Experimental study of antiangiogenic gene therapy targeting VEGF in oral cancer.
It is well known that tumor angiogenesis plays an important role in local growth and metastasis of oral cancer; therefore, inhibiting angiogenesis is considered to be effective for treating oral cancer. This study aimed to investigate the effectiveness of systemically available antiangiogenic gene therapy targeting vascular endothelial growth factor (VEGF), which is one of the most important angiogenesis accelerators. We administered a soluble form of VEGF receptor-expressing gene incorporated into adenovirus (AdVEGF-ExR) intraperitoneally to nude mice to which oral cancer cell lines (SAS, HSC-3, and Ca9-22) had been transplanted subcutaneously in vivo to inhibit angiogenesis and tumor proliferation. Then, we measured tumor volumes over time, and tumors were enucleated and examined histopathologically and immunohistologically at 28 days after AdVEGF-ExR administration. Compared to the controls to which we administered AdLacZ or saline, significant antiproliferative effects were observed (P < 0.05) in the AdVEGF-ExR administration group, and extensive tumor necrosis was found histopathologically. Immunohistochemical analysis with CD34 (NU-4A1) revealed tumor angiogenesis was suppressed significantly (P < 0.05), and that with ssDNA revealed apoptosis induction was significantly high (P < 0.05) in the AdVEGF-ExR group. However, analysis with Ki-67 (MIB-1) revealed tumor proliferative capacity was not significantly different between the groups. Consequently, we consider that AdVEGF-ExR administration achieved tumor growth suppression by inhibiting angiogenesis and inducing apoptosis, but not by inhibiting the proliferative capacity of tumor cells. Neither topical administration of a soluble form of VEGF receptor (sVEGFR) to the tumor nor a megadose was needed to achieve this inhibition effect. These results suggest gene therapy via sVEGFR would be an effective oral cancer therapy and benefit future clinical applications.
Department of Pathology, The Nippon Dental University, School of Life Dentistry at Niigata, 1-8 Hamaura-cho, Chuo-ku, Niigata, 951-8580, Japan. yokada@ngt.ndu.ac.jp
Yasuo
Y
Okada
Hikaru
H
Ueno
Masataka
M
Katagiri
Takahiro
T
Oneyama
Kana
K
Shimomura
Satoshi
S
Sakurai
Izumi
I
Mataga
Michiko
M
Moride
Hitoshi
H
Hasegawa
D000256:Adenoviridae / Q000235:genetics; D000704:Analysis of Variance; D020533:Angiogenesis Inhibitors / Q000235:genetics / Q000378:metabolism / Q000627:therapeutic use*; D000818:Animals; D002294:Carcinoma, Squamous Cell / Q000098:blood supply* / Q000378:metabolism / Q000473:pathology / Q000628:therapy; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D018014:Gene Transfer Techniques; D015316:Genetic Therapy; D005822:Genetic Vectors; D005887:Gingival Neoplasms / Q000098:blood supply* / Q000378:metabolism / Q000473:pathology / Q000628:therapy; D006801:Humans; D008207:Lymphatic Metastasis; D051379:Mice; D008819:Mice, Nude; D009374:Neoplasms, Experimental; D009389:Neovascularization, Pathologic / Q000517:prevention & control*; D040262:Receptors, Vascular Endothelial Growth Factor / Q000235:genetics / Q000378:metabolism / Q000627:therapeutic use*; D014062:Tongue Neoplasms / Q000098:blood supply* / Q000378:metabolism / Q000473:pathology / Q000628:therapy; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
D020533:Angiogenesis Inhibitors; D042461:Vascular Endothelial Growth Factor A; D040262:Receptors, Vascular Endothelial Growth Factor