Bone marrow multipotent mesenchymal stroma cells act as pericyte-like migratory vehicles in experimental gliomas.
Bone marrow-derived multipotent mesenchymal stroma cells (MSCs) have emerged as cellular vectors for gene therapy of solid cancers. We implanted enhanced green fluorescent protein-expressing rat MSCs directly into rat malignant gliomas to address their migratory capacity, phenotype, and effects on tumor neovascularization and animal survival. A single intratumoral injection of MSCs infiltrated the majority of invasive glioma extensions (72 +/- 14%) and a substantial fraction of distant tumor microsatellites (32 +/- 6%). MSC migration was highly specific for tumor tissue. Grafted MSCs integrated into tumor vessel walls and expressed pericyte markers alpha-smooth muscle actin, neuron-glia 2, and platelet-derived growth factor receptor-beta but not endothelial cell markers. The pericyte marker expression profile and perivascular location of grafted MSCs indicate that these cells act as pericytes within tumors. MSC grafting did not influence tumor microvessel density or survival of tumor-bearing animals. The antiangiogenic drug Sunitinib markedly reduced the numbers of grafted MSCs migrating within tumors. We found no MSCs within gliomas following intravenous (i.v.) injections. Thus, MSCs should be administered by intratumoral implantations rather than by i.v. injections. Intratumorally grafted pericyte-like MSCs might represent a particularly well-suited vector system for delivering molecules to affect tumor angiogenesis and for targeting cancer stem cells within the perivascular niche.
Bexell
Daniel
D
The Rausing Laboratory, Division of Neurosurgery, Department of Clinical Sciences, Lund University, Lund, Sweden. daniel.bexell@med.lu.se
Gunnarsson
Salina
S
Tormin
Ariane
A
Darabi
Anna
A
Gisselsson
David
D
Roybon
Laurent
L
Scheding
Stefan
S
Bengzon
Johan
J
D000818:Animals; D000941:Antigens / Q000378:metabolism; D001854:Bone Marrow Cells / Q000166:cytology / Q000502:physiology*; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D046169:Dermoscopy; D005260:Female; D005434:Flow Cytometry; D015316:Genetic Therapy / Q000379:methods*; D005910:Glioma / Q000628:therapy*; D007150:Immunohistochemistry; D017404:In Situ Hybridization, Fluorescence; D007211:Indoles / Q000494:pharmacology; D008297:Male; D059630:Mesenchymal Stem Cells / Q000166:cytology / Q000502:physiology*; D011509:Proteoglycans / Q000378:metabolism; D011758:Pyrroles / Q000494:pharmacology; D051381:Rats; D017479:Receptors, Platelet-Derived Growth Factor / Q000378:metabolism; D017154:Stromal Cells / Q000166:cytology / Q000502:physiology; D000077210:Sunitinib; D000099216:Chondroitin Sulfate Proteoglycan 4
D000941:Antigens; D007211:Indoles; D011509:Proteoglycans; D011758:Pyrroles; D017479:Receptors, Platelet-Derived Growth Factor; D000077210:Sunitinib; D000099216:Chondroitin Sulfate Proteoglycan 4