Mesenchymal stem cells as a vehicle for targeted delivery of CRAds to lung metastases of breast carcinoma
- 480 Downloads
Alternative and complementary therapeutic strategies need to be developed for metastatic breast cancer. Virotherapy is a novel therapeutic approach for the treatment of cancer in which the replicating virus itself is the anticancer agent. However, the success of virotherapy has been limited due to inefficient virus delivery to the tumor site. The present study addresses the utility of human mesenchymal stem cells (hMSCs) as intermediate carriers for conditionally replicating adenoviruses (CRAds) to target metastatic breast cancer in vivo.
HMSC were transduced with CRAds. We used a SCID mouse xenograft model to examine the effects of systemically injected CRAd loaded hMSC or CRAd alone on the growth of MDA-MB-231 derived pulmonary metastases (experimental metastases model) in vivo and on overall survival.
Intravenous injection of CRAd loaded hMSCs into mice with established MDA-MB-231 pulmonary metastatic disease homed to the tumor site and led to extended mouse survival compared to mice treated with CRAd alone.
Injected hMSCs transduced with CRAds suppressed the growth of pulmonary metastases, presumably through viral amplification in the hMSCs. Thus, hMSCs may be an effective platform for the targeted delivery of CRAds to distant cancer sites such as metastatic breast cancer.
KeywordsBreast cancer Cell vehicle CRAds Metastases Stem cells Virotherapy
This work was supported by Grant of the Deutsche Forschungsgemeinschaft Sto 647/1-1 (to M. A. Stoff-Khalili), by grants from the National Institutes of Health 5T32CA075930 (NIH Training Grant) and Department of Defense: W81Xwh-05-1-035 (to D. T. Curiel). R01CA93796, R01CA98543 and AR46031 (to G. P. Siegal) and from the Louisiana Gene Therapy Research Consortium, Inc. (to J. M. Mathis) and R01CA108585 (to J. T. Douglas).
- 7.Koc ON, Peters C, Aubourg P, Raghavan S, Dyhouse S, DeGasperi R, Kolodny EH, Yoseph YB, Gerson SL, Lazarus HM et al (1999) Bone marrow-derived mesenchymal stem cells remain host-derived despite successful hematopoietic engraftment after allogeneic transplantation in patients with lysosomal and peroxisomal storage diseases. Exp Hematol 27:1675–1681PubMedCrossRefGoogle Scholar
- 9.Liu Y, Ye T, Maynard J, Akbulut H, Deisseroth A (2005) Engineering conditionally replication-competent adenoviral vectors carrying the cytosine deaminase gene increases the infectivity and therapeutic effect for breast cancer gene therapy. Cancer Gene Ther 13:346–356Google Scholar
- 18.Stoff-Khalili MA, Stoff A, Rivera AA, Banerjee NS, Everts M, Young S, Siegal GP, Richter DF, Wang M, Dall P et al (2005) Preclinical evaluation of transcriptional targeting strategies for carcinoma of the breast in a tissue slice model system. Breast Cancer Res 7:R1141–R1152PubMedCrossRefGoogle Scholar