VEGF expression by mesenchymal stem cells contributes to angiogenesis in pancreatic carcinoma

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 þ 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.

45S5-Bioglass®-Based 3D-Scaffolds Seeded with Human Adipose Tissue-Derived Stem Cells Induce In Vivo Vascularization in the CAM Angiogenesis Assay

“…34,35 A variety of studies revealed that both, the scaffold material, 6 as well as scaffold-bound cells have their own, discrete bioactive properties, which may influence the scaffold/tissue interaction, respectively. 28,35,36 Bioactive glasses, as reviewed by Hoppe et al, 6 are known to release various ion products. The ion dissolution products of 45S5 Bioglass Ò , are presumed to comprise Si, Ca, Na, and P. 6 The subsequent release of these ions after exposure to a physiological environment is then believed to favorably affect the behavior of human cells and to enhance the bioactivity of the scaffolds related to both osteogenesis and angiogenesis.…”

“…This approach bears the chance that the cells constantly secrete capillary recruiting mediators [27][28][29] and therefore, induce long-term vessel growth. To biofunctionalize scaffolds, high numbers of adult progenitor cells can easily be isolated, for example, from human adipose tissuederived stem cells (hASC), but they are present and responsible for tissue repair and tissue regeneration in every adult tissue.…”

“…30 In addition, hASC are able to both differentiate into various specific cell types (e.g., chondrocytes, adipocytes and osteocytes) and to secrete different growth factors, including VEGF, which stimulates repair and regeneration processes, including angiogenesis. 28 In this study, we examined for the first time 45S5-Bioglass Ò -based 3D-scaffolds seeded with hASC for their effects on in vivo vascularization using the CAM angiogenesis assay. Commercial fibrous scaffolds (polypropylene hernia meshes) were used as biologically inert control material.…”

Mesenchymal Stem Cells: How Can we Realize their Therapeutic Potential in Cancer Therapy?

“…Other pro-tumorigenic effects of MSCs in tumour stroma include promotion of angiogenesis via differentiation to mural cells or pericytes, or the secretion of vascular endothelial growth factor [22][23][24]. MSCs in the tumour stroma were also found to regulate immune system function, with an overall immunosuppressive effect.…”

“…These growth factors attract MSCs across a Boyden chamber membrane without further stimulus being required, can act synergistically with cytokines and have their pro-migratory effect blocked by antibodies or specific inhibitors [24,[37][38][39][40]. In an intracranial mouse model of glioma, low PDGF-BB-expressing U87 cells attracted fewer MSCs and grew to a smaller size than high expressing clones [39].…”