Abstract 4030: Interactions between co-cultured myoblasts and prostate cancer cells kill myoblasts but promote cancer cell proliferation and fusion: implications for cachexia and metastasis to skeletal muscle

Abstract

Abstract Severe muscle loss (cachexia) is the major cause for the cancer related death and 70% prostate cancer patients suffer from cachexia. Multinucleated cells of skeletal muscles are generated and regenerated by cell-to-cell fusion. It has been suggested that cell-to-cell fusion also takes place during carcinogenesis and promotes tumor cell diversity, drug resistance and the ability to metastasize. However fusion between cancer cells has remained elusive due to a very low efficiency of this process in earlier studies. Here we explored interactions between cancer cells and muscle environment in vitro. Co-culturing cells of human prostate cancer line (PC3) with primary murine proliferating myoblasts (muscle stem cells) resulted in differentiation and then apoptosis in muscle stem cells. Conditioned medium from PC3 cells also caused 50% decrease in proliferation of muscle stem cells. On the other hand, fusion-committed myoblasts co-cultured with PC3 cells lost their characteristic shapes and went through apoptosis. In addition to these effects of PC3 cells on murine myoblasts, we observed striking effects of myoblasts on PC3 cells. Co-culturing of PC3 cells with either proliferating myoblasts or fusion-committed myoblasts resulted in a robust fusion between cancer cells that yielded PC3 syncytia with up to 5 nuclei. Fusion promotion between PC3 cells was accompanied by a 1.5-fold increase in expression of Annexin A5, a protein recently implicated in myoblast fusion. In contrast, the expression of Annexin A5 in myoblasts was halved. Both co-culturing and using conditioned medium from fusion-committed myoblasts also resulted in a 2-fold increase in cancer cells proliferation and a 3-fold increase in the expression of the phosphorylated protein kinase AKT (pAKT). pAKT activity is associated with proliferation, drug resistance and cancer stem cell phenotype generation. Therefore we examined cancer stem cell marker, CD133 expression in PC3 cells. Treatment with conditioned medium from either proliferating or fusion-committed myoblasts doubled a percentage of CD133-expressing cells. Our results suggest an intriguing interplay between prostate cancer and muscle cells that may contribute to the progression of cancer and potentially explain cachexia. Citation Format: Berna Uygur, Evgenia Leikina, Leonid V. Chernomordik. Interactions between co-cultured myoblasts and prostate cancer cells kill myoblasts but promote cancer cell proliferation and fusion: implications for cachexia and metastasis to skeletal muscle. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4030. doi:10.1158/1538-7445.AM2015-4030