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

✍ Scribed by Gaynor Davies; Malcolm D. Mason; Tracey A. Martin; Christian Parr; Gareth Watkins; Jane Lane; Kunio Matsumoto; Toshikazu Nakamura; Wen G. Jiang

• Book ID: 102271499
• Publisher: John Wiley and Sons
• Year: 2003
• Tongue: French
• Weight: 192 KB
• Volume: 106
• Category: Article
• ISSN: 0020-7136
• DOI: 10.1002/ijc.11220

✦ Synopsis

Abstract

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 (MRC5), 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 (MRC5; p < 0.01 vs. MRC5+NK4) and migration (MRC5; p < 0.05 vs. MRC5+NK4) induced by MRC5 cells. NK4 also suppressed HGF/SF‐ and MRC5‐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‐ (MRC5; 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‐ (MRC5; p < 0.05 vs. MRC5+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 MRC5‐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. © 2003 Wiley‐Liss, Inc.