Abstract 3596: The role of PIM1 kinase in the prostate tumor microenvironment

Abstract

Abstract Prostate cancer (PCa) remains the second leading cause of cancer-related deaths in men. The prostate is a tubulo-alveolar gland composed of epithelial tissues embedded in stromal components. PCa includes reactive stroma which consists of myofibroblasts and extracellular matrix (ECM) remodeling. Increasing evidence suggests that myofibroblasts may refine the prognostic assessment of tumors. The PIM1 serine/threonine protein kinase is a true oncogene and has been implicated in the initiation and progression of multiple cancer types including PCa. The level of PIM1 correlates with the disease state and Gleason grade and has been shown to stimulate growth of murine prostate cancer. The role of PIM1 in prostate stromal cells has never been investigated. Using human prostate tissue microarray analysis we now demonstrate that (1) the PIM1 protein is detected in human stroma adjacent to cancer tissue; (2) stromal cells isolated from PIM1 knockout mice contain a decreased number of myofibroblasts and expose slow growth rate when compared with wild type control, suggesting that kinase expression can alter stromal cell composition and proliferation; (3) elevated level of PIM1 kinase in human benign prostate stromal cells increases migration and growth of prostate epithelial cells and this effect can be reversed by PIM inhibitors; (4) PIM1 over-expressing stromal cells increase epithelial cell growth in tissue regeneration model; (5) stromal cells with elevated level of PIM1 expose increased number of myofibroblasts when co-cultivated with prostate epithelial cells. These data suggest that PIM1 kinase may contribute in formation of a “reactive stroma” phenotype. We used the conditioning media analysis to decipher the PIM1 specific signal transduction pathways that may lead to stroma activation and drive prostate cancer growth. Using cytokine/chemokine arrays and ECM protein analysis we found that overexpression of PIM1 kinase in stromal cells is associated with elevated level of CCL5 chemokine and increased secretion of collagen1. Examination of the pathways involved in formation of myofibroblasts revealed that PIM1 can modulate activation of PDGFRβ leading to the increased CCL5 expression. We are suggesting that PIM1 is a modulator of stromal cells response to the stimuli produced by prostate epithelial cells through increase of matrix stiffness, receptor activation and accumulation of myofibroblasts which induce further ECM remodeling and expression of the growth factors leading to epithelial cells transformation and cancer propagation. Citation Format: Marina Zemskova, Andrew S. Kraft. The role of PIM1 kinase in the prostate tumor microenvironment. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3596. doi:10.1158/1538-7445.AM2014-3596