期刊
CYTOTHERAPY
卷 12, 期 5, 页码 615-625出版社
ELSEVIER SCI LTD
DOI: 10.3109/14653241003631815
关键词
anti-inflammatory; CDDO-Me; drug delivery vehicle; mesenchymal stromal cells; pancreatic cancer; tumor microenvironment
类别
资金
- National Cancer Institute [RC1CA146381, CA-109451, CA-116199, CA-55164, CA-16672, CA-49639]
- National Institutes of Health [5 P20 CA 101936 04]
- Paul and Mary Haas Chair in Genetics
- Rosalie B. Hite Foundation
- Army Department of Defense [BC083397]
- Susan G. Komen Breast Cancer Foundation [BCTR0504372]
- NATIONAL CANCER INSTITUTE [P30CA016672, P20CA101936, P50CA116199, R01CA109451, RC1CA146381, P50CA083639, P01CA055164] Funding Source: NIH RePORTER
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)-beta 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-beta within the tumor site by MSC-IFN-beta 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 downregulated, including NF kappa B, 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-beta injections resulted in reduction of MSC in the tumors and reversed the positive effect of tumor inhibition by MSC IFN-beta alone (P = 0.041). Conclusions. These results suggest that MSC exhibit innate anti-tumor effects against PANG-1 cells and can serve as delivery vehicles for IFN-beta for the treatment of pancreatic cancer. However, these beneficial effects may be lost in therapies combining MSC with anti-inflammatory agents.
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