Gemcitabine-releasing mesenchymal stromal cells inhibit in vitro proliferation of human pancreatic carcinoma cells.
OBJECTIVE
Pancreatic cancer (pCa) is a tumor characterized by a fibrotic state and associated with a poor prognosis. The observation that mesenchymal stromal cells (MSCs) migrate toward inflammatory micro-environments and engraft into tumor stroma after systemic administration suggested new therapeutic approaches with the use of engineered MSCs to deliver and produce anti-cancer molecules directly within the tumor. Previously, we demonstrated that without any genetic modifications, MSCs are able to deliver anti-cancer drugs. MSCs loaded with paclitaxel by exposure to high concentrations release the drug both in vitro and in vivo, inhibiting tumor proliferation. On the basis of these observations, we evaluated the ability of MSCs (from bone marrow and pancreas) to uptake and release gemcitabine (GCB), a drug widely used in pCa treatment.


METHODS
MSCs were primed by 24-h exposure to 2000 ng/mL of GCB. The anti-tumor potential of primed MSCs was then investigated by in vitro anti-proliferation assays with the use of CFPAC-1, a pancreatic tumor cell line sensitive to GCB. The uptake/release ability was confirmed by means of high-performance liquid chromatography analysis. A cell-cycle study and secretome evaluation were also conducted to better understand the characteristics of primed MSCs.


RESULTS
GCB-releasing MSCs inhibit the growth of a human pCa cell line in vitro.


CONCLUSIONS
The use of MSCs as a "trojan horse" can open the way to a new pCa therapeutic approach; GCB-loaded MSCs that integrate into the tumor mass could deliver much higher concentrations of the drug in situ than can be achieved by intravenous injection.
Department of Biomedical, Surgical and Dental Sciences, University of Milan, Milan, Italy.
Arianna
A
Bonomi
Diabetes Research Institute, IRCCS S. Raffaele Scientific Institute, Milan, Italy.
Valeria
V
Sordi
Diabetes Research Institute, IRCCS S. Raffaele Scientific Institute, Milan, Italy.
Erica
E
Dugnani
Cellular Neurobiology Laboratory, Department of Cerebrovascular Diseases, IRCCS Neurological Institute C. Besta, Milan, Italy.
Valentina
V
Ceserani
Cellular Neurobiology Laboratory, Department of Cerebrovascular Diseases, IRCCS Neurological Institute C. Besta, Milan, Italy.
Marta
M
Dossena
Department of Biomedical, Surgical and Dental Sciences, University of Milan, Milan, Italy.
Valentina
V
Coccè
Department of Biomedical, Surgical and Dental Sciences, University of Milan, Milan, Italy.
Loredana
L
Cavicchini
Laboratory of Clinical Pathology and Neurogenetic Medicine, Fondazione IRCCS Neurological Institute Carlo Besta, Milan, Italy.
Emilio
E
Ciusani
Department of Medical Biotechnology and Translational Medicine, University of Milan, Milan, Italy.
Gianpietro
G
Bondiolotti
Biology and Genetics Division, Department of Molecular and Translational Medicine, University of Brescia, Brescia, Italy.
Giovanna
G
Piovani
Department of Veterinary Medicine, University of Perugia, Perugia, Italy.
Luisa
L
Pascucci
Department of Biomedical, Surgical and Dental Sciences, University of Milan, Milan, Italy.
Francesca
F
Sisto
Cellular Neurobiology Laboratory, Department of Cerebrovascular Diseases, IRCCS Neurological Institute C. Besta, Milan, Italy.
Giulio
G
Alessandri
Diabetes Research Institute, IRCCS S. Raffaele Scientific Institute, Milan, Italy.
Lorenzo
L
Piemonti
Cellular Neurobiology Laboratory, Department of Cerebrovascular Diseases, IRCCS Neurological Institute C. Besta, Milan, Italy.
Eugenio
E
Parati
Department of Biomedical, Surgical and Dental Sciences, University of Milan, Milan, Italy. Electronic address: augusto.pessina@unimi.it.
Augusto
A
Pessina
D000970:Antineoplastic Agents / Q000008:administration & dosage*; D002453:Cell Cycle; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D003841:Deoxycytidine / Q000008:administration & dosage / Q000031:analogs & derivatives*; D016503:Drug Delivery Systems / Q000379:methods*; D006801:Humans; D059630:Mesenchymal Stem Cells / Q000378:metabolism*; D017239:Paclitaxel / Q000008:administration & dosage; D010190:Pancreatic Neoplasms / Q000188:drug therapy*; D000093542:Gemcitabine
D000970:Antineoplastic Agents; D003841:Deoxycytidine; D017239:Paclitaxel; D000093542:Gemcitabine
MSCs; drug delivery; gemcitabine; pancreatic adenocarcinoma