Neuroendocrine Differentiation in Prostate Cancer: Role of Bone Morphogenetic Protein-6 and Macrophages

摘要

In the grant proposal we have hypothesized that tumor-derived bone morphogenetic protein-6 (BMP-6) induces tumor associated macrophages (TAMs) to express interleukin-6 (IL-6) via a crosstalk between the Smad-dependent and the p38 pathway; IL-6 in turn drives neuroendocrine (NE) differentiation of prostate cancer cells. To test this proposal, three specific aims were proposed: (1) To investigate the mechanism of NE differentiation induced by BMP- 6 in vivo; (2) To investigate the mechanism of IL-6 induction by BMP-6 in macrophages; (3) To study the efficacy of dorsomorphin, a small molecule inhibitor of BMP signaling, on NE differentiation of prostate cancer in vivo. To date, aims 1 and 2 have been completed while aim 3 is currently progressing. When BMP-6 overexpressing prostate cancer cell line Tramp-BMP6 was injected subcutaneously into IL-6 knockout (KO) and conditional macrophage-null mice, neuroendocrine differentiation was no longer observed. Mechanistically, series of studies including shRNA knockdowns and immunoprecipitation assays have confirmed that Smad5 and GAT4 interact to induce IL-6 expression in macrophages. Currently, these finding are being confirmed in vivo using a small molecule inhibitor of BMP-6, dorsomorphine.