Croci Diego O, Mendez-Huergo Santiago P, Cerliani Juan P, Rabinovich Gabriel A
Laboratorio de Inmunopatología, Instituto de Biología y Medicina Experimental (IBYME), Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), 1428, Buenos Aires, Argentina.
Departamento de Química Biológica, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, 1428, Buenos Aires, Argentina.
Handb Exp Pharmacol. 2018;249:31-61. doi: 10.1007/164_2017_29.
In contrast to mechanisms taking place during resistance to chemotherapies or other targeted therapies, compensatory adaptation to angiogenesis blockade does not imply a mutational alteration of genes encoding drug targets or multidrug resistance mechanisms but instead involves intrinsic or acquired activation of compensatory angiogenic pathways. In this article we highlight hypoxia-regulated and immune-mediated mechanisms that converge in endothelial cell programs and preserve angiogenesis in settings of vascular endothelial growth factor (VEGF) blockade. These mechanisms involve mobilization of myeloid cell populations and activation of cytokine- and chemokine-driven circuits operating during intrinsic and acquired resistance to anti-angiogenic therapies. Particularly, we focus on findings underscoring a role for galectins and glycosylated ligands in promoting resistance to anti-VEGF therapies and discuss possible strategies to overcome or attenuate this compensatory pathway. Finally, we highlight emerging evidence demonstrating the interplay between immunosuppressive and pro-angiogenic programs in the tumor microenvironment (TME) and discuss emerging combinatorial anticancer strategies aimed at simultaneously potentiating antitumor immune responses and counteracting aberrant angiogenesis.
与化疗或其他靶向治疗耐药过程中发生的机制不同，对血管生成阻断的代偿性适应并不意味着编码药物靶点的基因发生突变或多药耐药机制，而是涉及代偿性血管生成途径的内在激活或获得性激活。在本文中，我们重点介绍了在血管内皮生长因子（VEGF）阻断情况下，在内皮细胞程序中汇聚并维持血管生成的缺氧调节和免疫介导机制。这些机制涉及髓样细胞群体的动员以及在抗血管生成治疗的内在和获得性耐药过程中起作用的细胞因子和趋化因子驱动回路的激活。特别地，我们关注强调半乳糖凝集素和糖基化配体在促进抗VEGF治疗耐药中作用的研究结果，并讨论克服或减弱这种代偿途径的可能策略。最后，我们强调了新出现的证据，这些证据证明了肿瘤微环境（TME）中免疫抑制和促血管生成程序之间的相互作用，并讨论了旨在同时增强抗肿瘤免疫反应和对抗异常血管生成的新出现的联合抗癌策略。
