IGFBP-5 in the bone and bone marrow is a therapeutic target for metastatic prostate cancer

B38

Introduction: Anti-IGFBP-5 therapies are under development for the treatment of metastatic prostate cancer as IGFBP-5 stimulates cancer growth. IGFBP-5 expression increases in prostate cancer cells after androgen ablation. High levels of IGFBP-5 in the body are normally observed in the bone and bone marrow stroma. Therefore we questioned whether IGFBP-5 is regulated by androgen in the environment prostate cancer cells that have disseminated to the bone marrow.Methods: Gene expression in bone and bone marrow samples from castrated and sham-operated C57BL/6J mice was analyzed using a microarray with 16,000 cDNA probes. Differentially expressed genes were determined as with a 1.5 fold difference and a false discovery rate < 5% using SAM. Cells expressing IGFBP-5 in mouse bone and bone marrow were determined by IHC. Expression of IGFBP-5 in human primary and HS27a immortalized bone marrow stromal cells was measured by qPCR and Western blot. Proliferation of P69 immortalized prostate epithelial cells on extracellular matrices that were treated with recombinant IGFBP-5 was determined by MTS assay.Results: Expression of 249 genes changed in bone and bone marrow after castration, including 22 genes encoding extracellular proteins. Most changes were reversed by androgen supplementation. The most significant and consistent change was an increase in IGFBP-5 expression. IHC indicated that bone marrow stromal cells, osteoblasts and endothelial cells express IGFBP-5 in mouse bone marrow. IGFBP-5 was secreted and deposited into extracellular matrix by human primary bone marrow stromal and HS27a cells and expression of IGFBP-5 was regulated by androgen. When bound to extracellular matrix, IGFBP-5 sequestered IGF-1 or IGF-2 and increased the proliferation of P69 prostate epithelial cells.Conclusions: We conclude from these results that androgen ablative therapy increases the expression of IGFBP-5 in the bone and bone marrow microenvironment and that this might promote the growth of prostate cancer cells. Therefore, therapeutic approaches targeting IGFBP-5 are indicated as an adjunct to androgen withdrawal. Inhibition of IGFBP-5 would prevent the development of androgen-independent prostate cancer cells and inhibit the progression of metastatic prostate cancer.