TGF-β mediates homing of bone marrow-derived human mesenchymal stem cells to glioma stem cells.
Although studies have suggested that bone marrow human mesenchymal stem cells (BM-hMSC) may be used as delivery vehicles for cancer therapy, it remains unclear whether BM-hMSCs are capable of targeting cancer stem cells, including glioma stem cells (GSC), which are the tumor-initiating cells responsible for treatment failures. Using standard glioma models, we identify TGF-β as a tumor factor that attracts BM-hMSCs via TGF-β receptors (TGFβR) on BM-hMSCs. Using human and rat GSCs, we then show for the first time that intravascularly administered BM-hMSCs home to GSC-xenografts that express TGF-β. In therapeutic studies, we show that BM-hMSCs carrying the oncolytic adenovirus Delta-24-RGD prolonged the survival of TGF-β-secreting GSC xenografts and that the efficacy of this strategy can be abrogated by inhibition of TGFβR on BM-hMSCs. These findings reveal the TGF-β/TGFβR axis as a mediator of the tropism of BM-hMSCs for GSCs and suggest that TGF-β predicts patients in whom BM-hMSC delivery will be effective.
Department of Neurosurgery, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
Naoki
N
Shinojima
Anwar
A
Hossain
Tatsuya
T
Takezaki
Juan
J
Fueyo
Joy
J
Gumin
Feng
F
Gao
Felix
F
Nwajei
Frank C
FC
Marini
Michael
M
Andreeff
Jun-Ichi
J
Kuratsu
Frederick F
FF
Lang
D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D017209:Apoptosis; D015153:Blotting, Western; D001853:Bone Marrow / Q000378:metabolism / Q000473:pathology*; D001932:Brain Neoplasms / Q000378:metabolism / Q000473:pathology; D002454:Cell Differentiation; D049109:Cell Proliferation; D002478:Cells, Cultured; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D005910:Glioma / Q000378:metabolism / Q000473:pathology*; D006801:Humans; D059630:Mesenchymal Stem Cells / Q000166:cytology* / Q000378:metabolism; D014411:Neoplastic Stem Cells / Q000378:metabolism / Q000473:pathology*; D051381:Rats; D018125:Receptors, Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism*; D023041:Xenograft Model Antitumor Assays
D018125:Receptors, Transforming Growth Factor beta; D016212:Transforming Growth Factor beta