The Role of Tumor-Vessel Interface in Multimodal Cancer Therapy

肿瘤通过释放促血管生成和促生存因子来保护其血管系统免受放射和化疗的损害。因此，肿瘤-血管通讯正在成为规避化疗和放射耐药的重要靶点。最近，我们实验室提供了抗血管生成、放射治疗和化疗三联式癌症治疗有益的分子、细胞和生理基础。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过程来优化三模式治疗的概念：首先，我们计划系统地描述与肿瘤-血管-相互作用相关的分子和病理生理学事件，以响应多模式治疗，重点是新出现的对辅助抗血管生成治疗的耐药性发展问题。在通过全球表达谱确定了系统生物学的关键遗传因素后，将对有希望的靶点进行功能评估，以确定它们调节化疗-放射治疗反应的能力。在此背景下，我们还旨在研究放射治疗诱导的内源性血管生成抑制因子内皮抑素和凝血酶反应蛋白下调在获得性肿瘤放射抵抗中的未知作用。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，并测试它们的最佳治疗方案。

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.