Anti-angiogenic effects of pl6, p53, PTEN tumor suppressor gene transfer on human malignant gliomas

pl6、p53、PTEN抑癌基因转移对人恶性胶质瘤的抗血管生成作用

• 批准号: 13671441
• 负责人: NAKAGAWA Kou
• 金额: $ 1.09万
• 依托单位: Ehime University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2001
• 资助国家: 日本
• 起止时间: 2001 至 2002
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-13671441/
• 关键词: Malignant glioma; Tumor angiogenesis; Tumor suppressor gene; Angiogenic-related substance; Gene transduction; 血管新生関連因子

In addition to the alteration of p16, p53, and PTEN, the malignant progression from low to high-grade gliomas is accompanied by overproduction of angiogenic factors and suppression of anti-angiogenic effectors. However, the relationship between tumor suppressor genes and angiogenic-related substances in human gliomas has not been sufficiently resolved. The aim of the present study was to investigate the effects of p16, p53, and PTEN gene transfer on glioma angiogenesis. We focused on vascular endothelial growth factor (VEGF) as a potent angiogenic stimulator, and thrombospondin-1 (TSP-1) and TSP-2 as angiogenic inhibitors. The p16 gene is endogenously deleted in U251MG and U87MG. The p53 gene is mutated in U251MG but is intact in U87MG cells. Endogeneous PTEN is mutated in both U251MG and U87MG. Infection with recombinant replication-defective adenovirus vector containing the cDNA of wild-type p16, p53, or PTEN significantly reduced the expression of VEGF depending on the gene status of each glioma cell line. TSP-1 and TSP-2 expression was enhanced by the transduction of wild-type p53 or PTEN. In contrast, the restoration of wild-type p16 had no effect on TSP-1 expression, but increased TSP-2 in p16-deleted glioma cells. In vivo angiogenesis assay showed that adenovirus-mediated gene transfer of p16, p53, and PTEN markedly inhibited tumor neovascularization. In conclusion, these suppressor genes, which are frequently observed to lose function in human gliomas, are also closely related to tumor angiogenesis. The present study suggests that p16, p53, and PTEN gene transfer may be a suitable anti-angiogenic therapy for malignant gliomas.

除了p16、p53和PTEN的改变之外，从低级别到高级别胶质瘤的恶性进展还伴随着血管生成因子的过度产生和抗血管生成效应物的抑制。然而，肿瘤抑制基因和血管生成相关物质在人类胶质瘤中的关系尚未得到充分解决。本研究旨在探讨p16、p53和PTEN基因转染对胶质瘤血管生成的影响。我们重点研究了血管内皮生长因子（VEGF）作为一种有效的血管生成刺激因子，以及血小板反应蛋白-1（TSP-1）和TSP-2作为血管生成抑制因子。在U251 MG和U87 MG中p16基因内源性缺失。p53基因在U251 MG中突变，但在U87 MG细胞中是完整的。内源性PTEN在U251 MG和U87 MG中均发生突变。用含有野生型p16、p53或PTEN的cDNA的重组复制缺陷型腺病毒载体感染显著降低了VEGF的表达，这取决于每个胶质瘤细胞系的基因状态。TSP-1和TSP-2的表达通过转导野生型p53或PTEN而增强。相反，野生型p16的恢复对TSP-1的表达没有影响，但在p16缺失的胶质瘤细胞中增加TSP-2。体内血管生成实验表明，腺病毒介导的p16、p53和PTEN基因转染能显著抑制肿瘤血管生成。总之，这些抑制基因，这是经常观察到失去功能的人类胶质瘤，也密切相关的肿瘤血管生成。本研究提示，p16、p53和PTEN基因转移可能是一种合适的恶性胶质瘤抗血管生成治疗方法。

项目成果

Hironobu Harada, Kou Nakagawa, Masahiro Saito, Shohei Kohno, Shigeyuki Nagato, Koji Furakawa, Yoshiaki Kumon, Katsuyuki Hamada, Takanori Ohnishi: "Introduction of wild-type p53 enhances thrombospondin-1 expression in human glioma cells"Cancer Letters. (in

Hironobu Harada、Kou Nakakawa、Masahiro Saito、Shohei Kohno、Shigeyuki Nagato、Koji Furakawa、Yoshiaki Kumon、Katsuyuki Hamada、Takanori Ohnishi：“野生型 p53 的引入增强了人胶质瘤细胞中血小板反应蛋白-1 的表达”《癌症快报》。

Hironobu Harada, Kou Nakagawa, et al.: "Restoration of wild-type p16 down-regulates vascular endothelial growth factor expression and inhibits angiogenesis in human gliomas"Cancer Research. 59. 3783-3789 (1999)

Hironobu Harada、Kou Nakakawa 等人：“野生型 p16 的恢复下调血管内皮生长因子表达并抑制人类神经胶质瘤中的血管生成”癌症研究。

岩田慎治: "Endothelial nitric oxide synthase expression in tumor vasculature is correlated with malignancy in human supratentorial astrocytic tumors"Neurosurgery. 45. 24-29 (1999)

Shinji Iwata：“肿瘤血管系统中内皮一氧化氮合酶的表达与人类幕上星形细胞肿瘤的恶性程度相关”《神经外科》45. 24-29 (1999)。

Shinji Iwata, Kou Nakagawa, et al.: "Endothelial nitric oxide synthase expression in tumor vasculature is correlated with malignancy in human supratentorial astrocytic tumors"Neurosurgery. 45. 24-29 (1999)

Shinji Iwata、Kou Nakakawa 等人：“肿瘤血管系统中内皮一氧化氮合酶的表达与人类幕上星形细胞肿瘤的恶性肿瘤相关”神经外科。

中川晃, 原田広信: "ポストシークエンス時代における脳腫瘍の研究と治療"田淵和雄, 白石哲也. 561 (2002)

Akira Nakakawa、Hironobu Harada：“后序列时代脑肿瘤的研究和治疗”Kazuo Tabuchi、Tetsuya Shiraishi 561（2002）。