Reference - Detail
|Author||Tanoue K, Wang Y, Ikeda M, Mitsui K, Irie R, Setoguchi T, Komiya S, Natsugoe S, Kosai K.|
|Title||Survivin-responsive conditionally replicating adenovirus kills rhabdomyosarcoma stem cells more efficiently than their progeny.|
|Journal||J Transl Med|
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.
|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|
|WOS Category||MEDICINE, RESEARCH & EXPERIMENTAL|
|DNA material||Ax1 CA gfp (RDB01727) AxCAEGFP-F/RGD (RDB03010).|