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

Abstract

The Ron receptor tyrosine kinase is overexpressed in many cancers, including prostate cancer. In order 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 demonstrate that prostate tumors from 30-week-old TRAMP mice have increased Ron expression compared to 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 plays 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 VEGF and CXCL2. While 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 NF-kappaB 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.

Hepatocyte growth factor-like protein is required for prostate tumor growth in the TRAMP mouse model

“…However, a significant increase in the number of TdT-mediated dUTP nick end labeling (TUNEL) positive cells was detected in HGFL-/- TRAMP+ prostate tumors (Figure 5B). This finding correlated with previous findings wherein prostate tumors from Ron tyrosine kinase deficient (TK-/-) TRAMP+ mice also exhibited reduced survival [13]. To further analyze prostate epithelial cell survival, Cleaved-Caspase 3 immunohistochemical staining was performed on prostate tumors from mice proficient and deficient for HGFL.…”

“…Upon further analyses of downstream signaling targets of HGFL-induced Ron activation, decreases in the activation of AKT and MAPK were observed in prostate tumors of HGFL-/- TRAMP+ mice compared to HGFL+/+ TRAMP+ mice. We previously showed that prostate tumors from TRAMP+ mice deficient for Ron signaling exhibited reduced levels of nuclear NF-κB, suggesting reduced NF-κB activity [13]. Surprisingly, no appreciable differences in NF-κB signaling were detected between prostate tumors from HGFL+/+ TRAMP+ and HGFL-/- TRAMP+ mice (data not shown).…”

“…Given that our previous studies demonstrated that loss of Ron was important for the formation of the prostate tumor vasculature in TRAMP+ mice [13], we next assessed whether prostate tumor vessel formation was ligand dependent. Prostate tumor sections from HGFL+/+ TRAMP+ and HGFL-/- TRAMP+ mice were immunostained for CD31 expression.…”

“…Prostates of male TRAMP mice develop hyperplastic regions by 10 weeks, and by 28 weeks of age 100% of mice develop prostate cancer [17]. We have previously utilized this mouse model of prostate cancer to show the functional importance of the Ron receptor tyrosine kinase in prostate tumorigenesis [13], however our findings did not clarify if the functional role of Ron in prostate cancer was dependent on ligand activation. In this report, we demonstrate that HGFL is a critical factor for the development of prostate tumorigenesis in this model through the promotion of the oncogenic activation of Ron and the induction of strong signals required for efficient prostate cancer cell survival.…”

“…Ron activation triggers a wide variety of downstream signaling cascades that are utilized in cellular proliferation, migration and cell scattering amongst others [10, 12]. Recently, we have shown that in murine models of breast and prostate cancer, mice deficient in Ron downstream signaling present with reduced tumor burden [13, 14]. Despite our knowledge of Ron, HGFL function in tumorigenesis has not been well studied.…”