Drug-releasing mesenchymal cells strongly suppress B16 lung metastasis in a syngeneic murine model.
BACKGROUND
Mesenchymal stromal cells (MSCs) are considered an important therapeutic tool in cancer therapy. They possess intrinsic therapeutic potential and can also be in vitro manipulated and engineered to produce therapeutic molecules that can be delivered to the site of diseases, through their capacity to home pathological tissues. We have recently demonstrated that MSCs, upon in vitro priming with anti-cancer drug, become drug-releasing mesenchymal cells (Dr-MCs) able to strongly inhibit cancer cells growth.


METHODS
Murine mesenchymal stromal cells were loaded with Paclitaxel (Dr-MCsPTX) according to a standardized procedure and their ability to inhibit the growth of a murine B16 melanoma was verified by in vitro assays. The anti-metastatic activity of Dr-MCsPTX was then studied in mice injected i.v. with B16 melanoma cells that produced lung metastatic nodules. Lung nodules were counted under a dissecting stereomicroscope and metastasis investigated by histological analysis.


RESULTS
We found that three i.v. injections of Dr-MCsPTX on day 5, 10 and 15 after tumor injection almost completely abolished B16 lung metastasis. Dr-MCsPTX arrested into lung by interacting with endothelium and migrate toward cancer nodule through a complex mechanism involving primarily mouse lung stromal cells (mL-StCs) and SDF-1/CXCR4/CXCR7 axis.


CONCLUSIONS
Our results show for the first time that Dr-MCsPTX are very effective to inhibit lung metastasis formation. Actually, a cure for lung metastasis in humans is mostly unlikely and we do not know whether a therapy combining engineered MSCs and Dr-MCs may work synergistically. However, we think that our approach using Dr-MCs loaded with PTX may represent a new valid and additive therapeutic tool to fight lung metastases and, perhaps, primary lung cancers in human.
Department of Biomedical, Surgical and Dental Sciences, University of Milan, Via Pascal 36, Milan, 20133, Italy. leonetti@ifo.it.
Augusto
A
Pessina
Experimental Chemotherapy Laboratory, Regina Elena National Cancer Institute, Rome, Italy.
Carlo
C
Leonetti
Experimental Chemotherapy Laboratory, Regina Elena National Cancer Institute, Rome, Italy.
Simona
S
Artuso
Department of Clinical and Experimental Sciences, Institute of Pathological Anatomy, University of Brescia, Brescia, Italy.
Anna
A
Benetti
Department of Molecular and Translational Medicine, University of Brescia, Brescia, Italy.
Enrico
E
Dessy
Department of Veterinary Medicine, University of Perugia, Perugia, Italy.
Luisa
L
Pascucci
Department of Biopathology and Image Diagnostics, Anatomic Pathology Institute, University of Rome 'Tor Vergata', Rome, Italy.
Daniela
D
Passeri
Department of Biopathology and Image Diagnostics, Anatomic Pathology Institute, University of Rome 'Tor Vergata', Rome, Italy.
Augusto
A
Orlandi
Department of Clinical and Experimental Sciences, Institute of Pathological Anatomy, University of Brescia, Brescia, Italy.
Angiola
A
Berenzi
Department of Biomedical, Surgical and Dental Sciences, University of Milan, Via Pascal 36, Milan, 20133, Italy.
Arianna
A
Bonomi
Department of Biomedical, Surgical and Dental Sciences, University of Milan, Via Pascal 36, Milan, 20133, Italy.
Valentina
V
Coccè
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.
Anna
A
Ferri
Cellular Neurobiology Laboratory, Department of Cerebrovascular Diseases, IRCCS Neurological Institute C. Besta, Milan, Italy.
Marta
M
Dossena
Department of Microbiology, Brescia University, Brescia, Italy.
Pietro
P
Mazzuca
Laboratory of Clinical Pathology and Neurogenetic Medicine, Fondazione IRCCS Neurological Institute Carlo Besta, Milan, Italy.
Emilio
E
Ciusani
Department of Veterinary Medicine, University of Perugia, Perugia, Italy.
Piero
P
Ceccarelli
Department of Microbiology, Brescia University, Brescia, Italy.
Arnaldo
A
Caruso
Department of Medical and Surgical Sciences, University of Brescia, Brescia, Italy.
Nazario
N
Portolani
Department of Biomedical, Surgical and Dental Sciences, University of Milan, Via Pascal 36, Milan, 20133, Italy.
Francesca
F
Sisto
Cellular Neurobiology Laboratory, Department of Cerebrovascular Diseases, IRCCS Neurological Institute C. Besta, Milan, Italy.
Eugenio
E
Parati
Cellular Neurobiology Laboratory, Department of Cerebrovascular Diseases, IRCCS Neurological Institute C. Besta, Milan, Italy.
Giulio
G
Alessandri
D000818:Animals; D004195:Disease Models, Animal; D016503:Drug Delivery Systems; D006801:Humans; D008175:Lung Neoplasms / Q000473:pathology / Q000556:secondary*; D008297:Male; D008546:Melanoma, Experimental / Q000188:drug therapy*; D059630:Mesenchymal Stem Cells / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D009362:Neoplasm Metastasis