Abstract
Background aims. Because of the inflammatory nature and extensive stromal compartment in pancreatic tumors, we investigated the role of mesenchymal stromal cells (MSC) to engraft selectively in pancreatic carcinomas and serve as anti-tumor drug delivery vehicles to control pancreatic cancer progression. Methods. Human pancreatic carcinoma cells, PANC-1, expressing renilla luciferase were orthotopically implanted into SCID mice and allowed to develop for 10 days. Firefly luciferase-transduced MSC or MSC expressing interferon (IFN)-β were then injected intraperitoneally weekly for 3 weeks. Mice were monitored by bioluminescent imaging for expression of renilla (PANC-1) and firefly (MSC) luciferase. Results. MSC selectively homed to sites of primary and metastatic pancreatic tumors and inhibited tumor growth (P=0.032). The production of IFN-β within the tumor site by MSC–IFN-β further suppressed tumor growth (P=0.0000083). Prior studies indicated that MSC home to sites of inflammation; therefore, we sought to alter the tumor microenvironment through treatment with a potent anti-inflammatory agent. After treatment, inflammation-associated mediators were effectively down-regulated, including NFκB, vascular endothelial growth factor (VEGF) and interleukin (IL)-6 as well as chemokines involved in MSC migration (CCL3 and CCL25). Treatment with the anti-inflammatory agent CDDO-Me before and after MSC–IFN-β injections resulted in reduction of MSC in the tumors and reversed the positive effect of tumor inhibition by MSC–IFN-β alone (P=0.041). Conclusions. These results suggest that MSC exhibit innate anti-tumor effects against PANC-1 cells and can serve as delivery vehicles for IFN-β for the treatment of pancreatic cancer. However, these beneficial effects may be lost in therapies combining MSC with anti-inflammatory agents.
Acknowledgments
Supported in part by grants from the National Cancer Institute (RC1CA146381, CA-109451 and CA-116199 to FCM, CA-55164, CA-16672 and CA-49639 to MA), by a Pancreatic Spore Grant from the National Institutes of Health (5 P20 CA101936 04 for MK and IS) and by the Paul and Mary Haas Chair in Genetics (MA). SK is supported by the Rosalie B. Hite Foundation. ELS is supported in part by Army Department of Defense (BC083397). FCM is also supported in part by grants from the Susan G. Komen Breast Cancer Foundation (BCTR0504372).
Declaration of interest: The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.