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

Davies, Gaynor, Mason, Malcolm David ORCID: https://orcid.org/0000-0003-1505-2869, Martin, Tracey Amanda ORCID: https://orcid.org/0000-0003-2690-4908, Parr, Christian, Watkins, Gareth, Lane, Jane ORCID: https://orcid.org/0000-0002-1926-4909, Jiang, Wen Guo ORCID: https://orcid.org/0000-0002-3283-1111, Matsumoto, Kunio and Nakamura, Toshikazu 2003. The HGF/SF antagonist NK4 reverses fibroblast- and HGF-induced prostate tumor growth and angiogenesisin vivo. International Journal of Cancer 106 (3) , pp. 348-354. 10.1002/ijc.11220

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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 (mm3) 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

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Medicine
Subjects:	R Medicine > RC Internal medicine > RC0254 Neoplasms. Tumors. Oncology (including Cancer)
Uncontrolled Keywords:	NK4; HGF/SF; MRC5; prostate cancer; angiogenesis
Publisher:	Wiley-Liss
ISSN:	00207136
Funders:	Prostate Research Campaign, Cancer Research Wales
Date of Acceptance:	2 April 2003
Last Modified:	19 Oct 2022 06:47
URI:	https://orca.cardiff.ac.uk/id/eprint/87917

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