Tumor-specific expression of the RGD-alpha3(IV)NC1 domain suppresses endothelial tube formation and tumor growth in mice.
Angiogenesis plays an essential role in tumor growth. This study investigated expression of the noncollagenous domain of alpha3(IV) collagen (alpha3(IV)NC1) transduced into tumors and its inhibition of tumor growth. We hypothesized that if a human telomerase reverse transcriptase (hTERT) promoter-driven RGD motif containing alpha3(IV)NC1 (hTERT/RGD-alpha3(IV)NC1) were expressed in telomerase-expressing tumor cells, it would inhibit tumor growth by its anti-angiogenic property. Adenoviral transduction of hTERT/RGD-alpha3(IV)NC1 expressed RGD-alpha3(IV)NC1 in hTERT-positive tumor cell lines. However, hTERT/RGD-alpha3(IV)NC1 did not express RGD-alpha3(IV)NC1 in hTERT-negative cells such as keratinocytes and fibroblasts. The secreted RGD-alpha3(IV)NC1 in the conditioned medium from tumor cells inhibited cell proliferation as well as tube formation in cultured endothelial cells, but had no effect on other types of cells. In an in vivo model, adenoviral hTERT/RGD-alpha3(IV)NC1 gene therapy showed limited expression of RGD-alpha3(IV)NC1 in tumors and resulted in a significant decrease of vessel density in tumors. The growth of subcutaneous (s.c.) tumors in nude mice was significantly suppressed by treatment with hTERT/RGD-alpha3(IV)NC1. In addition, long-term inhibition of tumor growth was achieved by intermittent administration of hTERT/RGD-alpha3(IV)NC1. In conclusion, our findings demonstrate that tumor-specific anti-angiogenic gene therapy utilizing RGD-alpha3(IV)NC1 under the hTERT promoter inhibited angiogenesis in tumors, resulting in an antitumor effect.
Miyoshi
Toru
T
Department of Medicine and Medical Science, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Japan.
Hirohata
Satoshi
S
Ogawa
Hiroko
H
Doi
Masayuki
M
Obika
Masanari
M
Yonezawa
Tomoko
T
Sado
Yoshikazu
Y
Kusachi
Shozo
S
Kyo
Satoru
S
Kondo
Seiji
S
Shiratori
Yasushi
Y
Hudson
Billy G
BG
Ninomiya
Yoshifumi
Y
D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D001324:Autoantigens / Q000737:chemistry* / Q000378:metabolism*; D002455:Cell Division; D002460:Cell Line; D045744:Cell Line, Tumor; D002470:Cell Survival; D024141:Collagen Type IV / Q000737:chemistry* / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000378:metabolism*; D004730:Endothelium, Vascular / Q000473:pathology*; D005354:Fibrosarcoma / Q000473:pathology; D006801:Humans; D008175:Lung Neoplasms / Q000473:pathology; D008297:Male; D051379:Mice; D008819:Mice, Nude; D009389:Neovascularization, Pathologic / Q000517:prevention & control*; D009842:Oligopeptides / Q000378:metabolism*; D011471:Prostatic Neoplasms / Q000473:pathology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D019098:Telomerase / Q000378:metabolism*; D014162:Transfection; D014183:Transplantation, Heterologous; D014471:Umbilical Veins
D001324:Autoantigens; D024141:Collagen Type IV; D004268:DNA-Binding Proteins; D009842:Oligopeptides; C057112:type IV collagen alpha3 chain; C047981:arginyl-glycyl-aspartic acid; D019098:Telomerase