Suppression of tumor angiogenesis and growth by gene transfer of a soluble form of vascular endothelial growth factor receptor into a remote organ.
Antiangiogenic therapy shows promise as a strategy for cancer treatment. We constructed an adenovirus (AdVEGF-ExR) expressing the entire extracellular domain of the human vascular endothelial growth factor (VEGF) receptor (flt-1) fused to the Fc portion of human IgG. The soluble receptor secreted from AdVEGF-ExR-infected cells bound to VEGF and inhibited VEGF-induced DNA synthesis in endothelial cells. When human lung cancer cell line H157, which produces not only VEGF but also fibroblast growth factor 2 and interleukin 8 at substantial levels, was infected with AdVEGF-ExR, cell growth in vitro was not affected. However, when H157 cells infected with AdVEGF-ExR were injected s.c. into nude mice, tumor formation stopped on the 10th day after reaching a certain size (about 100 mm3), and tumor size declined gradually thereafter. When AdVEGF-ExR was injected into skeletal muscle and uninfected H157 cells were injected s.c., the soluble receptor was detectable in the circulating blood for 3 weeks, tumor growth ceased after 10 days, and tumor size declined thereafter. Histological examination revealed that intratumor angiogenesis was markedly suppressed, and apoptosis was enhanced. Using the same experimental protocol, a significant suppression of tumor growth was also seen in four of five other lung cancer cell lines, some of which secreted VEGF at nominal levels, at least under normoxic conditions in vitro. Our results demonstrate that adenovirus-mediated expression of a soluble VEGF receptor in a remote organ could inhibit tumor angiogenesis and enhance apoptosis and thereby suppress tumor growth in vivo. Adenovirus-mediated overexpression of a soluble VEGF receptor in a remote organ may have the potential to be a feasible and effective strategy for cancer treatment.
Takayama
K
K
Research Institute for Diseases of the Chest, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
Ueno
H
H
Nakanishi
Y
Y
Sakamoto
T
T
Inoue
K
K
Shimizu
K
K
Oohashi
H
H
Hara
N
N
D000260:Adenoviruses, Human / Q000235:genetics; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D002460:Cell Line; D004247:DNA / Q000096:biosynthesis; D016228:Endothelial Growth Factors / Q000378:metabolism / Q000494:pharmacology; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D016222:Fibroblast Growth Factor 2 / Q000378:metabolism / Q000494:pharmacology; D018014:Gene Transfer Techniques; D015316:Genetic Therapy; D006801:Humans; D007141:Immunoglobulin Fc Fragments / Q000097:blood / Q000737:chemistry / Q000235:genetics / Q000627:therapeutic use; D007074:Immunoglobulin G / Q000097:blood / Q000737:chemistry / Q000235:genetics / Q000627:therapeutic use; D007273:Injections, Intramuscular; D008175:Lung Neoplasms / Q000098:blood supply / Q000378:metabolism / Q000473:pathology* / Q000628:therapy*; D008222:Lymphokines / Q000378:metabolism / Q000494:pharmacology; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D009389:Neovascularization, Pathologic / Q000628:therapy*; D020794:Receptor Protein-Tyrosine Kinases / Q000097:blood / Q000235:genetics* / Q000627:therapeutic use*; D017978:Receptors, Growth Factor / Q000097:blood / Q000235:genetics* / Q000627:therapeutic use*; D040262:Receptors, Vascular Endothelial Growth Factor; D011993:Recombinant Fusion Proteins / Q000097:blood / Q000627:therapeutic use; D012995:Solubility; D014407:Tumor Cells, Cultured; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors
D016228:Endothelial Growth Factors; D007141:Immunoglobulin Fc Fragments; D007074:Immunoglobulin G; D008222:Lymphokines; D017978:Receptors, Growth Factor; D011993:Recombinant Fusion Proteins; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D016222:Fibroblast Growth Factor 2; D004247:DNA; D020794:Receptor Protein-Tyrosine Kinases; D040262:Receptors, Vascular Endothelial Growth Factor