Androgen-Independent Prostate Cancer Is a Heterogeneous Group of Diseases

Shah, Rajal B.; Mehra, Rohit; Chinnaiyan, Arul M.; Shen, Ronglai; Ghosh, Debashis; Zhou, Ming; MacVicar, Gary R.; Varambally, Sooryanarayana; Harwood, Jason; Bismar, Tarek A.; Kim, Robert; Rubin, Mark A.; Pienta, Kenneth J.

doi:10.1158/0008-5472.can-04-2442

Cited by 577 publications

(480 citation statements)

References 35 publications

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“…No association was found between WNT7b expression and bone phenotype in patients with bone metastases. However, WNT7b is known to activate Wnt canonical signaling in osteoblasts (Zhang et al, 2004;Hu et al, 2005), and prostate cancer bone metastases is known to be heterogeneous (Shah et al, 2004), and so WNT7b could be involved in prostate cancer-induced new bone formation in a subpopulation of patients.…”

Section: Lrp5 Mediates Prostate Cancer-induced New Bone Formationmentioning

confidence: 99%

Low-density lipoprotein receptor-related protein 5 (LRP5) mediates the prostate cancer-induced formation of new bone

Yang

Vázquez

et al. 2007

Oncogene

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The tendency of prostate cancer to produce osteoblastic bone metastases suggests that cancer cells and osteoblasts interact in ways that contribute to cancer progression. To identify factors that mediate these interactions, we compared gene expression patterns between two bonederived prostate cancer cell lines that produce osteoblastic (MDA PCa 2b) or osteolytic lesions (PC-3). Both cell lines expressed Wnt ligands, including WNT7b, a canonical Wnt implicated in osteogenesis. PC-3 cells expressed 50 times more Dickkopf-1 (DKK1), an inhibitor of Wnt pathways, than did MDA PCa 2b cells. Evaluation of the functional role of these factors (in cocultures of prostate cancer cells with primary mouse osteoblasts (PMOs) or in bone organ cultures) showed that MDA PCa 2b cells activated Wnt canonical signaling in PMOs and that DKK1 blocked osteoblast proliferation and new bone formation induced by MDA PCa 2b cells. MDA PCa 2b cells did not induce bone formation in calvaria from mice lacking the Wnt co-receptor Lrp5. In human specimens, WNT7b was not expressed in normal prostate but was expressed in areas of high-grade prostate intraepithelial neoplasia, in three of nine primary prostate tumor specimens and in 16 of 38 samples of bone metastases from prostate cancer. DKK1 was not expressed in normal or cancerous tissue but was expressed in two of three specimens of osteolytic bone metastases (P ¼ 0.0119). We conclude that MDA PCa 2b induces new bone formation through Wnt canonical signaling, that LRP5 mediates this effect, and that DKK1 is involved in the balance between bone formation and resorption that determines lesion phenotype.

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Section: Lrp5 Mediates Prostate Cancer-induced New Bone Formationmentioning

confidence: 99%

Low-density lipoprotein receptor-related protein 5 (LRP5) mediates the prostate cancer-induced formation of new bone

Yang

Vázquez

et al. 2007

Oncogene

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“…Additional evidence suggests that PSA may have a significant role in osteoblastic bone metastasis (Nelson et al, 1995;Shah et al, 2004).…”

Section: Introductionmentioning

confidence: 99%

PSA reduces prostate cancer cell motility by stimulating TRPM8 activity and plasma membrane expression

et al. 2010

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Although the transient receptor potential melastatin 8 (TRPM8) cold receptor is highly expressed in prostate cancer (PCa) and constitutes a promising diagnostic and prognostic indicator, the natural agonists of this channel in the prostate, as well as its physiological and pathological functions, remain unknown. In this study, we identified the well-known PCa marker, prostatespecific antigen (PSA), as a physiological TRPM8 agonist. Electrophysiological and Ca 2 þ imaging studies demonstrated that PSA activated TRPM8-mediated current by the bradykinin 2 receptor signaling pathway. Further investigation of this mechanism by cell-surface biotinylation revealed that the increase in TRPM8 current induced by PSA was due to an increase in the number of functional TRPM8 channels on the plasma membrane. Importantly, wound-healing and migration assays revealed that TRPM8 activation by PSA reduced motility of the PC3 PCa cell line, suggesting that plasma membrane TRPM8 has a protective role in PCa progression. Consequently, PSA was identified as a natural TRPM8 agonist in the prostate and we propose a putative physiological role for both of these proteins in carcinogenesis, making this pathway a potentially important target for anticancer agent development.

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“…Multiple mechanisms have been identified that contribute to the androgen sensitive (AS) transition to the AI phenotype [1][2][3][4][5]. In the outlaw pathway, receptor tyrosine kinases are activated, and the androgen receptor (AR) is phosphorylated by either the AKT (protein kinase B) or the mitogen-activated protein kinase (MAPK) pathway, producing a ligand-independent AR.…”

Section: Introductionmentioning

confidence: 99%

Development of the VCaP androgen-independent model of prostate cancer

Loberg

John

Day

et al. 2006

Urologic Oncology: Seminars and Original Investigations

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Prostate epithelial cell growth is dependent on the presence of androgens and the transition of prostate cancer to an androgen independent phenotype results in a highly aggressive, currently incurable cancer. We have developed a new preclinical model of androgen independent prostate cancer derived from the VCaP prostate cancer epithelial cell line. VCaP cells were subcutaneously implanted and serially passaged in castrated male SCID mice. Androgen independence was confirmed by WST-1 (a tetrazolium salt) cell proliferation assay in the absence or presence of dihydrotesterone (DHT) (1 -100 nM). VCaP androgen sensitive (VAS) cells responded dose dependently to DHT whereas VCaP androgen independent (VAI) cells did not alter their proliferation in response to DHT. Gene expression of androgen receptor, Bcl-2, DD3, prostate acid phosphatase, STEAP, and survivin was determined by PCR amplification. Bcl-2 expression was upregulated in the VAI lines compared to the VAS suggesting a possible mechanism of androgen independence. Futhermore, tumorassociated -angiogenesis was assessed by immunofluorescence confocal microscopy of CD31. VAI tumors demonstrated enhanced angiogenesis compared to VAS tumors. These results demonstrate the development of a novel model of prostate cancer androgen independence and provide a new system to study angiogenesis and the transition to androgen independence.

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Androgen-Independent Prostate Cancer Is a Heterogeneous Group of Diseases

Cited by 577 publications

References 35 publications

Low-density lipoprotein receptor-related protein 5 (LRP5) mediates the prostate cancer-induced formation of new bone

Low-density lipoprotein receptor-related protein 5 (LRP5) mediates the prostate cancer-induced formation of new bone

PSA reduces prostate cancer cell motility by stimulating TRPM8 activity and plasma membrane expression

Development of the VCaP androgen-independent model of prostate cancer

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