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The Ron receptor promotes prostate tumor growth in the TRAMP mouse model

Oncogene volume 30, pages 4990–4998 (2011)Cite this article

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Abstract

The Ron receptor tyrosine kinase (TK) is overexpressed in many cancers, including prostate cancer. To examine the significance of Ron in prostate cancer in vivo, we utilized a genetically engineered mouse model, referred to as TRAMP mice, that is predisposed to develop prostate tumors. In this model, we show that prostate tumors from 30-week-old TRAMP mice have increased Ron expression compared with age-matched wild-type prostates. Based on the upregulation of Ron in human prostate cancers and in this murine model of prostate tumorigenesis, we hypothesized that this receptor has a functional role in the development of prostate tumors. To test this hypothesis, we crossed TRAMP mice with mice that are deficient in Ron signaling (TK−/−). Interestingly, TK−/− TRAMP+ mice show a significant decrease in prostate tumor mass relative to TRAMP mice containing functional Ron. Moreover, TK−/− TRAMP+ prostate tumors exhibited decreased tumor vascularization relative to TK+/+ TRAMP+ prostate tumors, which correlated with reduced levels of the angiogenic molecules vascular endothelial growth factor and CXCL2. Although Ron loss did not alter tumor cell proliferation, a significant decrease in cell survival was observed. Similarly, murine prostate cancer cell lines containing a Ron deficiency exhibited decreased levels of active nuclear factor-κB, suggesting that Ron may be important in regulating prostate cell survival at least partly through this pathway. In total, our data show for the first time that Ron promotes prostate tumor growth, prostate tumor angiogenesis and prostate cancer cell survival in vivo.

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Acknowledgements

We thank Sandy Schwemberger for her assistance with the flow cytometry experiments as well as Gina Ciovacco for her technical contributions. This work was supported by Public Health Services Grant CA-125379 (SEW) from the National Institutes of Health, and by Grant Project No. PC060821 (MNT) from the Department of Defense Congressionally Directed Medical Research Program.

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Authors and Affiliations

  1. Department of Cancer and Cell Biology, University of Cincinnati College of Medicine, Cincinnati, OH, USA

    M N Thobe, J K Gray, D Gurusamy, A M Paluch, P K Wagh, P Pathrose & S E Waltz

  2. Department of Surgery, University of Cincinnati College of Medicine, Cincinnati, OH, USA

    A B Lentsch

  3. Cincinnati Veterans Affairs Medical Center, Cincinnati, OH, USA

    S E Waltz

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  1. M N Thobe
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  2. J K Gray
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  3. D Gurusamy
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  4. A M Paluch
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  5. P K Wagh
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  6. P Pathrose
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  7. A B Lentsch
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  8. S E Waltz
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Correspondence to S E Waltz.

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Thobe, M., Gray, J., Gurusamy, D. et al. The Ron receptor promotes prostate tumor growth in the TRAMP mouse model. Oncogene 30, 4990–4998 (2011). https://doi.org/10.1038/onc.2011.205

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