Abstract
The Ron receptor is deregulated in a variety of cancers. Hepatocyte growth factor-like protein (HGFL) is the ligand for Ron and is constitutively secreted from hepatocytes into the circulation. While a few recent reports have emerged analyzing ectopic HGFL overexpression of in cancer cells, no studies have examined host-produced HGFL in tumorigenesis. To examine HGFL function in prostate cancer, the TRAMP mouse model, which is predisposed to develop prostate tumors, was utilized. Prostate tumors from TRAMP mice exhibit elevated levels of HGFL, which correlated with upregulation in human prostate cancer. To directly implicate HGFL in prostate tumorigenesis, TRAMP mice deficient in HGFL (HGFL-/-TRAMP+) were generated. HGFL-/- TRAMP+ mice developed significantly smaller prostate tumors compared to controls. Analysis of HGFL-/- tumors revealed reduced tumor vascularization. No differences in cancer cell proliferation were detected between HGFL-/- TRAMP+ and HGFL+/+ TRAMP+ mice. However, a significant increase in cancer cell death was detected in HGFL-/- TRAMP+ prostates which correlated with decreased pro-survival targets. In vitro analysis demonstrated robust STAT3 activation resulting in Bcl2-dependent survival following treatment of prostate cancer cells with HGFL. These data document a novel function for endogenous HGFL in prostate cancer by imparting a critical survival signal to tumor cells.
Highlights
Prostate cancer persists as one of the highest incidences of cancer in men in the United States
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], our findings did not clarify if the functional role of Ron in prostate cancer was dependent on ligand activation
Several reports have implicated the Ron receptor tyrosine kinase as a driver of tumorigenesis [4, 13, 14, 26, 27]
Summary
Receptor tyrosine kinases have been implicated in the development and progression of various cancers including prostate cancer [reviewed in [2]]. Hepatocyte growth factor-like protein, HGFL, is the ligand for Ron receptor tyrosine kinase. 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], our findings did not clarify if the functional role of Ron in prostate cancer was dependent on ligand activation. 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
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