Verheul H M W, Voest E E, Schlingemann R O
Department of Medical Oncology, University Medical Centre Utrecht, The Netherlands.
J Pathol. 2004 Jan;202(1):5-13. doi: 10.1002/path.1473.
The final proof of principle that cancer patients can be effectively treated with angiogenesis inhibitors is eagerly awaited. Various preclinical in vivo experiments have proven that most tumours need new vessel formation in order to grow and to form metastases. First of all, tumours do not grow in avascular corneas until new blood vessels reach the implant. Secondly, the introduction of only one angiogenic gene can cause a switch from tumour dormancy to progressive tumour growth. Thirdly, tumour growth can be inhibited and sometimes tumour regression can be obtained just by attacking the vascular compartment with specific angiogenesis inhibitors. These three examples of preclinical experiments and many others have led to the conclusion that, in general, tumours are angiogenesis-dependent. Supported by disappointing clinical results, the angiogenesis dependency of tumours has been questioned, mainly because of the immaturity and the presumed lack of a functional blood supply (oxygen delivery and discarding of waste products) from a newly formed tumour vasculature. However, human tumours are highly heterogeneous in vascular architecture, differentiation, and functional blood supply. Vascular immaturity is a natural consequence of a genetically based unlimited expansion of tumour cells, compared to the well-regulated growth of different organs during embryonic development, for example. Unlimited tumour expansion and therefore the continuous stimulation of vessel outgrowth prevent endothelial cells from generating a mature vasculature, but instead continuously stimulate them to expand the vascular compartment of the growing tumour. In this review, the translation of angiogenesis inhibitors as a treatment for cancer from preclinical experiments to the clinic is evaluated. The preclinical evidence that tumours are angiogenesis-dependent is summarized and explanations are put forward for why the clinical results so far are not as exciting as was expected from preclinical studies. Reviewing the translation, one may conclude that human tumours are heterogeneous in their vascular architecture and function and that tumour-induced angiogenesis in humans is a more complex (multifactorially regulated) process compared with angiogenesis in preclinical cancer models.
人们急切期待着能够有效治疗癌症患者的血管生成抑制剂的最终原理验证。各种临床前体内实验已经证明，大多数肿瘤需要形成新的血管才能生长并形成转移灶。首先，在新血管到达植入物之前，肿瘤不会在无血管的角膜中生长。其次，仅引入一个血管生成基因就能使肿瘤从休眠状态转变为进行性生长。第三，仅通过用特定的血管生成抑制剂攻击血管部分，就能抑制肿瘤生长，有时还能使肿瘤消退。这三个临床前实验的例子以及许多其他例子都得出结论，一般来说，肿瘤依赖血管生成。尽管临床结果令人失望，但肿瘤对血管生成的依赖性仍受到质疑，主要原因是新形成的肿瘤血管系统不成熟，且推测缺乏功能性血液供应（氧气输送和代谢废物排出）。然而，人类肿瘤在血管结构、分化和功能性血液供应方面具有高度异质性。与胚胎发育期间不同器官生长受到良好调控相比，血管不成熟是肿瘤细胞基于基因的无限增殖导致的自然结果。肿瘤的无限增殖以及因此对血管生长的持续刺激，阻止内皮细胞生成成熟的血管系统，反而持续刺激它们扩展生长中肿瘤的血管部分。在这篇综述中，评估了血管生成抑制剂作为癌症治疗手段从临床前实验到临床应用的转化情况。总结了肿瘤依赖血管生成的临床前证据，并对为何目前的临床结果不如临床前研究所预期的那样令人兴奋提出了解释。回顾这一转化过程，可以得出结论，人类肿瘤在血管结构和功能上具有异质性，与临床前癌症模型中的血管生成相比，人类肿瘤诱导的血管生成是一个更复杂（多因素调控）的过程。
