Abstract A6: Epithelial and myeloid-specific Ron receptor expression promotes tumor growth in a murine model of prostate cancer
Authors: Gurusamy Devikala , Gray Jerilyn K. , Kulkarni Rishikesh M. , Finkleman Fred D. , Waltz Susan E. 
Published: June 2012

Abstract
The Ron receptor tyrosine kinase is expressed on epithelial cells and in several tissue resident macrophage populations. Over-expression and/or constitutive activation of the Ron receptor have been reported in several epithelial cancers, including prostate cancer. To investigate the significance of Ron receptor expression in prostate cancer our laboratory has examined the loss of function of Ron in the transgenic adenocarcinoma of the mouse prostate (TRAMP) mouse model. In this model, TRAMP mice crossed with mice that have a germline loss of the tyrosine kinase signaling domain of Ron referred to as the TK-/- mice had decreased prostate tumor size when compared to the wild type mice TK +/+. This study demonstrated the functional importance of Ron signaling in promoting prostate tumor growth; however, the data do not address the selective contributions of Ron signaling in epithelial versus stromal cells in tumor formation. Analysis of Ron expression by qRT-PCR in normal prostates and in several epithelial and stromal cell types indicated Ron expression in prostate epithelial cells and stromal cells including the macrophages. Utilizing human cell lines, we demonstrated that knockdown of Ron in PC-3 luc cells leads to decreased prostate tumor development and metastasis following orthotopic transplantation into the prostate compared to cells with high Ron expression suggesting that the Ron receptor expressed in epithelial cells is an important factor in prostate tumorigenesis. Given the expression pattern of Ron in the various stromal cell types, Ron expressing TRAMPC2RE3 tumor cells were orthotopically implanted into the prostates of TK +/+ and TK-/- animals. Our data shows that prostate tumor cells transplanted into TK-/- mice exhibited a significant decrease in prostate tumor growth compared to cells transplanted into TK +/+ prostates, suggesting that Ron signaling in the tumor microenvironment is critical to prostate tumor development in this model. Reciprocal bone marrow transplantation studies and studies using mice that have myeloid specific deletion of Ron, have demonstrated the importance of the Ron signaling pathway in myeloid cells for promoting tumor growth. Current studies are underway to examine the Ron dependent signaling pathways and molecules that contribute to prostate tumor growth. Taken together, our work has uncovered the novel role of the Ron receptor in regulating both the tumor intrinsic and extrinsic cellular compartments in regulating tumor growth and suggests that the Ron receptor signaling pathway may be a novel and efficacious therapeutic target in the treatment of this disease through targeting of multiple cell types.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the Second AACR International Conference on Frontiers in Basic Cancer Research; 2011 Sep 14-18; San Francisco, CA. Philadelphia (PA): AACR; Cancer Res 2011;71(18 Suppl):Abstract nr A6.