Ron receptor overexpression in the murine prostate induces prostate intraepithelial neoplasia

Abstract

Previous studies have shown that the Ron receptor is overexpressed in prostate cancer and Ron expression increases with disease severity in humans and the mouse TRAMP model. Here, the causal role of Ron overexpression in the murine prostate was examined in the development and progression of prostate cancer. Transgenic mouse strains were generated which selectively overexpressed Ron in the prostate epithelium and prostate histopathology was evaluated and compared to wild type controls. Ron overexpression led to the development of prostate intraepithelial neoplasia (mPIN) with local invasion and was associated with increases in prostate cell proliferation and decreases in cell death.

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

“…Several reports have implicated the Ron receptor tyrosine kinase as a driver of tumorigenesis [4, 13, 14, 26, 27]. However, much less is known about the requirement of the Ron ligand, HGFL, in tumorigenesis.…”

“…Murine prostate histopathology was graded as previously defined [26]. Immunohistochemistry of prostate sections from paraffin-embedded 30-week-old wild-type (HGFL+/+), HGFL-/-, HGFL+/+ TRAMP+ and HGFL-/- TRAMP+ prostates were processed as described previously [4, 14].…”

Ron receptor tyrosine kinase signaling as a therapeutic target

“…Further, we demonstrated the important requirement for β-catenin in mammary tumorigenesis, as loss of β-catenin leads to a delay in mammary hyperplasia and reduced the metastatic burden in mice that overexpress Ron in the mammary epithelium [43]. Additionally, work in the prostate has supported the role of Ron in β-catenin activation where overexpression of Ron leads to accumulation of β-catenin protein and increased pErk [44]. This signaling paradigm is similar to that described in mammary tumors [45].…”

“…Erk activation can activate multiple pathways, including the phosphorylation and nuclear translocation of RSK, which leads to EMT [39]. Alternatively, Erk phosphorylates β-catenin, leading to nuclear translocation and increases in c-myc and cyclin D expression [44]. For HGFL independent activation, Ron activates FAK and leads to increased cell spreading and survival [29].…”

Receptor Tyrosine Kinases: Structure, Functions and Role in Human Disease

“…Only male mice were used for experiments. The Pb-Ron construct resulted in four founder lines, the ARR 2 Pb-Ron construct in two founder lines [ 468 ].…”