Abstract 1091: Role of growth differentiation factor-15 in prostate cancer-bone environment: Understanding on bone metastasis
Authors: Jawed A. Siddiqui, Sakthivel Muniyan, Parthasarathy Seshacharyulu, Satyanarayana Rachagani, Suprit Gupta, Mohd W. Nasser, Kaustubh Datta, Surinder K. Batra
Journal: Cancer Research (2018)

Abstract Background: Prostate cancer (PCa) cells preferentially metastasize to bone and skeleton resulting in the poor 5-year survival of less than 1%. Growth differentiation factor-15 (GDF15) is overexpressed in several cancers, including PCa. However, the role of GDF15 in prostate cancer bone metastasis remains elusive. The interaction between cancer cells and the bone microenvironment forms a vicious cycle that increases bone deformities and drives tumor growth in the bone. Therefore, we question whether GDF15 secreted by the PCa cells alters the bone environment by uncoupling bone formation and resorption. Methods: Murine calvarial-derived osteoblast (MCO) cells were used for the functional effect of GDF15 on differentiation, proliferation, and mineralization. Mineralization of mouse bone marrow stromal cell (BMSCs) derived osteoblasts was determined by Alizarin Red S staining. Bone marrow macrophages (BMMs) were isolated from C57 mice and cultured along with M-CSF and RANKL to identify osteoclasts. Results: Conditioned media (CM) from PCa (LNCaP and C4-2B) cells and rhGDF15 increased osteoblast proliferation and differentiation in MCO cells. However, GDF15 deletion in PCa (LNCaP and C4-2B) cells prevented PCa-mediated osteoblast differentiation. Further, CM from PCa and rhGDF15 increased the alkaline phosphatase+ CFU-F (Colony Forming Unit- Fibroblast) in mouse bone marrow stromal cells culture. Supportively, stable knockout of GDF15 decreased mineralized nodule formation in MCO. qRT-PCR assay revealed that the PCa and rhGDF15 increased mRNA expression of osteoblast-related genes such as alkaline phosphatase, Runx-2, collagen type-1 and osteocalcin. PCa cells derived CM and rhGDF15 increase the osteoblast-derived osteoclastic signal (RANKL/OPG ratio), suggesting that GDF15 promotes RANKL-dependent osteoclastogenesis. Furthermore, rhGDF15 treatment increased TRAP-positive multinucleated cells, pit resorption and osteoclast-specific genes such as TRAP, Cathepsin K, Carbonic anhydrase and NFATc1 in BMMs. Conclusions: Altogether, our results suggest that GDF15 is crucial for PCa-mediated osteoblast differentiation and mineralization. GDF15 also increased bone marrow osteoclast formation and its function. Our finding suggests that GDF15 mediated increase in osteoblastic-RANKL further enhance osteoclast activity and favor PCa cell to metastasize to bone. Citation Format: Jawed A. Siddiqui, Sakthivel Muniyan, Parthasarathy Seshacharyulu, Satyanarayana Rachagani, Suprit Gupta, Mohd W. Nasser, Kaustubh Datta, Surinder K. Batra. Role of growth differentiation factor-15 in prostate cancer-bone environment: Understanding on bone metastasis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1091.