title: The HGF/SF antagonist NK4 reverses fibroblast- and HGF-induced prostate tumor growth and angiogenesis in vivo.
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.
authors.affiliation: Metastasis Research Group, University Department of Surgery, University of Wales College of Medicine, Cardiff CF14 4XN, Wales, UK. daviesg11@cf.ac.uk
authors.forename: Gaynor
authors.initials: G
authors.lastname: Davies
authors.forename: Malcolm D
authors.initials: MD
authors.lastname: Mason
authors.forename: Tracey A
authors.initials: TA
authors.lastname: Martin
authors.forename: Christian
authors.initials: C
authors.lastname: Parr
authors.forename: Gareth
authors.initials: G
authors.lastname: Watkins
authors.forename: Jane
authors.initials: J
authors.lastname: Lane
authors.forename: Kunio
authors.initials: K
authors.lastname: Matsumoto
authors.forename: Toshikazu
authors.initials: T
authors.lastname: Nakamura
authors.forename: Wen G
authors.initials: WG
authors.lastname: Jiang
mesh_terms: D000818:Animals; D015153:Blotting, Western; D002448:Cell Adhesion / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects*; D005260:Female; D005347:Fibroblasts / Q000187:drug effects; D017228:Hepatocyte Growth Factor / Q000494:pharmacology*; D006801:Humans; D008297:Male; D051379:Mice; D008819:Mice, Nude; D008934:Mitogens; D009361:Neoplasm Invasiveness; D009389:Neovascularization, Pathologic / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D010750:Phosphoproteins / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D011471:Prostatic Neoplasms / Q000098:blood supply* / Q000473:pathology / Q000517:prevention & control*; D019859:Proto-Oncogene Proteins c-met / Q000378:metabolism; D015996:Survival Rate; D014407:Tumor Cells, Cultured; D014443:Tyrosine / Q000378:metabolism; D001618:beta-Lactamases / Q000235:genetics / Q000378:metabolism
chemical_list: C066855:HGF protein, human; D008934:Mitogens; D010750:Phosphoproteins; D014443:Tyrosine; D017228:Hepatocyte Growth Factor; D019859:Proto-Oncogene Proteins c-met; D001618:beta-Lactamases; C034413:beta-lactamase TEM-1; C056342:beta-lactamase TEM-2