Growth suppression of cervical carcinoma by pigment epithelium-derived factor via anti-angiogenesis
Growth suppression of cervical carcinoma by pigment epithelium-derived factor via anti-angiogenesis
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DOI：
10.4161/cbt.9.12.11635
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发表时间：
2010-06
影响因子：
3.6
通讯作者：
Jun Yang;Shuqin Chen;Xuan Huang;Jiande Han;Qingsong Wang;Dingbo Shi;Rui Cheng;G. Gao;Xia Y
中科院分区：
文献类型：
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作者：
Jun Yang;Shuqin Chen;Xuan Huang;Jiande Han;Qingsong Wang;Dingbo Shi;Rui Cheng;G. Gao;Xia Y
色素上皮衍生因子 (PEDF) 是一种具有多种其他功能的血管生成抑制剂，可平衡眼部血管生成并阻止肿瘤进展。宫颈癌是一种血管生成依赖性肿瘤，在没有有效治疗的情况下是女性中第二常见的癌症。据报道，PEDF可以抑制多种类型的肿瘤，然而，PEDF治疗宫颈癌的潜力尚未得到充分探索。本研究旨在探讨重组PEDF对宫颈癌新生血管形成和生长的影响。我们首次发现，与正常宫颈上皮或非肿瘤周围上皮相比，PEDF 在人宫颈癌巢中的表达明显下调，表明补充 PEDF 在宫颈癌中具有潜在的抗血管生成功能。异种移植宫颈癌小鼠腹腔注射 PEDF 可抑制肿瘤生长，减少 68%。经过PEDF处理的肿瘤组织中的微血管密度显着降低。 PEDF剂量依赖性地抑制内皮细胞增殖并诱导其凋亡，但在常氧和缺氧条件下对Hela细胞的增殖和凋亡无直接影响。这些结果表明，PEDF 通过阻断血管生成来抑制肿瘤生长，而不是对肿瘤细胞产生直接的细胞毒性作用。 VEGF 是一种主要的血管生成刺激物，在 Hela 细胞中，PEDF 通过下调 HIF-1α（VEGF 表达的关键转录因子）来下调 VEGF。通过抑制 HIF-1α 下调肿瘤细胞中 VEGF 的表达，从而减弱 VEGF 对内皮细胞的旁分泌作用，可能代表了 PEDF 抗血管生成活性的机制。
Pigment epithelium-derived factor (PEDF), an angiogenesis inhibitor with multiple other functions, balances angiogenesis in the eye and blocks tumor progression. Cervical cancer, an angiogenesis-dependent tumor, is the second most common cancer in women without effective treatment. It has been reported that PEDF can inhibit several types of tumors, however, the potential of PEDF for the treatment of cervical carcinoma has not been well explored. The present study was designed to investigate the effect of recombinant PEDF on the neovascularization and growth of cervical carcinoma. We found for the first time that PEDF was down-regulated apparently in human cervical carcinoma nests compared to either normal cervical epithelium or nonneoplastic peritumoral epithelium, suggesting potential anti-angiogenesis function by supplement of PEDF in cervical carcinoma. Intraperitoneal injection of PEDF in xenografted cervical carcinoma mice suppressed tumor growth with 68% reduction. Microvessel density in tumor tissues treated with PEDF was significantly decreased. PEDF dose-dependently inhibited proliferation and induced apoptosis of endothelial cells, but had no direct effect on proliferation and apoptosis of Hela cells under both normoxia and hypoxia. These results suggested that PEDF suppressed tumor growth by blocking angiogenesis instead of a direct cytotoxic effect on tumor cells. VEGF, a major angiogenic stimulator, was down-regulated by PEDF in Hela cells by down-regulation of HIF-1α, a crucial transcriptional factor for VEGF expression. Down-regulation of VEGF expression in tumor cells through inhibiting HIF-1α, thus attenuating the paracrine effect of VEGF on endothelial cells, may represent a mechanism for the anti-angiogenic activity of PEDF.