title: The Ron receptor promotes prostate tumor growth in the TRAMP mouse model.
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.
authors.affiliation: Department of Cancer and Cell Biology, University of Cincinnati College of Medicine, OH, USA.
authors.forename: M N
authors.initials: MN
authors.lastname: Thobe
authors.forename: J K
authors.initials: JK
authors.lastname: Gray
authors.forename: D
authors.initials: D
authors.lastname: Gurusamy
authors.forename: A M
authors.initials: AM
authors.lastname: Paluch
authors.forename: P K
authors.initials: PK
authors.lastname: Wagh
authors.forename: P
authors.initials: P
authors.lastname: Pathrose
authors.forename: A B
authors.initials: AB
authors.lastname: Lentsch
authors.forename: S E
authors.initials: SE
authors.lastname: Waltz
mesh_terms: D000818:Animals; D049109:Cell Proliferation; D002470:Cell Survival / Q000235:genetics; D054426:Chemokine CXCL2 / Q000235:genetics / Q000378:metabolism; D003433:Crosses, Genetic; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism*; D009389:Neovascularization, Pathologic / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D011471:Prostatic Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism*; D053219:Receptors, Tumor Necrosis Factor, Member 25 / Q000235:genetics / Q000378:metabolism*
chemical_list: D054426:Chemokine CXCL2; C404915:Cxcl2 protein, mouse; D016328:NF-kappa B; D009363:Neoplasm Proteins; D053219:Receptors, Tumor Necrosis Factor, Member 25; C506034:Tnfrsf25 protein, mouse; C080835:RON protein; D020794:Receptor Protein-Tyrosine Kinases