title: Hepatocyte growth factor and its receptor (c-MET) in prostatic carcinoma.
abstract: Hepatocyte growth factor (scatter factor) and its receptor, the c-met proto-oncogene product (c-MET), have been implicated in embryogenesis, tissue reorganization, and tumor progression. Little is known, however, of the expression and functional significance of these molecules in prostatic cells and tissue. In this investigation, we assessed the expression of hepatocyte growth factor (HGF) and c-MET in prostatic tissues and cell lines and also determined the effect of purified recombinant HGF on cell proliferation and scattering of prostatic carcinoma cell lines. HGF was expressed by human prostatic stromal myofibroblasts in primary culture but not by three human prostatic carcinoma cell lines (LNCaP, DU 145, and PC-3) as assessed by Northern blot analysis. HGF was also detected by reverse transcriptase-polymerase chain reaction in both benign and malignant tissues from radical prostatectomy specimens. c-MET transcripts were identified by Northern blot in two androgen-insensitive human prostatic carcinoma cell lines (DU 145 and PC-3) but not the androgen-sensitive LNCaP cell line. Additional evidence of linkage of androgen responsiveness and c-MET was provided by experiments in which androgen deprivation of normal rat prostates via castration produced a marked up-regulation of c-MET expression as determined by Northern blot and immunohistochemistry. c-MET protein was detected by immunohistochemical analysis in a substantial percentage (58 of 128 or 45%) of prostatic carcinomas and was found more often in metastatic growths of human prostatic carcinoma (15 of 20 patients) compared with primary tumors (43 of 108 patients; P < 0.005). Moreover, in Dunning R-3327 rat prostatic carcinoma cell lines, c-MET expression was highest in the androgen-insensitive subline with the highest metastatic capacity. Purified recombinant human HGF induced dose-dependent cellular proliferation and scattering in the DU 145 carcinoma cell line. These data indicate that HGF may function in the prostate gland as a paracrine growth factor, with synthesis by stromal cells and with biological target cells being the epithelial cells. Expression of the HGF receptor, c-MET, is up-regulated by androgen deprivation and c-MET appears to be preferentially expressed on androgen-insensitive, metastatic cells, suggesting a possible linkage of c-MET expression with prostatic carcinoma progression.
authors.affiliation: Department of Pathology, Washington University Medical Center, St. Louis, Missouri 63110, USA.
authors.forename: P A
authors.initials: PA
authors.lastname: Humphrey
authors.forename: X
authors.initials: X
authors.lastname: Zhu
authors.forename: R
authors.initials: R
authors.lastname: Zarnegar
authors.forename: P E
authors.initials: PE
authors.lastname: Swanson
authors.forename: T L
authors.initials: TL
authors.lastname: Ratliff
authors.forename: R T
authors.initials: RT
authors.lastname: Vollmer
authors.forename: M L
authors.initials: ML
authors.lastname: Day
mesh_terms: D000818:Animals; D001483:Base Sequence; D002277:Carcinoma / Q000378:metabolism* / Q000473:pathology; D002455:Cell Division / Q000187:drug effects; D017228:Hepatocyte Growth Factor / Q000378:metabolism*; D006801:Humans; D008297:Male; D008969:Molecular Sequence Data; D009919:Orchiectomy; D011471:Prostatic Neoplasms / Q000378:metabolism* / Q000473:pathology; D000090063:Proto-Oncogene Mas; D019859:Proto-Oncogene Proteins c-met; D051381:Rats; D017207:Rats, Sprague-Dawley; D020794:Receptor Protein-Tyrosine Kinases / Q000378:metabolism*; D011994:Recombinant Proteins; D012542:Scattering, Radiation; D014407:Tumor Cells, Cultured; D015854:Up-Regulation
chemical_list: C000715470:MAS1 protein, human; D000090063:Proto-Oncogene Mas; D011994:Recombinant Proteins; D017228:Hepatocyte Growth Factor; D019859:Proto-Oncogene Proteins c-met; D020794:Receptor Protein-Tyrosine Kinases