title: Human bone marrow-derived mesenchymal stem cells suppress human glioma growth through inhibition of angiogenesis.
abstract: Tumor tropism of human bone marrow-derived mesenchymal stem cells (MSC) has been exploited for the delivery of therapeutic genes for anticancer therapy. However, the exact contribution of these cells in the tumor microenvironment remains unknown. In this study, we examined the biological effect of MSC on tumor cells. The results showed that MSC inhibited the growth of human glioma cell lines and patient-derived primary glioma cells in vitro. Coadministration of MSC and glioma cells resulted in significant reduction in tumor volume and vascular density, which was not observed when glioma was injected with immortalized normal human astrocytes. Using endothelial progenitor cells (EPC) from healthy donors and HUVEC endothelial cells, the extent of EPC recruitment and capacity to form endothelial tubes was significantly impaired in conditioned media derived from MSC/glioma coculture, suggesting that MSC suppressed tumor angiogenesis through the release of antiangiogenic factors. Further studies using antibody array showed reduced expression of platelet-derived growth factor (PDGF)-BB and interleukin (IL)-1β in MSC/glioma coculture when compared with controls. In MSC/glioma coculture, PDGF-BB mRNA and the corresponding proteins (soluble and membrane bound forms) as well as the receptors were found to be significantly downregulated when compared with that of glioma cocultured with normal human astrocytes or glioma monoculture. Furthermore, IL-1β, phosphorylated Akt, and cathepsin B proteins were also reduced in MSC/glioma. Taken together, these data indicated that the antitumor effect of MSC may be mediated through downregulation of PDGF/PDGFR axis, which is known to play a key role in glioma angiogenesis. STEM Cells2013;31:146-155.
authors.affiliation: Laboratory of Cancer Gene Therapy, Humphrey Oei Institute of Cancer Research, National Cancer Center, Singapore.
authors.forename: Ivy A W
authors.initials: IA
authors.lastname: Ho
authors.forename: Han C
authors.initials: HC
authors.lastname: Toh
authors.forename: Wai H
authors.initials: WH
authors.lastname: Ng
authors.forename: Yuan L
authors.initials: YL
authors.lastname: Teo
authors.forename: Chang M
authors.initials: CM
authors.lastname: Guo
authors.forename: Kam M
authors.initials: KM
authors.lastname: Hui
authors.forename: Paula Y P
authors.initials: PY
authors.lastname: Lam
mesh_terms: D000818:Animals; D001253:Astrocytes; D000077214:Becaplermin; D001854:Bone Marrow Cells / Q000502:physiology; D001932:Brain Neoplasms / Q000378:metabolism / Q000628:therapy; D002401:Cathepsin B / Q000096:biosynthesis; D045744:Cell Line, Tumor; D018920:Coculture Techniques; D015536:Down-Regulation; D005910:Glioma / Q000473:pathology* / Q000628:therapy; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D053583:Interleukin-1beta / Q000096:biosynthesis; D045164:Mesenchymal Stem Cell Transplantation; D059630:Mesenchymal Stem Cells / Q000502:physiology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009389:Neovascularization, Pathologic; D051057:Proto-Oncogene Proteins c-akt / Q000096:biosynthesis; D020574:Proto-Oncogene Proteins c-sis / Q000096:biosynthesis / Q000235:genetics*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D017479:Receptors, Platelet-Derived Growth Factor / Q000096:biosynthesis / Q000235:genetics*; D059016:Tumor Microenvironment
chemical_list: D053583:Interleukin-1beta; D020574:Proto-Oncogene Proteins c-sis; D012333:RNA, Messenger; D000077214:Becaplermin; D017479:Receptors, Platelet-Derived Growth Factor; D051057:Proto-Oncogene Proteins c-akt; D002401:Cathepsin B