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Abstract：
The vasculature is a key player and regulatory component in the multicellular microenvironment of solid tumors and, consequently, a therapeutic target. In colorectal carcinoma (CRC), antiangiogenic treatment was approved almost 20 years ago, but there are still no valid predictors of response. In addition, treatment resistance has become a problem. Vascular heterogeneity and plasticity due to species-, organ-, and milieu-dependent phenotypic and functional differences of blood vascular cells reduced the hope of being able to apply a standard approach of antiangiogenic therapy to all patients. In addition, the pathological vasculature in CRC is characterized by heterogeneous perfusion, impaired barrier function, immunosuppressive endothelial cell anergy, and metabolic competition-induced microenvironmental stress. Only recently, angiocrine proteins have been identified that are specifically released from vascular cells and can regulate tumor initiation and progression in an autocrine and paracrine manner. In this review, we summarize the history and current strategies for applying antiangiogenic treatment and discuss the associated challenges and opportunities, including normalizing the tumor vasculature, modulating milieu-dependent vascular heterogeneity, and targeting functions of angiocrine proteins. These new strategies could open perspectives for future vascular-targeted and patient-tailored therapy selection in CRC.
摘要：
脉管系统是实体瘤多细胞微环境中的关键角色和调节成分，因此,治疗目标。在大肠癌（CRC）中，近20年前批准了抗血管生成治疗，但是仍然没有有效的反应预测因子。此外,治疗抵抗已经成为一个问题。由于物种引起的血管异质性和可塑性-，器官-，血管细胞的环境依赖性表型和功能差异降低了对所有患者应用标准抗血管生成治疗方法的希望。此外,CRC中的病理性脉管系统的特征是不均匀的灌注，屏障功能受损，免疫抑制内皮细胞无反应，和代谢竞争诱导的微环境应激。只是最近,血管分泌蛋白已被鉴定为特异性地从血管细胞释放,并且可以以自分泌和旁分泌的方式调节肿瘤的起始和进展。在这次审查中,我们总结了应用抗血管生成治疗的历史和当前策略，并讨论了相关的挑战和机遇，包括使肿瘤血管正常化,调节环境依赖性血管异质性，和血管分泌蛋白的靶向功能。这些新策略可以为将来在CRC中选择血管靶向和患者定制的治疗方法开辟前景。
