Mesenchymal stromal cells producing TNFα lack inhibitory effect against A375 experimental lung metastases
Abstract:
Cell-based anticancer therapy using mesenchymal stromal cells (MSCs) engineered to express therapeutic genes has a potential to target the cancer cells in vivo. Metastatic dissemination of melanoma remains a serious problem in the treatment. In our previous work we used MSCs overexpressing gene for tumor necrosis factor α (TNFα; MSCs/TNFα), and we achieved inhibition of melanoma xenograft growth when engineered MCSs/TNFα were coinjected with tumor cells subcutaneously. The TNFα as a pleiotropic cytokine induces apoptosis of tumor cells, creates “tumor resistant” microenvironment, enhances immune response and can have tumor destructive capacity in selected tumor types, especially in tumors of mesodermal origin.In this study we investigated the possibility of intravenously administered MCSs/TNFα to inhibit metastatic spread of A375 melanoma cells in the lungs. We confirmed elevated expression of TNFα transgene in the lung tissue 20 days after MCSs/TNFα intravenous infusion. We also documented that constitutive expression of TNFα transgene is able to neutralize the supportive effect of MSCs on melanoma cells growth. Metastatic spread of A375 melanoma cells in the lung was inhibited approximately to 50% after MCSs/TNFα i.v. administration in comparison to control group with parental MSCs supporting tumor growth. In conclusion, engineered MCSs/TNFα administered intravenously did not demonstrate significant antitumor effect against experimental melanoma lung metastases in this model settings.