Normal and Malignant Prostate Epithelial Cells Differ in Their Response to Hepatocyte Growth Factor/Scatter Factor

Abstract

Hepatocyte growth factor/scatter factor (HGF/SF) promotes the proliferation, differentiation, motility, and invasion of epithelial cells by binding to its cell surface receptor, the Met tyrosine kinase. In the prostate, Met is expressed predominantly by prostate epithelial cells (PrEC), whereas HGF/SF is synthesized by prostate stromal cells (PrSCHepatocyte growth factor/scatter factor (HGF/SF) 1,2 has been implicated in the communication between stromal and epithelial cells of many different organs. HGF/SF is secreted predominantly by stromal cells and binds to its receptor, Met 3,4 mostly expressed on epithelial cells. Activation of the Met receptor tyrosine kinase affects a wide range of cellular processes, including growth and differentiation, morphogenesis and invasiveness. [5][6][7] The critical function of HGF/SF-Met in early development and during organogenesis is illustrated by the expression of Met in human embryonic tissues and by the identical phenotypes of HGF/SF and Met targeted knockout mice with early placental and hepatic defects. 8 -10 Gerald Cunha and collaborators 11,12 demonstrated the reciprocal nature of interactions between the stroma and epithelium in the determination of final organ structure. Several studies have suggested that mechanisms mediating the inductive interactions between the stroma and normal epithelium may also stimulate neoplastic cells during carcinogenesis and metastasis. 11,[13][14][15] This occurs through inappropriate expression or activation of receptors for stromal derived growth factors in tumor cells. 16 One of these receptors is Met which is aberrantly expressed or activated in a variety of human cancers. [17][18][19][20] Met was originally identified by its oncogenic potential in gene transfer experiments with DNA from transformed osteogenic sarcoma cells using the NIH 3T3 cell focus forming assay. 3 Dimerization of the cytoplasmic Met kinase activates its oncogenic function. 4,21 Constitutive Met activation is achieved through germline or somatic mutations in the Met kinase domain as detected in familial papillary renal cell carcinomas. 22,23 Transgenic expression of two independent strongly activating Met mutations as well as transgenic expression of tpr-met resulted in mammary carcinogenesis. 24,25 Furthermore, Met can be persistently activated through autocrine stimulation in tumor cells co-expressing Met and HGF/ SF. 26 -31 Based on the ability of HGF/SF to cause the dissociation of tumor cells from the primary tumor mass, to stimulate cell motility, and to elicit the activation of proteolytic cascades that degrade the extracellular matrix, 32-34 the HGF/SF-Met ligand-receptor system is a likely regulator of tumor metastases. As previously demonstrated, autocrine secretion of HGF/SF promotes metastases in a mouse model of tumor metastasis and Supported by Department of the Army grant DAMA-17-98-1-8592 (to B.S.K.).

Enhanced invasion of hormone refractory prostate cancer cells through hepatocyte growth factor (HGF) induction of urokinase‐type plasminogen activator (u‐PA)

“…Recently, others have reported that HGF enhances the in vitro attachment to and subsequent invasion through Matrigel of DU145 and PC-3 human CaP cells [34][35][36]. It has also been shown that the serum level of HGF in men with metastatic CaP is significantly elevated compared to men with localized disease [37].…”

Imatinib mesylate inhibits the proliferation-stimulating effect of human lung cancer-associated stromal fibroblasts on lung cancer cells

“…Taken together, these findings suggested that the growth stimulants produced by CAFs in lung tumor promoted the proliferation of lung cancer cells in a paracrine manner. Furthermore, other reports have shown that growth factors and angiogenic factors, such as HGF, FGFs and VEGF, were induced or up-regulated in CAFs and that the up-regulation promoted proliferation and progression of cancer cells (34)(35)(36)(37)(38). Conversely, paracrine stimulation by PDGFs secreted from cancer cells has been shown to induce CAFs in tumor stroma to recruit and proliferate in in vivo transplant tumor models of melanoma (15), breast carcinoma (17), colorectal carcinoma (39), and lung carcinoma (40).…”

The Gene Expression Program of Prostate Fibroblast Senescence Modulates Neoplastic Epithelial Cell Proliferation through Paracrine Mechanisms

“…The methods for isolating and propagating the primary human prostate stromal cells used in this study were described previously (isolates PSC27, PSC31, and PSC36; ref. 14). Briefly, tissues from benign areas of radical prostatectomy specimens were collected under approval by the institutional review board.…”