A Novel Antiangiogenic Effect for Telomerase-Specific Virotherapy through Host Immune System
A Novel Antiangiogenic Effect for Telomerase-Specific Virotherapy through Host Immune System
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DOI：
10.4049/jimmunol.182.3.1763
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发表时间：
2009-02-01
影响因子：
4.4
通讯作者：
Fujiwara, Toshiyoshi
中科院分区：
文献类型：
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作者：
Ikeda, Yoshihiro;Kojima, Toru;Fujiwara, Toshiyoshi
肿瘤微环境中的可溶性因子可能影响血管生成的过程;血管生成是恶性肿瘤生长和进展所必需的过程。在这项研究中，我们描述了一种新的抗血管生成作用的条件复制选择性腺病毒通过刺激宿主的免疫反应。一种减毒腺病毒（OBP-301，Telomelysin），其中人端粒酶逆转录酶启动子元件驱动El基因的表达，可以在癌细胞中复制并引起癌细胞的选择性裂解。混合淋巴细胞-肿瘤细胞培养证明OBP-301感染的癌细胞刺激PBMC产生IFN-γ进入上清液。当对上清液进行体外血管生成测定时，HUVEC的管形成比重组IFN-γ更有效地被抑制。此外，使用膜扩散室系统s.c.移植到nu/nu小鼠中的结果显示，当小室含有混合的淋巴细胞-肿瘤细胞培养物上清液时，肿瘤细胞诱导的新血管形成显著减少。s.c.的增长。由于肿瘤内注射OBP-301减少了血管分布，同系小鼠中的鼠结肠肿瘤被显著抑制。然而，由于缺乏宿主免疫应答，抗肿瘤和抗血管生成作用在SCID小鼠中不太明显。我们的数据表明，OBP-301似乎通过刺激宿主免疫细胞产生内源性抗血管生成因子如IFN-γ而具有抗血管生成特性。免疫学杂志，2009，182：1763-1769.
Soluble factors in the tumor microenvironment may influence the process of angiogenesis; a process essential for the growth and progression of malignant tumors. In this study, we describe a novel antiangiogenic effect of conditional replication-selective adenovirus through the stimulation of host immune reaction. An attenuated adenovirus (OBP-301, Telomelysin), in which the human telomerase reverse transcriptase promoter element drives expression of El genes, could replicate in and cause selective lysis of cancer cells. Mixed lymphocyte-tumor cell culture demonstrated that OBP-301-infected cancer cells stimulated PBMC to produce IFN-gamma into the supernatants. When the supernatants were subjected to the assay of in vitro angiogenesis, the tube formation of HUVECs was inhibited more efficiently than recombinant IFN-gamma. Moreover, in vivo angiogenic assay using a membrane-diffusion chamber system s.c. transplanted in nu/nu mice showed that tumor cell-induced neovascularization was markedly reduced when the chambers contained the mixed lymphocyte-tumor cell culture supernatants. The growth of s.c. murine colon tumors in syngenic mice was significantly inhibited due to the reduced vascularity by intratumoral injection of OBP-301. The antitumor as well as antiangiogenic effects, however, were less apparent in SCID mice due to the lack of host immune responses. Our data suggest that OBP-301 seems to have antiangiogenic properties through the stimulation of host immune cells to produce endogenous antiangiogenic factors such as IFN-gamma. The Journal of Immunology, 2009, 182: 1763-1769.