VEGF expression by mesenchymal stem cells contributes to angiogenesis in pancreatic carcinoma.
Little is known about the factors that enable the mobilisation of human mesenchymal stem cells (MSC) from the bone marrow into the blood stream and their recruitment to and retention in the tumour. We found specific migration of MSC towards growth factors present in pancreatic tumours, such as PDGF, EGF, VEGF and specific inhibitors Glivec, Erbitux and Avastin interfered with migration. Within a few hours, MSC migrated into spheroids consisting of pancreatic cancer cells, fibroblasts and endothelial cells as measured by time-lapse microscopy. Supernatant from subconfluent MSC increased sprouting of HUVEC due to VEGF production by MSC itself as demonstrated by RT-PCR and ELISA. Only few MSCs were differentiated into endothelial cells in vitro, whereas in vivo differentiation was not observed. Lentiviral GFP-marked MSCs, injected in nude mice xenografted with orthotopic pancreatic tumours, preferentially migrated into the tumours as observed by FACS analysis of green fluorescent cells. By immunofluorescence and intravital microscopic studies, we found the interaction of MSC with the endothelium of blood vessels. Mesenchymal stem cells supported tumour angiogenesis in vivo, that is CD31(+) vessel density was increased after the transfer of MSC compared with siVEGF-MSC. Our data demonstrate the migration of MSC toward tumour vessels and suggest a supportive role in angiogenesis.
Beckermann
B M
BM
Molecular OncoSurgery Group, Department of General Surgery, University of Heidelberg and German Cancer Research Center, Heidelberg, Germany.
Kallifatidis
G
G
Groth
A
A
Frommhold
D
D
Apel
A
A
Mattern
J
J
Salnikov
A V
AV
Moldenhauer
G
G
Wagner
W
W
Diehlmann
A
A
Saffrich
R
R
Schubert
M
M
Ho
A D
AD
Giese
N
N
Büchler
M W
MW
Friess
H
H
Büchler
P
P
Herr
I
I
D000199:Actins / Q000378:metabolism; D020533:Angiogenesis Inhibitors / Q000494:pharmacology; D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents / Q000494:pharmacology; D001549:Benzamides; D000068258:Bevacizumab; D002454:Cell Differentiation / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation; D002478:Cells, Cultured; D000068818:Cetuximab; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D004815:Epidermal Growth Factor / Q000037:antagonists & inhibitors / Q000378:metabolism; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D000068877:Imatinib Mesylate; D016086:Lentivirus / Q000235:genetics; D008297:Male; D045164:Mesenchymal Stem Cell Transplantation; D059630:Mesenchymal Stem Cells / Q000378:metabolism*; D051379:Mice; D008819:Mice, Nude; D009130:Muscle, Smooth / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D009389:Neovascularization, Pathologic / Q000378:metabolism*; D010190:Pancreatic Neoplasms / Q000098:blood supply* / Q000378:metabolism / Q000473:pathology; D010879:Piperazines / Q000494:pharmacology; D010982:Platelet-Derived Growth Factor / Q000037:antagonists & inhibitors / Q000378:metabolism; D011743:Pyrimidines / Q000494:pharmacology; D018874:Spheroids, Cellular / Q000473:pathology; D014183:Transplantation, Heterologous; D014471:Umbilical Veins / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors / Q000378:metabolism*
D000199:Actins; D020533:Angiogenesis Inhibitors; D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D001549:Benzamides; D010879:Piperazines; D010982:Platelet-Derived Growth Factor; D011743:Pyrimidines; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D000068258:Bevacizumab; D004815:Epidermal Growth Factor; D000068877:Imatinib Mesylate; D000068818:Cetuximab