Normal and malignant prostate epithelial cells differ in their response to hepatocyte growth factor/scatter factor.
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 (PrSC). Met is also expressed in localized and metastatic prostate cancers. Our results show that PrECs in in vitro culture maintain expression of Met at a level comparable to DU145 cancer cell expression. HGF/SF secreted by PrSC stimulates tyrosine phosphorylation of the Met receptor. In normal PrEC, HGF/SF causes growth inhibition, sustained phosphorylation of mitogen-activated protein kinase, and increased CK18 expression consistent with cell differentiation. In contrast, HGF/SF significantly stimulates the proliferation of DU145 prostate cancer cells. HGF/SF in the conditioned medium of PrSC specifically induces migration of both normal and malignant prostate epithelial cells through MatriGel-coated Transwell filters. HGF/SF depletion reduces cell migration by approximately 50%. The response of PrEC is specific for HGF/SF since the other growth factors tested do not significantly affect growth or migration of PrECs. These results support the in vivo importance of the prostate stroma and specifically of HGF/SF as a unique stromal derived factor in the development and progression of prostate cancer.
Gmyrek
G A
GA
Department of Pathology, Weill Medical College of Cornell University, 1300 York Avenue, New York, NY 10021, USA.
Walburg
M
M
Webb
C P
CP
Yu
H M
HM
You
X
X
Vaughan
E D
ED
Vande Woude
G F
GF
Knudsen
B S
BS
D000818:Animals; D002454:Cell Differentiation; D002455:Cell Division / Q000187:drug effects; D002460:Cell Line; D002465:Cell Movement / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D003094:Collagen; D017077:Culture Media, Conditioned; D003893:Desmin / Q000032:analysis / Q000235:genetics; D004285:Dogs; D004338:Drug Combinations; D004847:Epithelial Cells / Q000166:cytology / Q000187:drug effects* / Q000473:pathology; D017228:Hepatocyte Growth Factor / Q000032:analysis / Q000235:genetics* / Q000494:pharmacology*; D006801:Humans; D007150:Immunohistochemistry; D007633:Keratins / Q000032:analysis / Q000235:genetics; D007797:Laminin; D008297:Male; D011467:Prostate / Q000166:cytology* / Q000187:drug effects / Q000473:pathology; D011471:Prostatic Neoplasms / Q000473:pathology*; D011509:Proteoglycans; D011944:Receptors, Androgen / Q000032:analysis / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014407:Tumor Cells, Cultured; D014746:Vimentin / Q000032:analysis / Q000235:genetics
D017077:Culture Media, Conditioned; D003893:Desmin; D004338:Drug Combinations; D007797:Laminin; D011509:Proteoglycans; D011944:Receptors, Androgen; D014746:Vimentin; C059485:matrigel; D017228:Hepatocyte Growth Factor; D007633:Keratins; D003094:Collagen