaoka H., Tsuji S., Tsujii M., et al. Cyclooxygenase inhibitors suppress angiogenesis and reduce tumor growth in vivo. Lab Invest 79 (1999) 1469-1477
Masferrer J.L., Leahy K.M., Koki A.T., et al. Antiangiogenic and antitumor activities of cyclooxygenase-2 inhibitors. Cancer Res 60 (2000) 1306-1311
Nelson W.G., De Marzo A.M., DeWeese T.L., and Isaacs W.B. The role of inflammation in the pathogenesis of PCa. J Urol 172 (2004) S6-S11 discussion S2
DeMarzo A.M., Nelson W.G., Isaacs W.B., and Epstein J.I. Pathological and molecular aspects of PCa. Lancet 361 (2003) 955-964
Xu J., Zheng S.L., Komiya A., et al. Germline mutations and sequence variants of the macrophage scavenger receptor 1 gene are associated with PCa risk. Nat Genet 32 (2002) 321-325
Porkka K.P., and Visakorpi T. Molecular mechanisms of prostate cancer. Eur Urol 45 (2004) 683-691
Rennert H., Zeigler-Johnson C.M., Addya K., et al. Association of susceptibility alleles in ELAC2/HPC2, RNASEL/HPC1, and MSR1 with PCa severity in European American and African American men. Cancer Epidemiol Biomarkers Prev 14 (2005) 949-957