Rüegg C, Dormond O, Foletti A
Centre Pluridisciplinaire d'Oncologie, University of Lausanne Medical School, Switzerland.
Endothelium. 2002;9(3):151-60. doi: 10.1080/10623320213635.
Tumor angiogenesis is an essential step in tumor progression and metastasis formation. Suppression of tumor angiogenesis results in the inhibition of tumor growth. Recent evidence indicates that vascular integrins, in particular alpha V beta 3, are important regulators of angiogenesis, including tumor angiogenesis. Integrin alpha V beta 3 antagonists, such as blocking antibodies or peptides, suppress tumor angiogenesis and tumor progression in many preclinical tumor models. The potential therapeutic efficacy of extracellular integrin antagonists in human cancer is currently being tested in clinical trials. Selective disruption of the tumor vasculature by high doses of tumor necrosis factor (TNF) and interferon gamma (IFN-gamma), and the antiangiogenic activity of nonsteroidal anti-inflammatory drugs are associated with the suppression of integrin alpha V beta 3 function and signaling in endothelial cells. Furthermore, expression of isolated integrin cytoplasmic domains disrupts integrin-dependent adhesion, resulting in endothelial cell detachment and apoptosis. These results confirm the critical role of vascular integrins in promoting endothelial cell survival and angiogenesis and suggest that intracellular targeting of integrin function and signaling may be an alternative strategy to extracellular integrin antagonists for the therapeutic inhibition of tumor angiogenesis.
肿瘤血管生成是肿瘤进展和转移形成的关键步骤。抑制肿瘤血管生成会导致肿瘤生长受到抑制。最近的证据表明，血管整合素，尤其是αVβ3，是血管生成（包括肿瘤血管生成）的重要调节因子。整合素αVβ3拮抗剂，如阻断抗体或肽，在许多临床前肿瘤模型中可抑制肿瘤血管生成和肿瘤进展。细胞外整合素拮抗剂在人类癌症中的潜在治疗效果目前正在临床试验中进行测试。高剂量肿瘤坏死因子（TNF）和干扰素γ（IFN-γ）对肿瘤血管系统的选择性破坏，以及非甾体抗炎药的抗血管生成活性，与内皮细胞中整合素αVβ3功能和信号传导的抑制有关。此外，分离的整合素细胞质结构域的表达会破坏整合素依赖性黏附，导致内皮细胞脱离和凋亡。这些结果证实了血管整合素在促进内皮细胞存活和血管生成中的关键作用，并表明整合素功能和信号传导的细胞内靶向可能是细胞外整合素拮抗剂治疗性抑制肿瘤血管生成的替代策略。
