贝伐珠单抗之 乳腺癌篇.ppt

血管依赖性理论使人们认识到了传统的抗肿瘤细胞增殖治疗的不足： 抗增殖药物仅作用于肿瘤细胞，部分细胞可产生耐药，尽管抗细胞增殖药物可以杀死肿瘤细胞，但由于周围血管的支持，残存肿瘤细胞仍可获得血供而得以继续生长。同时，异常的肿瘤血管使药物向肿瘤组织内部递送减少，最终导致抗细胞增殖治疗的疗效受限。 对肿瘤血管生成的重要性以及对抗增殖药物局限性的反思，使科学家们从肿瘤治疗的全局出发，建立了新的治疗策略：就是治疗肿瘤时不仅针对肿瘤细胞，更要针对肿瘤血管生成，全方位地打击肿瘤，最大限度地控制和杀灭肿瘤。这种Anti-angiogenesis联合抗细胞增殖的策略（简称 A+策略）已在国际上成为肿瘤治疗的新核心策略 1971年，哈佛大学Judah Folkman博士提出了肿瘤生长的血管依赖性理论，即肿瘤的发生发展不仅与肿瘤细胞本身的增殖有关，更离不开微环境，尤其是肿瘤血管的支持。 当肿瘤体积不超过2mm3时，肿瘤无独立血供，主要依靠弥散获得营养，肿瘤处于静息期。 随着肿瘤的发展，肿瘤细胞分泌多种因子，促使供应肿瘤的血管生成，拥有血供的肿瘤迅速生长并可发生侵袭、转移。 同时，肿瘤血管不成熟，结构紊乱扭曲，有裂隙，易渗漏，使肿瘤组织间压增高，肿瘤组织特别是中心的肿瘤细胞相对血供不足，总是处于缺氧状态，营养物质相对缺乏，这些都进一步促使肿瘤细胞增殖并易于发生侵袭转移。 Reference: Fukumura D, Xavier R, Sugiura T, Cell, 1998, 94 ( 6) :715-725.; Hagendoorn J, Tong R, Fukumura D, et al. Cancer Res, 2006, 66 ( 7) :3360-3364.；Nikolai NK, Jianqing Y, Edwardine L, et al. J CellSci, 2003, 116 (6):1013.; Sottile Biochim Biophys Acta, 2004, 1654(1), 13-22 For vessels to mature, they need to be exposed to a mix of angio- and arteriogenic factors for enough time for endothelial cells to tighten up and become covered with supporting cells. Flow is a critical determinant of vessel maintenance and durability. Tumour blood vessels are architecturally different from normal blood vessels. They are irregularly shaped, dilated, tortuous, and can have dead ends. They are not organised into definite venules, arterioles and capillaries like normal blood vessel, but instead have chaotic versions of all of them. The vascular network in tumours is often leaky and haemorrhagic, at least in part due to the overproduction of VEGF. When not enough angiogenic and arteriogenic factors are present, and angiogenesis inhibitors are present, endothelial cell channels remain naked, leaky and fragile, are easily ruptured and bleed, resulting in reduced flow and vessel regression.1,2 Endothelial cells migrate through interactions between integrins and the matrix.3 Integrins are cell surface receptors for specific endothelial cell matrix molecules that transmit information between the outside an