The HGF/SF antagonist NK4 reverses fibroblast- and HGF-induced prostate tumor growth and angiogenesis in vivo

Our study examined the in vitro and in vivo responses of a newly discovered HGF/SF antagonist, NK4, on HGF/SF-promoted growth of human prostate cancer cells (PC-3). Nude mice were s.c. injected with either PC-3- and/or HGF/SF-producing fibroblasts (MRCS), and tumor size was measured over a 4-week period. rh-HGF/SF and/or NK4 were introduced by osmotic minipumps. An in vitro study found that NK4 significantly suppressed HGF/SF-induced invasion (HGF/SF; p < 0.01 vs. HGF/SF+NK4) and migration (HGF/SF; p < 0.05 vs. HGF/SF+NK4). Similarly, NK4 also suppressed the invasion (MRCS; p < 0.01 vs. MRCS+NK4) and migration (MRCS; p < 0.05 vs. MRCS+NK4) induced by MRCS cells. NK4 also suppressed HGF/SF- and MRCS-induced tyrosine phosphorylation of the HGF/SF receptor Met as assessed by immunoprecipitation. Using a nude mouse model, prostate tumor volume (mm(3)) was significantly increased in both HGF/SF- (HGF/SF; p < 0.05 vs. control) and MRC5- (MRCS; p < 0.01 vs. control) treated groups compared to the control. In contrast, NK4 alone significantly reduced the growth of prostate tumors (NK4; p < 0.01 vs. control). In addition, NK4 also suppressed both HGF/SF(HGF/SF; p < 0.01 vs. HGF/SF+NK4) and MRC5- (MRCS; p < 0.05 vs. MRCS+NK4) induced tumor growth in vivo by significantly reducing (p < 0.05) the degree of tumor angiogenesis using a recently discovered family of tumor endothelial markers (TEMs) by Q-RT-PCR analysis. In conclusion, NK4 suppresses both HGF/SF- and MRCS-induced invasion/migration of PC-3 cells in vitro. Furthermore, the HGF/SF antagonist NK4 significantly reduces prostate tumor growth in vivo by inhibiting the degree of tumor angiogenesis as determined by TEM-1 and TEM-8. Finally, our study provides evidence of the therapeutic potential of NK4 in prostate cancer development by antagonising HGF/SF-mediated events. (C) 2003 Wiley-Liss, Inc.