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
  • 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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