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Bone stromal production of insulin-like growth factor binding protein 5 promotes growth and survival of prostate cancer

University of British Columbia

Prostate cancer (PCa) is the most common cancer among Canadian men and is continuing to be the third-leading cause of male cancer death in Canada. PCa is initially androgen-dependent. Some patients developed metastasis at diagnosis, and are treated by androgen withdrawal therapy. The majority of patients will respond, resulting in tumor growth arrest. However, PCa eventually progresses to androgen-independence and no effective treatment is available. Stromal-epithelial interaction is critical to PCa survival and proliferation. The bone metastasis in PCa indicated compatibility between bone stroma cells and PCa epithelial cells in bone microenvironment. IGF-I and IGF-II are the most abundant growth factors stored in bone. The bioavailability of lGF-I can be modulated by IGFBP-5, the most abundant IGFBP in bone stroma. IGFBP-5 is one of few consistently upregulated genes in mice bone stroma after castration. The functions of IGFs and IGFBP-5 are implicated in PCa growth and survival. The objective of this thesis was to investigate the role of stroma-derived IGFBP-5 in PCa bone metastasis and progression to androgen-independence. We generated IGFBP-5 expressing bone stroma MG63-BP5 clone, and its vector counterpart MG63-mock clone. We investigated the anti-apoptotic effect of MG63-BP5 conditioned medium on LNCaP PCa cells under androgen-deprived condition through enhancing IGF-I-mediated survival signaling. We observed the ability of MG63 cells to support LNCaP tumor formation in nude mice coinoculated with LNCaP/MG63 cells. We also observed an increase in growth rate and PSA level in LNCaP/MG63-BP5 xenografts compared to LNCaP/MG63-mock xenografts both in intact and castrated mice. Immunohistochemical staining of these xenografts showed no difference in proliferation, however decreased apoptosis was seen in LNCaP/MG63-BP5 xenografts. Our study is the first to demonstrate that bone stroma-produced paracrine IGFBP-5 played a role in bone microenvironment that favors PCa cell survival as well as androgen-independent progression. We propose that IGFBP-5 can act as a reservoir for IGF-I that allows slowly release of IGF-I for receptor interactions, resulting in amplification of downstream signaling pathways, which promote cell survival. We concluded that this is an adaptive mechanism for PCa to resist undergoing apoptosis and survive under androgen deprivation stress.

Text

2011-03-02

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http://hdl.handle.net/2429/31887

Experimental Medicine

University of British Columbia

Graduate