Mesenchymal stromal cells alone or expressing interferon-beta suppress pancreatic tumors in vivo, an effect countered by anti-inflammatory treatment.
OBJECTIVE
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 down-regulated, including NFkappaB, 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 PANC-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.
Section of Molecular Hematology and Therapy, Department of Stem Cell Transplantation and Cellular Therapy, UT-MD Anderson Cancer Center, Houston, TX, USA.
Shannon
S
Kidd
Lisa
L
Caldwell
Martin
M
Dietrich
Ismael
I
Samudio
Erika L
EL
Spaeth
Keri
K
Watson
Yuexi
Y
Shi
James
J
Abbruzzese
Marina
M
Konopleva
Michael
M
Andreeff
Frank C
FC
Marini
D000818:Animals; D000970:Antineoplastic Agents / Q000276:immunology / Q000627:therapeutic use; D048708:Cell Growth Processes / Q000276:immunology; D045744:Cell Line, Tumor; D015316:Genetic Therapy; D006131:Growth Inhibitors / Q000276:immunology / Q000627:therapeutic use; D006801:Humans; D007165:Immunosuppression Therapy; D007249:Inflammation; D016899:Interferon-beta / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D045164:Mesenchymal Stem Cell Transplantation; D059630:Mesenchymal Stem Cells / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D016513:Mice, SCID; D009368:Neoplasm Transplantation; D010190:Pancreatic Neoplasms / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D017154:Stromal Cells / Q000378:metabolism* / Q000473:pathology / Q000637:transplantation; D019076:Transgenes / Q000235:genetics
D000970:Antineoplastic Agents; D006131:Growth Inhibitors; D016899:Interferon-beta