Enhanced invasion of hormone refractory prostate cancer cells through hepatocyte growth factor (HGF) induction of urokinase-type plasminogen activator (u-PA).
BACKGROUND
Increased expression of the hepatocyte growth factor (HGF) receptor (MET) is associated with high-grade prostatic adenocarcinoma and metastasis. However, the mechanism through which MET signaling contributes to prostate cancer (CaP) metastasis remains unclear.


METHODS
Human PC-3 CaP cells and in vivo selected, isogeneic variant cells of increasing metastatic potential (PC-3M, PC-3M-Pro4, and PC-3M-LN4) were used to investigate the effect of HGF on CaP cell growth, protease production, and invasion. Cell-free urokinase-type plasminogen activator (u-PA) expression and function following HGF treatment were analyzed by Western blot, ELISA, and casein/plasminogen zymography. In vitro invasion stimulated by HGF was measured using Matrigel-coated invasion chambers.


RESULTS
Both mRNA and functional protein for MET were detected in each of the CaP cell lines. HGF treatment (0-40 ng/ml) weakly increase proliferation, however, HGF induced soluble u-PA protein and activity 3-fold in the metastatic variant cells. HGF significantly stimulated the invasion of highly metastatic PC-3M-LN4 cells through Matrigel and treatment with specific urokinase receptor inhibitors diminished the HGF-stimulated invasion in a dose-dependent manner.


CONCLUSIONS
These results demonstrate the biological significance of u-PA up-regulation in response to HGF in highly metastatic hormone refractory CaP cells.
Hall
Christopher L
CL
Department of Cancer Biology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas, USA. clhall@umich.edu
Tsan
Rachel
R
Mugnai
Gabriele
G
Mazar
Andrew
A
Radinsky
Robert
R
Pettaway
Curtis A
CA
D000230:Adenocarcinoma / Q000473:pathology*; D018931:Antineoplastic Agents, Hormonal / Q000494:pharmacology; D002455:Cell Division; D019008:Drug Resistance, Neoplasm; D015972:Gene Expression Regulation, Neoplastic; D017228:Hepatocyte Growth Factor / Q000494:pharmacology*; D006801:Humans; D008297:Male; D009361:Neoplasm Invasiveness / Q000503:physiopathology*; D010960:Plasminogen Activators / Q000494:pharmacology*; D011471:Prostatic Neoplasms / Q000473:pathology*; D015398:Signal Transduction; D014407:Tumor Cells, Cultured; D015854:Up-Regulation; D014568:Urokinase-Type Plasminogen Activator / Q000494:pharmacology*
D018931:Antineoplastic Agents, Hormonal; D017228:Hepatocyte Growth Factor; D010960:Plasminogen Activators; D014568:Urokinase-Type Plasminogen Activator