Since Judah Folkman hypothesized in 1971 that angiogenesis is required for solid tumor growth, numerous studies have been conducted to unravel the angiogenesis process, analyze its role in primary tumor growth, metastasis and angiogenic diseases, and to develop inhibitors of proangiogenic factors. These studies have led in 2004 to the approval of the first antiangiogenic agent (bevacizumab, a humanized antibody targeting vascular endothelial growth factor) for the treatment of patients with metastatic colorectal cancer. This approval launched great expectations for the use of antiangiogenic therapy for malignant diseases. However, these expectations have not been met and, as knowledge of blood vessel formation accumulates, many of the original paradigms no longer hold. Therefore, the regulators and clinical implications of angiogenesis need to be revisited. In this review, we discuss recently identified angiogenesis mediators and pathways, new concepts that have emerged over the past 10 years, tumor resistance and toxicity associated with the use of currently available antiangiogenic treatment and potentially new targets and/or approaches for malignant and nonmalignant neovascular diseases.

中文翻译：

---

肿瘤血管新生的再探讨：调节剂和临床意义

自1971年Judah Folkman假设实体瘤生长需要血管生成以来，已经开展了许多研究来阐明血管生成过程，分析其在原发性肿瘤生长，转移和血管生成疾病中的作用，并开发促血管生成因子的抑制剂。这些研究在2004年导致批准了用于治疗转移性结直肠癌患者的第一种抗血管生成剂（贝伐单抗，一种靶向血管内皮生长因子的人源化抗体）。该批准对将抗血管生成疗法用于恶性疾病提出了很高的期望。然而，这些期望没有得到满足，并且随着对血管形成的知识的积累，许多原始范例不再成立。所以，需要重新研究血管生成的调节剂和临床意义。在这篇综述中，我们讨论了最近发现的血管生成介质和途径，在过去十年中出现的新概念，与使用目前可用的抗血管生成治疗相关的肿瘤耐药性和毒性以及潜在的新靶标和/或恶性和非恶性新血管生成方法疾病。