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Epithelial and Stromal Ron Receptor Expression Promotes Tumor Growth in a Murine Model of Prostate Cancer

Gurusamy, Devikala
http://rave.ohiolink.edu/etdc/view?acc_num=ucin1367929231

Abstract Details

2013, PhD, University of Cincinnati, Medicine: Molecular and Cellular Physiology.
The Ron receptor tyrosine kinase is an oncogene expressed on epithelial cells and on several tissue resident macrophage populations. Over-expression and/or constitutive activation of Ron have been reported in several epithelial cancers, including prostate cancer. To investigate the significance of Ron expression in prostate cancer our laboratory had 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 TK-/-, had decreased prostate tumor size when compared to wild type, TK+/+ mice. This study demonstrated the functional importance of Ron signaling in promoting prostate tumor growth; however, the data did not address the selective contributions of Ron signaling in epithelial versus stromal cells during tumorigenesis. Analysis for Ron expression by qRT-PCR showed Ron expression in normal prostate epithelial cells and stromal cells including macrophages. Utilizing human epithelial cell line PC-3, we demonstrated that knockdown of Ron in PC-3 cells leads to decreased prostate tumor growth and metastasis following orthotopic prostate transplantation compared to cells with high Ron expression suggesting that the Ron receptor expressed in epithelial cells is an important factor in prostate tumorigenesis. To test the significance of stromal Ron expression, prostate cancer cells were orthotopically implanted into the prostates of either TK+/+ or TK-/- hosts. In TK-/- hosts, prostate cancer cell growth was significantly reduced compared to controls, suggesting that Ron signaling in the tumor microenvironment is critical to prostate tumor development. Prostate tumors in TK-/- hosts exhibited an increase in tumor cell apoptosis, macrophage infiltration and altered cytokine expression. Reciprocal bone marrow transplantation studies and studies utilizing mice with myeloid cell specific ablation of Ron, demonstrated that loss of Ron in myeloid cells is sufficient to inhibit prostate cancer cell growth. Interestingly, depletion of CD8+ T-cells, but not CD4+ T-cells, was able to restore prostate tumor growth in hosts devoid of myeloid-specific Ron expression. These studies demonstrated a critical role for the Ron receptor in the tumor microenvironment, whereby Ron loss in tumor-associated macrophages inhibits prostate cancer cell growth, at least in part, through the regulation of CD8+ T lymphocytic activity. We also demonstrated that Ron deficient macrophages function dominant negatively and its potential use as an immunotherapeutic tool for therapeutic intervention. Furthermore, bone marrow transplantation experiments hinted the importance of Ron expression on other non-hematopoietic stromal cells, as TK+/+ myeloid cells were not able to promote tumor growth in the TK-/- animals. Our data shows that Ron is expressed on fibroblasts isolated from normal and tumor bearing prostates and that Ron expression in the fibroblasts increases TRAMP-C2Re3 tumor growth in an in vivo co-culture model system. Taken together, we propose a model that Ron expression in epithelial cells, tumor associated macrophages and tumor associated fibroblasts is important for supporting prostate tumorigenesis. Targeting Ron in the clinic would be thus beneficial for the treatment of prostate cancer through its impact on multitude of cell types.
Susan Waltz, PhD (Committee Chair)
Vladimir Kalinichenko, M.D. Ph.D. (Committee Member)
David Plas, Ph.D. (Committee Member)
Shao-Chun Wang, Ph.D. (Committee Member)
Shao-Chun Wells, Ph.D. (Committee Member)
Aaron Zorn, Ph.D. (Committee Member)
136 p.
Oncology
Ron receptor; Tumor Microenvironment; MST1R; Tumor associated Macrophages; Myeloid cells; Tumor Associated Fibroblasts;

Recommended Citations

Citations

  • Gurusamy, D. (2013). Epithelial and Stromal Ron Receptor Expression Promotes Tumor Growth in a Murine Model of Prostate Cancer [Doctoral dissertation, University of Cincinnati]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1367929231

    APA Style (7th edition)

  • Gurusamy, Devikala. Epithelial and Stromal Ron Receptor Expression Promotes Tumor Growth in a Murine Model of Prostate Cancer. 2013. University of Cincinnati, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=ucin1367929231.

    MLA Style (8th edition)

  • Gurusamy, Devikala. "Epithelial and Stromal Ron Receptor Expression Promotes Tumor Growth in a Murine Model of Prostate Cancer." Doctoral dissertation, University of Cincinnati, 2013. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1367929231

    Chicago Manual of Style (17th edition)

ucin1367929231
465
© , some rights reserved.Creative Commons License Epithelial and Stromal Ron Receptor Expression Promotes Tumor Growth in a Murine Model of Prostate Cancer by Devikala Gurusamy is licensed under a Creative Commons Attribution-NonCommercial-NoDerivs 3.0 Unported License. Based on a work at etd.ohiolink.edu.
This open access ETD is published by University of Cincinnati and OhioLINK.
Release 3.2.12