Experimental study of antiangiogenic gene therapy targeting VEGF in oral cancer

Abstract

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.

Transcutaneous Carbon Dioxide Induces Mitochondrial Apoptosis and Suppresses Metastasis of Oral Squamous Cell Carcinoma In Vivo

“…HSC-3 cells in Eagle's minimum essential medium (Sigma-Aldrich, St Louis, MO, USA) supplemented with 10% fetal bovine serum (Sigma-Aldrich) and 1000 units/mL penicillin/streptomycin solution (Sigma-Aldrich) were routinely cultured in an incubator in 5% CO 2 at 37°C. Trypsin (0.25%) and ethylenediaminetetraacetic acid (0.02%; Sigma-Aldrich) solution was used to isolate cells for subculture, as previously described [16].…”

Inhibitory Effects of Glycerol on Growth and Invasion of Human Oral Cancer Cell Lines

“…No DNA ladder was detected in Gin-1 treated with 0.2 M and Ltd, Tokyo, Japan) during admission to neurosurgery 5) . Since…”

“…In those experiments, on the other hand, glycerol in isolation has not been considered to inhibit growth and invasion of cancer cell lines 4) . However, inhibition of tumor growth was observed after glycerol was administrated to a patient with oral cancer complicated by cerebral infarction 5) , suggesting a tumor-inhibitory effect of the sole administration. Thus, the present study aimed to clarify to what extent separate administration of glycerol inhibited growth and invasion of cancer cell lines and how the inhibitory mechanisms worked.…”

Nanotechnology-based drug delivery systems for treatment of oral cancer: a review

“…57 Angiogenesis is a crucial step in the processes of uncontrolled tumor proliferation and metastasis, and inhibiting angiogenesis is considered to be effective for treating oral cancer. Vascular endothelial growth factor (VEGF) is thought to be an important angiogenic factor, 58 and studies have shown that OSCC is associated with an elevated VEGF concentration in the serum. These higher levels of VEGF are correlated with lymph node metastasis, clinical stage, and the prognosis and treatment of OSCC.…”