Elsevier

European Urology

Volume 50, Issue 5, November 2006, Pages 1021-1031
European Urology

Prostate Cancer
Activation of the Thromboxane A2 Pathway in Human Prostate Cancer Correlates with Tumor Gleason Score and Pathologic Stage

https://doi.org/10.1016/j.eururo.2006.01.036Get rights and content

Abstract

Objective

We investigated the potential involvement of the thromboxane A2 (TXA2) pathway in human prostate cancer (PCa).

Methods

Expression of cyclooxygenase-2 (COX-2), TXA2 synthase (TXS), and TXA2 receptors (TPRs), the main actors of the TXA2 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 TXA2 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 TXA2 receptors and results suggest that the TXA2 pathway may be a potential target for PCa prevention/therapy.

Introduction

Intake of nonsteroidal anti-inflammatory drugs (NSAIDs), which act as inhibitors of cyclooxygenases, has been associated in humans with a significantly reduced risk of developing several types of cancer including prostate cancer (PCa) [1], [2], [3], [4]. A recent comprehensive review of 91 epidemiologic studies, assessing the impact of daily intake of NSAIDs, has indicated that such a treatment may result in cancer development risk reduction of 39% for PCa [1]. Use of NSAIDs has also been associated with a significantly reduced incidence of colon, breast, lung, esophageal, stomach, and ovarian cancers [1]. For most patients, NSAID anticancer preventive effects become apparent after ≥5 yr of use, with a positive association between intake duration and the importance of risk reduction [1]. These data support the observations that prostanoids, which are derived from arachidonic acid (AA) through the activity of cyclooxygenases (COXs), usually display antiapoptotic, growth- promoting, and proangiogenic properties [5]. It is thus assumed that the chemopreventive effects of COX inhibitors are predominantly achieved as a result of the inhibition of AA conversion into prostanoids (see Fig. 1 for a schematic description of the prostanoid pathway). However, prostanoids may exert opposing roles in tumor development/progression. For example, in the study by Pradono et al., retroviral vectors carrying thromboxane A2 (TXA2) synthase (TXS) cDNA, or prostacyclin (PGI2) synthase cDNA were transduced to colon cancer cells and each transformant was inoculated to mice. Tumors derived from TXA2 synthase transformants grew almost three times faster and showed more abundant vasculature, whereas tumors from PGI2 synthase transformants presented opposite effects. These effects were reversed by administration of specific inhibitors [6]. Therefore, the profile of COX metabolites in cancer cells can be a significant determinant for tumor development. Results from several other studies have largely supported the implication of TXA2 in tumor invasiveness, angiogenesis, and metastasis [7], [8], [9], [10], [11], [12], [13], [14], [15]. TXA2 is thus currently considered as a valuable anticancer target [11], [12], [13], [15], [16]. In this respect, it is important to consider that the selective targeting of downstream COX-2 pathways, such as the TXA2 pathway, may appear as a promising strategy bearing the potential of avoiding COX-2 inhibitors cardiovascular toxicity while maintaining their anticancer properties.

Several studies on the human prostate have yielded contradictory results regarding the possible overexpression of COX-2 in PCa lesions [17], [18], [19], [20], [21], [22], [23], [24], [25], [26], [27], [28], [29]. On the other hand, TXS has been shown to be up-regulated in PCa and its increased expression has been associated with advanced disease [8]. To the best of our knowledge, no data on expression of TXA2 receptors (TPRs) in PCa are currently available. Two different TPRs, named TPα and TPβ receptors, have been identified and are generated by alternative splicing [30]. TPRs are transmembrane receptors belonging to the G protein-coupled receptor superfamily. Although no differences were observed in ligand binding and coupling of TPα and TPβ receptors, the β splice variant becomes internalized to a greater extent than the α variant on exposure to agonist. TPα and TPβ form homo- and heterodimers/oligomers [31].

The present study investigated whether the TXA2 pathway may be activated in PCa. The expression of the main proteins involved in TXA2 biosynthesis and activity (COX-2, TXS, and TPR) was assessed using immunohistochemistry in serial tissue sections of human PCa samples.

Section snippets

Tissue samples

Tissue samples from human PCa were surgically obtained from 46 patients who had undergone a radical retropubic prostatectomy for localized PCa. All radical prostatectomy specimens used in this study had been entirely submitted for histopathologic examination (complete sampling), as previously described [32]. Most of the tissue sections analyzed in our study contained portions of both peripheral and transitional zones. No patient who had received prior hormonal therapy, chemotherapy, or

The two main TXA2 biosynthetic enzymes, COX-2 and TXS, and its receptors are overexpressed and colocalized in human PCa

We examined the expression of the main components of the TXA2 pathway in human PCa cells. The expression of the TPRs and that of the 2 enzymes involved in its synthesis, COX-2 and TXS, was evaluated using immunohistochemistry in a series of human PCa lesions. Among the enzymes responsible for TXA2 synthesis, no detectable or a weak level of expression of COX-2 and TXS was observed in nontumoral glands, whereas adjacent cancer cells usually expressed high levels of the enzymes (Fig. 2A and C).

Discussion

A detailed analysis of the key actors of the TXA2 pathway is definitely warranted to justify the use of existing or future inhibitors of this pathway as preventive or therapeutic agents. Indeed, the administration of such inhibitors would obviously not be recommended if the enzymes belonging to this pathway are not expressed in the targeted tissue.

It is generally accepted that COX-2, an inducible enzyme as opposed to the more constitutively expressed COX-1, is normally undetectable in most

Conclusions

In conclusion, the results of the present study indicate for the first time that the expression of the key proteins involved in the TXA2 pathway are up-regulated in HGPIN and PCa cells. In PCa lesions, overexpression of these proteins is associated with tumor extraprostatic extension and loss of differentiation. Overall, these findings identify the TXA2 pathway as a potential target for PCa prevention or treatment or both.

Editorial comment

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Acknowledgments

The authors thank Pascale Heneaux for technical assistance. D. Waltregny and L. de Leval are Research Associates and T. Dassesse is a Télévie research Fellow at the National Fund for Scientific Research (FNRS, Belgium).

Grant sponsors: National Fund for Scientific Research (Belgium), Centre Anti-Cancéreux de l’Université de Liège, Fonds Léon Frédéricq, TELEVIE, European Union FP6 LSHC-CT-2003-503233, Interuniversity Attraction Pole (IAP-P5/31) and the support of European Commission through

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    1

    T.D. and X.dL. contributed equally to this work.

    2

    V.C. and D.W. codirected this work.

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