Abstract 3470: Differential expression of angiogenesis and hypoxia in benign hyperplasia and cancer of the prostate

Abstract

Introduction. Targeting tumour angiogenesis, lymphoangiogenesis and hypoxia mechanisms as well as anti-inflammatory agents are promising therapeutic strategies for the treatment of also prostate cancer (PCA). A key regulator in the adaptation to hypoxic situations occurring when tumors outgrow is the transcriptional activator hypoxia-inducible factor I (HIF1), which increases when oxygen pressure drops. To gain access to adequate supply of oxygen and nutrients, tumor and stroma cells can release mediators to induce migration and proliferation of endothelial cells resulting in the formation of new blood vessels. To monitor such interactions in human, we assessed selected genes expressions in benign prostatic hyperplasia (BPH), in several stages of PCA as well as in paired non-malignant prostatic and seminal vesicle specimens. Patients and methods. The quantitative expression levels of selected genes representative for these pathways were assessed by real time PCR in a total of 170 samples obtained from patients with BPH and PCA. Tissue samples from the 122 PCA patients, which underwent radical prostatectomy, included 26 focal and 90 diffuse PCA with known pathological staging, 6 BPH, 13 paired non-malignant adjacent prostate and 24 seminal vesicles. Results Nonparametric correlation comparison and unsupervised hierarchical clustering revealed that BPH expressed significantly higher transcript levels of HIF1, ETS1, Vascular Endothelial Growth Factor A, VEGFB, VEGFC, FIGF, FLT1, KDR, Adrenomedullin, IL 6 and its receptor IL6R, Insulin Growth Factor 1 and IGF2, MMP2 and TGFR2 as compared to PCA. Though sporadically high values of such factors occurred in some PCA, no significant correlation was found between the levels of these transcripts and the Gleason grade or the tumor size. Intermediate (between the one of BPH and of PCA) transcripts levels were often found in adjacent non-malignant prostate tissue. Of interest, VEGFA, FIFG and HIF1 high levels were also observed in the seminal vesicles of patients with PCA. Moreover, cyclooxygenase 2 (COX2) transcripts were found distinctly (100 fold) higher in the seminal vesicle specimens as compared to all other samples. Discussion. Key players in angiogenesis and hypoxia pathways have been used for the successful development of drug target therapies. Yet, the same markers revealed to have poor diagnostic and predictive values. In our study we demonstrated that such molecules are differentially expressed in benign hyperplasia as compared to PCA independently of the Gleason grade and tumor size. It is therefore possible that angiogenesis would be differentially regulated under hypoxic or inflammatory conditions also involving other molecules and could influence metastatic dissemination at early steps of the tumor progression while the majority of tumors would continue growing under minimal vascular supply. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3470. doi:10.1158/1538-7445.AM2011-3470