2. Academic Validation
  3. Combined Therapy Targeting MET and Pro-HGF Activation Shows Significant Therapeutic Effect Against Liver Metastasis of CRPC

Combined Therapy Targeting MET and Pro-HGF Activation Shows Significant Therapeutic Effect Against Liver Metastasis of CRPC

  • Int J Mol Sci. 2025 Mar 5;26(5):2308. doi: 10.3390/ijms26052308.
Shoichi Kimura 1,  Satoshi Iwano 2,  Takahiro Akioka 1,  Takahiro Kuchimaru 3,  Makiko Kawaguchi 4,  Tsuyoshi Fukushima 4,  Yuichiro Sato 4,  Hiroaki Kataoka 5,  Toshiyuki Kamoto 1,  Shoichiro Mukai 1,  Atsuro Sawada 1
Affiliations

Affiliations

  • 1 Department of Urology, Faculty of Medicine, University of Miyazaki, Miyazaki 889-1692, Japan.
  • 2 Institute for Tenure Track Promotion, University of Miyazaki, Miyazaki 889-1692, Japan.
  • 3 Center for Molecular Medicine, Jichi Medical University, Tochigi 329-0498, Japan.
  • 4 Section of Oncopathology and Morphological Pathology, Department of Pathology, Faculty of Medicine, University of Miyazaki, Miyazaki 889-1692, Japan.
  • 5 Organization for Promotion of Research and Industry Academic Regional Collaboration, University of Miyazaki, Miyazaki 889-1692, Japan.
PMID: 40076928 DOI: 10.3390/ijms26052308
Abstract

The liver is the most lethal metastatic site in castration-resistant prostate Cancer (CRPC). Overexpression of MET protein has been reported in CRPC, and MET is an important driver gene in androgen-independent CRPC cells. Mouse CRPC cell line CRTC2 was established by subcutaneous injection of hormone-sensitive PC cells (TRAMP-C2) in castrated nude mice. CRCT2/luc2 cells were injected into the spleen of castrated nude mice, and liver metastasis was confirmed at 2 weeks post-injection. We administered Met Inhibitor (MET-I) and HGF activator inhibitor (HGFA-I) to this liver metastasis model and assessed the therapeutic effect. After intrasplenic injection, CRTC2 showed a higher incidence of liver metastasis whereas no metastasis was observed in TRAMP-C2. Microarray analysis revealed increased expression of HGF, MET, and HPN, HGFAC (encoding HGF activating proteases) in liver metastasis. Proliferation of CRCT2 was significantly inhibited by co-administration of MET-I and HGFA-I by in vitro analysis with HGF-enriched condition. In an analysis of the mouse model, the combination-therapy group showed the strongest reduction for liver metastasis. Immunohistochemical staining also revealed the strongest decrease in phosphorylation of MET in the combination-therapy group. Co-culture with HGF-expressed mouse fibroblasts showed attenuation of the inhibitory effect of MET-I; however, additional HGFA-I overcame the resistance. We established an androgen-independent CRPC cell line, CRTC2, and liver metastasis model in mice. Significant effect was confirmed by combined treatment of MET-I and HGFA-I by in vitro and in vivo analysis. The results suggested the importance of combined treatment with both MET- and HGF-targeting agents in the treatment of HGF-enriched conditions including liver metastasis.

Keywords

CRPC; HGF; MET; liver metastasis.

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