| 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
|
| リソース情報 |
| 遺伝子材料 |
CSII-CMV-MCS (RDB04377)
pCMV-VSV-G-RSV-Rev (RDB04393) |
