1. ¹Molecular OncoSurgery Group, Department of General Surgery, University of Heidelberg and German Cancer Research Center, Heidelberg, Germany
2. ²Department of General Surgery, University of Heidelberg, Heidelberg, Germany
3. ³Department of Neonatology, University of Heidelberg, Heidelberg, Germany
4. ⁴Department of Molecular Immunology, German Cancer Research Center, Heidelberg, Germany
5. ⁵Department of Medicine V, University of Heidelberg, Heidelberg, Germany
6. ⁶Department of General Surgery, Klinikum rechts der Isar, Technische Universität München, Munich, Germany

Correspondence: Dr I Herr, Department of Experimental Surgery/Molecular OncoSurgery, University of Heidelberg, Im Neuenheimer Feld 365, 69120 Heidelberg, Germany. E-mail: i.herr@dkfz.de

⁷These authors contributed equally to this work.

Received 6 May 2008; Revised 16 June 2008; Accepted 17 June 2008; Published online 29 July 2008.

Abstract

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.