Bone marrow-derived cells contribute to tumor neovasculature and, when modified to express an angiogenesis inhibitor, can restrict tumor growth in mice.
Inhibition of tumor-induced neovascularization appears to be an effective anticancer approach, although long-term angiogenesis inhibition may be required. An alternative to chronic drug administration is a gene therapy-mediated approach in which long-term in vivo protein expression is established. We have tested this approach by modifying murine bone marrow-derived cells with a gene encoding an angiogenesis inhibitor: a soluble, truncated form of the vascular endothelial growth factor receptor-2, fetal liver kinase-1 (Flk-1). Murine bone marrow cells were transduced with a retroviral vector encoding either truncated, soluble Flk-1 (tsFlk-1) together with green fluorescent protein (GFP) or GFP alone. Tumor growth in mice challenged 3 months after transplantation with tsFlk-1-expressing bone marrow cells was significantly inhibited when compared with tumor growth in control-transplanted mice. Immunohistochemical analysis of tumors in each group demonstrated colocalization of GFP expression in cells staining with endothelial cell markers, suggesting that the endothelial cells of the tumor-induced neovasculature were derived, at least in part, from bone marrow precursors. These results suggest that long-term expression of a functional angiogenesis inhibitor can be generated through gene-modified, bone marrow-derived stem cells, and that this approach can have significant anticancer efficacy. Modifying these cells seems to have the added potential benefit of targeting transgene expression to the tumor neovasculature, because bone marrow-derived endothelial cell precursors seem to be recruited in the process of tumor-induced angiogenesis.
Davidoff
A M
AM
Department of Surgery, St. Jude Children's Research Hospital, Memphis, Tennessee 38105, USA. andrew.davidoff@stjude.org
Ng
C Y
CY
Brown
P
P
Leary
M A
MA
Spurbeck
W W
WW
Zhou
J
J
Horwitz
E
E
Vanin
E F
EF
Nienhuis
A W
AW
D020533:Angiogenesis Inhibitors / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D001854:Bone Marrow Cells / Q000378:metabolism*; D002455:Cell Division / Q000235:genetics; D005260:Female; D005455:Fluorescent Antibody Technique; D005786:Gene Expression Regulation; D015316:Genetic Therapy / Q000379:methods; D005822:Genetic Vectors / Q000235:genetics; D049452:Green Fluorescent Proteins; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D008164:Luminescent Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008815:Mice, Inbred Strains; D016513:Mice, SCID; D009374:Neoplasms, Experimental / Q000235:genetics / Q000473:pathology / Q000517:prevention & control*; D009389:Neovascularization, Pathologic / Q000235:genetics / Q000473:pathology / Q000517:prevention & control*; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism; D017978:Receptors, Growth Factor / Q000235:genetics / Q000378:metabolism; D040262:Receptors, Vascular Endothelial Growth Factor; D014162:Transfection; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
D020533:Angiogenesis Inhibitors; D008164:Luminescent Proteins; D017978:Receptors, Growth Factor; D049452:Green Fluorescent Proteins; D020794:Receptor Protein-Tyrosine Kinases; D040262:Receptors, Vascular Endothelial Growth Factor