論文 - 詳細
| RRC ID | 83310 |
|---|---|
| 著者 | Kimura S, Iwano S, Akioka T, Kuchimaru T, Kawaguchi M, Fukushima T, Sato Y, Kataoka H, Kamoto T, Mukai S, Sawada A. |
| タイトル | Combined Therapy Targeting MET and Pro-HGF Activation Shows Significant Therapeutic Effect Against Liver Metastasis of CRPC. |
| ジャーナル | Int J Mol Sci |
| 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. |
| 巻・号 | 26(5) |
| 公開日 | 2025-3-5 |
| DOI | 10.3390/ijms26052308 |
| PII | ijms26052308 |
| PMID | 40076928 |
| PMC | PMC11900290 |
| MeSH | Animals Cell Line, Tumor Cell Proliferation / drug effects Gene Expression Regulation, Neoplastic / drug effects Hepatocyte Growth Factor* / genetics Hepatocyte Growth Factor* / metabolism Humans Liver Neoplasms* / drug therapy Liver Neoplasms* / metabolism Liver Neoplasms* / secondary Male Mice Mice, Nude Prostatic Neoplasms, Castration-Resistant* / drug therapy Prostatic Neoplasms, Castration-Resistant* / metabolism Prostatic Neoplasms, Castration-Resistant* / pathology Proto-Oncogene Proteins c-met* / antagonists & inhibitors Proto-Oncogene Proteins c-met* / metabolism Serine Endopeptidases |
| IF | 4.556 |
| オルトメトリクス指標 |
オルトメトリクス指標項目
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| 最多言及媒体 | Bluesky |
| 各媒体での言及数の合計 | 1 |
| 過去6か月間でのオルトメトリクス指標の変動値 | 0.0 |
| リソース情報 | |
| 遺伝子材料 | CSII-CMV-MCS (RDB04377) pCMV-VSV-G-RSV-Rev (RDB04393) |