Complete Regression of Metastatic Renal Cell Carcinoma by Multiple Injections of Engineered Mesenchymal Stem Cells Expressing Dodecameric TRAIL and HSV-TK

Abstract

Purpose: Durable complete remission of metastatic renal cell carcinoma (RCC) has rarely been achieved with current treatment modalities. To solve this problem, alternative therapeutic options with high efficacy and minimal side effects are strongly needed.Experimental Design: Mesenchymal stem cells (MSC) were engineered to coexpress dodecameric TRAIL and herpes simplex virus thymidine kinase (MSC/dTRAIL-TK). The antitumor effects of MSCs expressing dTRAIL (MSC/dTRAIL) or HSV-TK alone (MSC/TK) and MSC/dTRAIL-TK were compared with murine RCC cells using in vitro coculture system and in vivo experimental lung metastasis model. The effects of different doses and schedules of engineered MSCs on mice survival were also evaluated.Results: MSC/dTRAIL-TK exerted stronger apoptotic response in Renca cells than did MSC/TK or MSC/ dTRAIL after ganciclovir (GCV) treatment. In vivo imaging results suggest that MSCs reside longer in the lungs of metastatic tumor-bearing mice, compared with that of control mice, regardless of genetic engineering. In addition, MSC/dTRAIL-TK treatment followed by ganciclovir administrations significantly decreased the number of tumor nodules in the lung, to a greater degree than MSC/dTRAIL or MSC/TK, and led to a prolonged survival. More importantly, the antimetastatic effect of MSC/dTRAIL-TK was markedly enhanced by repeated injections but not by increased dose, and resulted in 100% survival of tumor-bearing mice after three injections.Conclusion: Sequential combination gene therapy using MSC/dTRAIL-TK achieved long-term remission of metastatic RCC without noticeable toxicity. Our findings provide an innovative therapeutic approach to completely eradicate metastatic tumors by simple, repeated administrations of MSC/dTRAIL-TK.

The cell death and DNA damages caused by the Tet-On regulating HSV-tk/GCV suicide gene system in MCF-7 cells

“…In our previous study, we found that the GCV regulating suicide gene system can significantly adjust the cell cycle of breast cancer, and most of the cells arrested in the S phase [6,7]. But how the breast cancer cells react to the GCV treatment, whether the critical targets of cell cycle checkpoint and apoptosis were changed in the GCV regulating suicide gene system is still unknown.…”

In vivo near-infrared imaging for the tracking of systemically delivered mesenchymal stem cells: tropism for brain tumors and biodistribution

“…For MSC transduction, a mixture of 50 multiplicity of infection of Ad and 50 µmol/L of Fe3 + was pre-incubated in SFM at room temperature for 30 minutes and then infected into MSCs for 30 minutes, as described previously. 24 In vivo bioluminescence and fluorescence imaging…”

The Antitumor Effect of Suicide Gene Therapy Using Bifidobacterium infantis–mediated Herpes Simplex Virus Thymidine Kinase/Ganciclovir in a Nude Mice Model of Renal Cell Carcinoma

“…The transfer of toxic GCV-3-phosphate from TKexpressing cells to TK-negative bystander cells via gap junctions may enhance therapeutic potential. 15 It has been widely accepted that the success of the strategy relies on the transfer effective gene into tumor microenvironments by specific targeting vector. 16 So far, viruses and liposomes are widely used as gene therapy vectors, but they are poor in specific tumor targeting and gene transferring, thus causing the failure of cancer gene therapy and resulting in several side effects and potential toxicity.…”