Combination of hTERT knockdown and IFN-gamma treatment inhibited angiogenesis and tumor progression in glioblastoma.
Combination of hTERT knockdown and IFN-gamma treatment inhibited angiogenesis and tumor progression in glioblastoma.
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DOI：
10.1158/1078-0432.ccr-09-1425
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发表时间：
2009-12-01
期刊：
影响因子：
--
通讯作者：
Ray SK
中科院分区：
文献类型：
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作者：
George J;Banik NL;Ray SK
肿瘤细胞无限的侵袭和增殖能力与端粒酶及其催化组分人端粒酶逆转录酶（human telomerase reverse transcriptase，hTERT）的表达有关。干扰素-γ（IFN-γ）通过转录调节调节多种细胞活动，包括信号通路和细胞周期。我们使用hTERT siRNA cDNA重组质粒，在IFN-γ处理人胶质母细胞瘤SNB-19和LN-18细胞系期间下调hTERT，并检查这种组合是否可以抑制裸鼠中的血管生成和肿瘤生长。采用肿瘤细胞与人微血管内皮细胞共培养的方法进行体外血管生成试验。在裸鼠背部皮肤下使用扩散室进行体内血管生成测定。在裸鼠中进行脑内肿瘤发生的体内成像和纵向实体瘤发展研究。在体外和体内血管生成实验表明，抑制微血管内皮细胞的毛细血管样网络的形成和裸鼠背部皮肤下的新生血管，分别。我们观察了hTERT siRNA和IFN-γ联合治疗后对裸鼠脑内肿瘤发生和皮下实体瘤形成的抑制作用。实体瘤样品的蛋白质印迹显示调节细胞侵袭、血管生成和肿瘤进展的分子的显著下调。我们的研究表明，hTERT siRNA和IFN-γ的组合通过下调参与这些过程的分子而有效地抑制血管生成和肿瘤进展。因此，hTERT siRNA和IFN-γ的组合是控制人胶质母细胞瘤生长的有希望的治疗策略。
The limitless invasive and proliferative capacities of tumor cells are associated with telomerase and expression of its catalytic component, human telomerase reverse transcriptase (hTERT). Interferon-γ (IFN-γ) modulates several cellular activities including signaling pathways and cell cycle through transcriptional regulation. Using a recombinant plasmid with hTERT siRNA cDNA, we down regulated hTERT during IFN-γ treatment in human glioblastoma SNB-19 and LN-18 cell lines and examined whether such a combination could inhibit angiogenesis and tumor growth in nude mice. In vitro angiogenesis assay was performed using co-culture of tumor cells with human microvascular endothelial cells. In vivo angiogenesis assay was performed using diffusion chambers under the dorsal skin of nude mice. In vivo imaging of intracerebral tumorigenesis and longitudinal solid tumor development studies were conducted in nude mice. In vitro and in vivo angiogenesis assays demonstrated inhibition of capillary-like network formation of microvascular endothelial cells and neovascularization under dorsal skin of nude mice, respectively. We observed inhibition of intracerebral tumorigenesis and subcutaneous solid tumor formation in nude mice after treatment with combination of hTERT siRNA and IFN-γ. Western blotting of solid tumor samples demonstrated significant down regulation of the molecules that regulate cell invasion, angiogenesis, and tumor progression. Our study demonstrated that combination of hTERT siRNA and IFN-γ effectively inhibited angiogenesis and tumor progression through down regulation of molecules involved in these processes. Therefore, combination of hTERT siRNA and IFN-γ is a promising therapeutic strategy for controlling growth of human glioblastoma.