The Role of Tumor-Vessel Interface in Multimodal Cancer Therapy

肿瘤通过释放促血管生成因子和促存活因子来保护其脉管系统免受放疗和化疗诱导的损伤。因此，肿瘤-血管通信正在成为规避化疗和放射抗性的重要靶点。最近，我们的实验室提供了有益使用由抗血管生成、放疗和化疗组成的三模式癌症治疗的分子、细胞和生理学原理。抗血管生成治疗通过使内皮细胞对凋亡重新敏感和使肿瘤血管正常化来增强放疗和化疗的效果。在这里，我们提出了一个四步的过程来优化三模式治疗的概念：首先，我们计划系统地表征参与肿瘤-血管相互作用的分子和病理生理学事件，以响应多模式治疗，重点是对辅助抗血管生成治疗的耐药性发展的新问题。在确认通过全球表达谱确定的系统生物学的关键遗传参与者后，将对有希望的靶点进行功能评估，以确定其调节化疗-放疗反应的能力。在这种情况下，我们还旨在研究放射治疗诱导的内源性血管生成抑制剂，内皮抑制素和血小板反应蛋白的下调，在获得性肿瘤放射抵抗的尚未未知的作用。最后，我们将使用这些数据来合理设计有意义的抗血管生成鸡尾酒，并测试其最佳治疗方案。

Tumors protect their vasculature from radiation- and chemotherapy induced damage by releasing pro-angiogenic and pro-survival factors. Thus tumor-vessel communication is emerging as an important target to circumvent chemo- and radio-resistance. Very recently, molecular, cellular and physiological rationales for the beneficial use of trimodal cancer therapy consisting of antiangiogenesis, radiotherapy and chemotherapy were provided by our laboratory. Antiangiogenic treatment enhances the effects of radiotherapy and chemotherapy by resensitizing endothelial cells to apoptosis and normalizing the tumor vasculature. Here we propose a four step process to optimize the concept of trimodal therapy: first, we plan to systematically characterize the molecular and pathophysiological events that are involved in ¿tumor-vessel-interaction¿ in response to multimodal therapies with emphasis on the emerging problem of resistance development to adjuvant antiangiogenic treatment. After confirming the key genetic players of systems biology identified by global expression profiling the promising ¿targets¿ will be functionally evaluated for their ability to modulate chemo-radiotherapy response. In this context we also aim to investigate the yet unknown role of radiotherapy-induced downregulation of endogenous angiogenesis inhibitors, endostatin and thrombospondin, in acquired tumor radio-resistance. Finally, we will use these data to rationally design meaningful ¿antiangiogenic cocktails¿ and to test for their optimal therapeutic scheduling.