BackgroundConstitutively active androgen receptor variants (AR-V) lacking the ligand binding domain (LBD) may promote the development of castration-resistant prostate cancer (CRPC). The expression of AR-Vs in the clinically most important metastatic site, the bone, has, however, not been well documented. Our aim was therefore to compare levels of AR-Vs in hormone-naive (HN) and CRPC bone metastases in comparison to primary PC and non-malignant prostate tissue, as well as in relation to AR protein expression, whole-genome transcription profiles and patient survival.Methodology/Principal FindingsHormone-naïve (n = 10) and CRPC bone metastases samples (n = 30) were obtained from 40 patients at metastasis surgery. Non-malignant and malignant prostate samples were acquired from 13 prostatectomized men. Levels of full length AR (ARfl) and AR-Vs termed AR-V1, AR-V7, and AR-V567es mRNA were measured with RT-PCR and whole-genome transcription profiles with an Illumina Beadchip array. Protein levels were examined by Western blotting and immunohistochemistry. Transcripts for ARfl, AR-V1, and AR-V7 were detected in most primary tumors and metastases, and levels were significantly increased in CRPC bone metastases. The AR-V567es transcript was detected in 23% of the CRPC bone metastases only. A sub-group of CRPC bone metastases expressed LBD-truncated AR proteins at levels comparable to the ARfl. Detectable AR-V567es and/or AR-V7 mRNA in the upper quartile, seen in 1/3 of all CRPC bone metastases, was associated with a high nuclear AR immunostaining score, disturbed cell cycle regulation and short survival.Conclusions/SignificanceExpression of AR-Vs is increased in CRPC compared to HN bone metastases and associated with a particularly poor prognosis. Further studies are needed to test if patients expressing such AR-Vs in their bone metastases benefit more from drugs acting on or down-stream of these AR-Vs than from therapies inhibiting androgen synthesis.

Despite its high prevalence, very little is known regarding genetic predisposition to prostate cancer. A genome-wide scan performed in 66 high-risk prostate cancer families has provided evidence of linkage to the long arm of chromosome 1 (1q24-25). Analysis of an additional set of 25 North American and Swedish families with markers in this region resulted in significant evidence of linkage in the combined set of 91 families. The data provide strong evidence of a major prostate cancer susceptibility locus on chromosome 1.

Angiogenesis sustains tumor growth and metastasis, and recent studies indicate that the vascular endothelium regulates tissue mass. In the prostate, androgens drive angiogenic inducers to stimulate growth, whereas androgen withdrawal leads to decreased vascular endothelial growth factor, vascular regression and epithelial cell apoptosis. Here, we identify the angiogenesis inhibitor pigment epithelium-derived factor (PEDF) as a key inhibitor of stromal vasculature and epithelial tissue growth in mouse prostate and pancreas. In PEDF-deficient mice, stromal vessels were increased and associated with epithelial cell hyperplasia. Androgens inhibited prostatic PEDF expression in cultured cells. In vivo, androgen ablation increased PEDF in normal rat prostates and in human cancer biopsies. Exogenous PEDF induced tumor epithelial apoptosis in vitro and limited in vivo tumor xenograft growth, triggering endothelial apoptosis. Thus, PEDF regulates normal pancreas and prostate mass. Its androgen sensitivity makes PEDF a likely contributor to the anticancer effects of androgen ablation.

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Mast cells affect growth in various humanCancer growth is dependent on the reciprocal interaction between tumor cells and their microenvironment. Cancerassociated fibroblasts, 1 vascular cells, and inflammatory cells such as macrophages [2][3][4] have been shown to promote prostate tumor growth. Mast cells are also of importance for tumor growth and have been shown to affect angiogenesis 5-7 but are also potent regulators of inflammation and thus their specific function during tumor progression is complex and shows significant plasticity. 8 -10 Their role in prostate cancer (PC) in patients was recently explored in two separate studies using tryptase and c-Kit as markers for mast cells. These studies lacked the discrepancy between intra-and peritumoral mast cells and did not identify mast cells as independent prognostic variables. One of the studies showed that tryptase-positive mast cells were related to poor outcome in PC patients. 12 The other study analyzed c-Kit-positive cells in tumor samples from PC patients and found an association between increased mast cell numbers and a favorable prognosis. 13Castration therapy is the gold standard for treatment of patients with metastatic PC, but in the majority of cases the formation of castrate-resistant prostate tumors is inevitable. The mechanisms behind the relapse are not fully understood but could be related to changes in the androgen receptor and the tumor stroma.

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The data demonstrate that T lymphocytes and macrophages appeared to play an important role in the induction of COX-2 expression in prostate epithelium, which was associated with increased cell proliferation and possibly, due to overexpression of Bcl-2, apoptotic resistance. This suggests that pro-inflammatory cytokines released by adjacent inflammatory cells may induce COX-2 in the epithelial cells in prostate atrophic lesions. In addition, COX-2 expressing cells may be involved in the pathogenesis of prostate cancer.