Role of Macrophages in the Development of Castration-Resistant Prostate Cancer

Prostate cancer (PCa) is the second most common cancer affecting men in Canada and USA, and accounts for thousands of deaths each year. While most prostate tumours are considered localized disease at initial diagnosis and can be treated with androgen-deprivation therapy (ADT), tumours eventually progress to become therapeutically resistant (castration-resistant prostate cancer, CRPC) and metastasize. The objective of this study was to investigate the role of chronic inflammation in the progression of tumours to become CRPC, and we hypothesized that Timp3 loss and increased post-castration inflammation would confer androgen-independent growth to androgen-dependent PCa cells. RM2 cells are a mouse PCa cell line on a C57Bl/6 (B6) background that are sensitive to ADT. We injected RM2 cells into the dorsolateral prostates of Timp3+/+ (WT) or Timp3-/- (KO) mice (both on a B6 background). Mice bearing established orthotopic tumours underwent either castration or sham surgery and were euthanized at 3 or 6 days post-surgery (DPS). Gross and histopathologic data were collected, and tumours were immunostained for CD3 and F4/80. In parallel in vitro experiments, bone marrow-derived macrophages of WT or KO mice were grown on their own, or in co-culture with RM2 cells, and culture media (conditioned media, CM) was collected. Naïve RM2 cells were exposed to CM in a variety of cell culture experiments. Similar experiments were performed using human macrophages differentiated from THP-1 cells (a monocytic leukemia cell line) and LNCaP cells (androgen-sensitive PCa cell line). Tumours in castrated WT mice were smaller than in sham mice, while those in KO mice were slightly larger than sham (mock castration) mice. There were significantly more macrophages in KO mice at 3 DPS compared to WT. RM2 cells exposed to CM from macrophages or co-cultured cells had greater growth than those exposed to fresh androgen-depleted media. LNCaP cells demonstrated similar trends. A multiplex cytokine ELISA performed on CM identified CCL4 and IL-12 as potential effectors in the mechanism for LNCaP cells, while neither cytokine convincingly altered growth of RM2 cells. These data indicate a role for macrophages in the development of CRPC, and point to macrophage-derived cytokines as potential mediators.

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