Renal cell carcinoma (RCC) is one of the most resistant tumors to radiation and chemotherapy. Gene therapy represents a promising treatment for patient with RCC. However, the efficiency of systemic delivery and tumor specific targeting using currently developed gene therapy approach is limited. Human mesenchymal stem cells (hMSCs) have been recently reported to home to tumor sites and could act as a vehicle for anti-cancer agents including oncolytic Adenoviruses. Previous studies have demonstrated that conditional replication-competent adenoviral vector, Ad-hOC-E1, selectively replicated in osteocalcin(OC)-expressing cells with the enhancement of cytotoxicity upon vitamin D3 induction. Here, we test the feasibility of using hMSCs as a targeting cellular vehicle to deliver Ad-hOC-E1 into RCC and successively induce tumor-kill by vitamin D3 treatment to improve the therapeutic efficiency. Our in vitro migration assay demonstrated that RCC attracted hMSCs much more than normal human renal epithelial cells did. On the other hand, hMSCs rapidly migrated toward RCC compared to differentiated bone marrow stromal cells, HS27A. Antibody array analysis revealed PDGF-AA might be a candidate of RCC-derived chemoattractant for hMSCs. In addition, like RCC, the nearly undetectable basal-level of OC in hMSCs can be dramatically induced by vitamin D3 up to 160 folds, as determined by qRT-PCR. Similarly, Ad-hOC-E1 has no cytotoxic effect on hMSCs but markedly kill cells upon vitamin D3 treatment. Moreover, with vitamin D3 induction, Ad-hOC-E1 but not a replication-defective Ad-CMV-PA pre-infected hMSCs released viruses and then transferred to co-cultured RCC cells, which resulted in cancer cell-kill. Taken together, these results present for the first time to develop an inducible stem cell-based gene delivery system carrying oncolytic adenoviruses for renal cell carcinoma targeted therapy. Our in vitro results warrant a future evaluation in vivo.
