論文 - 詳細
RRC ID | 34498 |
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著者 | Tanoue K, Wang Y, Ikeda M, Mitsui K, Irie R, Setoguchi T, Komiya S, Natsugoe S, Kosai K. |
タイトル | Survivin-responsive conditionally replicating adenovirus kills rhabdomyosarcoma stem cells more efficiently than their progeny. |
ジャーナル | J Transl Med |
Abstract |
BACKGROUND:Effective methods for eradicating cancer stem cells (CSCs), which are highly tumorigenic and resistant to conventional therapies, are urgently needed. Our previous studies demonstrated that survivin-responsive conditionally replicating adenoviruses regulated with multiple factors (Surv.m-CRAs), which selectively replicate in and kill a broad range of cancer-cell types, are promising anticancer agents. Here we examined the therapeutic potentials of a Surv.m-CRA against rhabdomyosarcoma stem cells (RSCs), in order to assess its clinical effectiveness and usefulness. METHODS:Our previous study demonstrated that fibroblast growth factor receptor 3 (FGFR3) is a marker of RSCs. We examined survivin mRNA levels, survivin promoter activities, relative cytotoxicities of Surv.m-CRA in RSC-enriched (serum-minus) vs. RSC-exiguous (serum-plus) and FGFR3-positive vs. FGFR3-negative sorted rhabdomyosarcoma cells, and the in vivo therapeutic effects of Surv.m-CRAs on subcutaneous tumors in mice. RESULTS:Both survivin mRNA levels and survivin promoter activities were significantly elevated under RSC-enriched relative to RSC-exiguous culture conditions, and the elevation was more prominent in FGFR3-positive vs. FGFR3-negative sorted cells than in RSC-enriched vs. RSC-exiguous conditions. Although Surv.m-CRA efficiently replicated and potently induced cell death in all populations of rhabdomyosarcoma cells, the cytotoxic effects were more pronounced in RSC-enriched or RSC-purified cells than in RSC-exiguous or progeny-purified cells. Injections of Surv.m-CRAs into tumor nodules generated by transplanting RSC-enriched cells induced significant death of rhabdomyosarcoma cells and regression of tumor nodules. CONCLUSIONS:The unique therapeutic features of Surv.m-CRA, i.e., not only its therapeutic effectiveness against all cell populations but also its increased effectiveness against CSCs, suggest that Surv.m-CRA is promising anticancer agent. |
巻・号 | 12 |
ページ | 27 |
公開日 | 2014-1-27 |
DOI | 10.1186/1479-5876-12-27 |
PII | 1479-5876-12-27 |
PMID | 24467821 |
PMC | PMC3925355 |
MeSH | Adenoviridae / physiology* Animals Cell Death Cell Differentiation Cell Fractionation Cell Line, Tumor Cell Proliferation Flow Cytometry Genetic Vectors / metabolism Humans Inhibitor of Apoptosis Proteins / genetics Inhibitor of Apoptosis Proteins / metabolism* Mice Neoplastic Stem Cells / pathology* Promoter Regions, Genetic / genetics RNA, Messenger / genetics RNA, Messenger / metabolism Receptor, Fibroblast Growth Factor, Type 3 / metabolism Rhabdomyosarcoma / pathology* Survivin Transduction, Genetic Virus Replication* Xenograft Model Antitumor Assays |
IF | 4.124 |
引用数 | 10 |
WOS 分野 | MEDICINE, RESEARCH & EXPERIMENTAL |
リソース情報 | |
遺伝子材料 | Ax1 CA gfp (RDB01727) AxCAEGFP-F/RGD (RDB03010). |