Angiogenesis research in the past two decades has contributed significantly towards understanding the molecular pathophysiology of cancer progression and inspired target-oriented research and pharma industry for the development of novel anti-angiogenic agents. Currently, over eleven drugs targeting angiogenesis have been approved by the FDA for the treatment of various malignancies. Of the registered anti-angiogenic clinical trials until the end of 2017 (ClinicalTrials.gov), over 47% were completed, 10% were terminated, 3% withdrawn, over 0.5% were suspended and only 4 trials have culminated in FDA approval for marketing. On the one hand, the clinical benefits of anti-angiogenic drugs prompted the development of novel anti-angiogenic agents. On the other hand, however, a plethora of recent studies demonstrated the emergence of tumor drug resistance towards currently used anti-angiogenic therapeutics. Series of preclinical and clinical studies have highlighted the enigma of drug resistance with functional bypass pathways, and identified compensatory or alternative angiogenic mechanisms assuring tumor growth in the midst of an anti-angiogenic stress environment. In the present review the classical literature of such redundant angiogenic pathways in concert with the key angiogenic factors and specialized cells involved in anti-angiogenic escape mechanisms is described. A strategic discourse regarding increasing tumor drug resistance and future modalities for anti-angiogenic therapy is also discussed in view of recent advances.

在过去的二十年中，血管生成研究对理解癌症进展的分子病理生理学做出了重大贡献，并激发了针对靶标的研究和制药行业开发新型抗血管生成剂。目前，FDA已经批准了超过十一种靶向血管生成的药物用于治疗各种恶性肿瘤。截至2017年底（ClinicalTrials.gov）的已注册抗血管生成临床试验（ClinicalTrials.gov）中，超过47％已完成，已终止10％，已撤回3％，已暂停0.5％以上，只有4个试验最终获得FDA批准上市。一方面，抗血管生成药物的临床益处促使新型抗血管生成药物的开发。另一方面，大量的最新研究证明了对目前使用的抗血管生成治疗剂的肿瘤耐药性的出现。一系列的临床前和临床研究强调了功能旁路途径的耐药性，并确定了在抗血管生成应激环境中确保肿瘤生长的补偿性或替代性血管生成机制。在本综述中，描述了与关键血管生成因子和参与抗血管生成逃逸机制的特化细胞相一致的这种冗余血管生成途径的经典文献。鉴于最近的进展，还讨论了有关增加肿瘤耐药性和抗血管生成治疗的未来方式的战略性论述。一系列的临床前和临床研究强调了功能旁路途径的耐药性，并确定了在抗血管生成应激环境中确保肿瘤生长的补偿性或替代性血管生成机制。在本综述中，描述了与关键血管生成因子和参与抗血管生成逃逸机制的特化细胞相一致的这种冗余血管生成途径的经典文献。鉴于最近的进展，还讨论了有关增加肿瘤耐药性和抗血管生成治疗的未来方式的战略性论述。一系列的临床前和临床研究强调了功能旁路途径的耐药性，并确定了在抗血管生成应激环境中确保肿瘤生长的补偿性或替代性血管生成机制。在本综述中，描述了与关键血管生成因子和参与抗血管生成逃逸机制的特化细胞相一致的这种冗余血管生成途径的经典文献。鉴于最近的进展，还讨论了有关增加肿瘤耐药性和抗血管生成治疗的未来方式的战略性论述。并确定了补偿性或替代性血管生成机制，以确保在抗血管生成应激环境中的肿瘤生长。在本综述中，描述了与关键血管生成因子和参与抗血管生成逃逸机制的特化细胞相一致的这种冗余血管生成途径的经典文献。鉴于最近的进展，还讨论了有关增加肿瘤耐药性和抗血管生成治疗的未来方式的战略性论述。并确定了补偿性或替代性血管生成机制，以确保在抗血管生成应激环境中的肿瘤生长。在本综述中，描述了与关键血管生成因子和参与抗血管生成逃逸机制的特化细胞相一致的这种冗余血管生成途径的经典文献。鉴于最近的进展，还讨论了有关增加肿瘤耐药性和抗血管生成治疗的未来方式的战略性论述。