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

• Published in: Oncogene Vol. 30; no. 50; pp. 4990 - 4998
• Main Authors: Thobe, M N, Gray, J K, Gurusamy, D, Paluch, A M, Wagh, P K, Pathrose, P, Lentsch, A B, Waltz, S E
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 15.12.2011; Nature Publishing Group
• Subjects: 692/420/755; 692/699/67/589/466; Angiogenesis; Animal models; Animals; Apoptosis; Biological and medical sciences; Care and treatment; Cell Biology; Cell growth; Cell physiology; Cell Proliferation; Cell receptors; Cell structures and functions; Cell survival; Cell Survival - genetics; Cell transformation and carcinogenesis. Action of oncogenes and antioncogenes; Chemokine CXCL2 - genetics; Chemokine CXCL2 - metabolism; Chemokines; Crosses, Genetic; Data processing; Diagnosis; Disease Models, Animal; Female; Fundamental and applied biological sciences. Psychology; Genetic engineering; Growth factors; Health aspects; Human Genetics; Humans; Internal Medicine; Kinases; Male; Medical sciences; Medicine; Medicine & Public Health; Mice; Mice, Knockout; Miscellaneous; Molecular and cellular biology; Neoplasm Proteins - genetics; Neoplasm Proteins - metabolism; Neovascularization, Pathologic - genetics; Neovascularization, Pathologic - metabolism; Neovascularization, Pathologic - pathology; Nephrology. Urinary tract diseases; NF-kappa B - genetics; NF-kappa B - metabolism; Oncology; original-article; Physiological aspects; Prostate cancer; Prostatic Neoplasms - genetics; Prostatic Neoplasms - metabolism; Prostatic Neoplasms - pathology; Protein-tyrosine kinase; Protein-tyrosine kinase receptors; Receptor Protein-Tyrosine Kinases - genetics; Receptor Protein-Tyrosine Kinases - metabolism; Receptors, Tumor Necrosis Factor, Member 25 - genetics; Receptors, Tumor Necrosis Factor, Member 25 - metabolism; Signal transduction; Transcription factors; Tumor cell lines; Tumor cells; Tumorigenesis; Tumors; Tumors of the urinary system; Tyrosine; Urinary tract. Prostate gland; Vascular endothelial growth factor; Vascularization; United States; United States > US; prostate cancer; receptor tyrosine kinase; MST1R; hepatoctye growth factor-like protein; Ron receptor; Animal model; Prostate tumor; Urinary system disease; Prostate disease; Enzyme; Transferases; Rodentia; Malignant tumor; Carcinogenesis; Protein; Vertebrata; Mammalia; Mouse; Male genital diseases; Prostate cancer; Protein-tyrosine kinase; Cancer; Growth factor; Biological receptor
• ISSN: 0950-9232; 1476-5594
• DOI: 10.1038/onc.2011.205

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 .