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

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 in cancer cells, no studies have examined the effect of 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.

HGFL supports mammary tumorigenesis by enhancing tumor cell intrinsic survival and influencing macrophage and T-cell responses

“…Importantly, this is the first study to describe the tumor cell autonomous production of HGFL from mammary tumors cells. Recent publications from our group have shown that HGFL expression is present in the developing mammary gland as well as in prostate tumor cells [ 39 , 50 ]. In this study, we demonstrate heightened HGFL mRNA expression during tumorigenesis.…”

Tumor Cell Autonomous RON Receptor Expression Promotes Prostate Cancer Growth Under Conditions of Androgen Deprivation

“…RON receptor signaling has been established as a central factor in promoting prostate cancer in several murine models [6] , [12] , [13] , [16] , [17] . To assess the significance of RON expression in human prostate cancer, multiple human data sets were analyzed using the Cancer Outlier Profile Analysis (COPA) method [20] , [21] , [22] , [23] , [24] , [25] , [26] , [27] .…”

“…RON is a cell surface RTK that is primarily expressed on epithelial cells and select macrophage populations, where activation of RON will function to reduce inflammation and promote wound healing [6] , [7] , [8] , [9] , [10] , [11] . Overexpression of RON has been observed in a number of solid cancers, and within cancer, RON promotes phenotypes such as survival, proliferation, migration/invasion, angiogenesis, and stemness [12] , [13] , [14] , [15] . Specifically, in prostate cancer, previous studies have established the RON receptor as critical for cancer development and progression [6] , [12] , [16] , [17] .…”

“…Selective overexpression of RON in the prostate epithelium of mice induces prostate intraepithelial neoplasia with invasion or adenocarcinoma in the majority of animals, indicating RON as sufficient to drive prostate cancer [16] . The necessity of RON signaling for prostate cancer growth was determined through genetic loss of RON signaling in the probasin driven T-antigen (PB-TAg/TRAMP) murine model of prostate cancer, where mice deficient in RON signaling developed significantly smaller prostate tumors compared to control mice [13] , [17] . Furthermore, plasma levels of the ligand for RON (hepatocyte growth factor-like protein/macrophage stimulating protein) positively correlate with prostate cancer progression in patients and were observed to be significantly elevated in CRPC patients [18] .…”

“…Furthermore, plasma levels of the ligand for RON (hepatocyte growth factor-like protein/macrophage stimulating protein) positively correlate with prostate cancer progression in patients and were observed to be significantly elevated in CRPC patients [18] . Mechanistically, our laboratory has connected RON to activation of several oncogenic signaling pathways in prostate cancer, such as NF-κB/RELA, STAT3, and BCL-2 signaling [12] , [13] , [14] , [19] . Despite the strides made in understanding the function of RON in prostate cancer, research regarding its role in promoting CRPC has been minimal but is of the utmost importance due to the high number of deaths each year resulting from this form of disease.…”