Abstract 925: IL-4 / IL-13 mediated cell-to-cell fusion in prostate cancer progress

Abstract

Abstract Poorly understood interactions between prostate cancer (PCa) cells and their microenvironment direct the epithelial to mesenchymal transition (EMT) during disease progression. Cell-to-cell fusion, such as cell fusion in muscles and placenta, is one of the ways in which cells can drastically change their properties. Cell fusion has been proposed to promote tumor cell diversity and the ability to metastasize. Metastatic disease has been also suggested to depend on the interleukin 4 (IL-4) signaling. Patients with hormone-refractory PCa have elevated levels of IL-4 and it has been proposed that targeting IL4 -receptor interactions limits metastatic disease. Here, to mimic conditions at the interphase between rhabdosphincter myofibers and apical anterior regions of prostatic gland we explored interactions of PC3 cells (human PCa cell line) with skeletal muscle cells. Co-culturing of these cells resulted in an elevated concentration of related cytokines IL-4 and/or IL-13 in the tissue culture medium from the co-cultured cells but not from muscle cells cultured on their own. The co-culturing (i); the application of the conditioned medium from the co-cultured cells (ii); and treating PC3 cells with recombinant IL-4 (iii) resulted in a robust fusion between PC3 cells, in a significant increase in the percentage of PC3 cells expressing stem cell marker CD133, in the drug resistance, in an increase of the expression of mesenchymal-characteristic markers pAKT, MMP9, desmin, and in the loss of E-cadherin that is another marker for EMT. The described effects required co-culturing of the PC3 cells and muscle cells. Moreover, the co-culturing and recombinant IL-4 application also upregulated the expression of the two proteins - annexin A5 and syncytin that play important role in several cell-cell fusion processes. Significantly, application of either (i) IL-4-neutralizing antibodies or (ii) peptide inhibitors of syncytin; and (iii) lowering annexin A5 expression suppressed cell proliferation and fusion. Our findings substantiate a hypothesis that IL-4 and IL-13 in the microenvironment of PCa cells promote the EMT and raise metastatic potential of PCa cells by their fusion mediated by upregulated syncytin- and annexin A5. Citation Format: Berna Uygur, Evgenia Leikina, Leonid Chernomordik. IL-4 / IL-13 mediated cell-to-cell fusion in prostate cancer progress. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 925.