Abstract 527: Loss of TGF-β responsiveness in stromal cells of the prostate facilitates early prostate cancer bone lesion development

Abstract

Abstract The death of late stage prostate cancer patients is commonly due to incurable bone metastasis. Prostate cancer associated fibroblasts (CAF) play a role in cancer progression at the primary site, however it is unclear whether they are significant players at the bone metastatic site. We hypothesize that the primary CAF facilitate prostate tumor cell establishment in the bone environment and initial bone lesion development. Around two thirds of human prostate cancer tissues show loss of stromal TGFbeta type II receptor (Tgfbr2) expression at the primary site. We observed Tgfbr2 expression was also lost in bone marrow adjacent to prostate cancer cells. In addition, prostate cancer bone metastases expressed androgen receptor (AR) in the cancer cells and alpha-smooth muscle actin (SMA) in the adjacent CAF. Neither AR nor SMA was seen in the bone marrow environment when no prostate cancer cells were present. A mouse model of conditional Tgfbr2 knock-out in the stromal cells was used in this study. Since there is no evidence, so far, of CAF metastasis along with cancer cells, we focused on the paracrine effects of CAFs from primary site on prostate cancer bone metastasis. GFP labeled prostate cancer C4-2B cells, were incubated with conditioned medium from primary cultured Tgfbr2-flox or Tgfbr2-KO mouse prostate stromal cells for 48hrs. The C4-2B cells were then injected into the tibiae of SCID mice. Bone lesion was monitored weekly and the tumor growth was imaged by Maestro when the tibiae were harvested. It was found that the conditioned medium from Tgfbr2-KO mice prostate stromal cells promoted prostate cancer growth in the bone and mixed bone lesion development early at week 4 and week 5. The incidence and area of the bone lesions were not significant different between week 6 and 10. The tumor growth in the tibia was not different week 10. After 48 hr of incubation with the conditioned medium from Tgfbr2-KO mice prostate stromal cells, the adhesion of C4-2B cells to collagen I was increased by 5.8 fold compared to the cells without previous conditioned media incubation, and 1.5 fold compared to incubation with stromal conditioned medium from Tgfbr2-Flox mice. To examine the secreted factors from the Tgfbr2-KO prostate stromal cells we performed cytokine antibody array analysis. GCSF, KC(Cxcl1), Cxcl16, LIX(Cxcl5) and Decorin were found to be increased more than 2 fold in the medium conditioned by prostate stromal cells from Tgfbr2-KO mice compared to that conditioned by Tgfbr2-flox mice. In conclusion, loss of TGF-β responsiveness in prostate stromal cells resulted in up-regulation of some cytokines. These changes are proposed to increase prostate cancer cell adhesion in the bone microenvironment promoting early establishment of prostate cancer cells in the bone and subsequent bone lesion development. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 527. doi:10.1158/1538-7445.AM2011-527