The Role of Tumor-Vessel Interface in Multimodal Cancer Therapy
Final Report Abstract
Radiotherapy is an integral component of cancer therapy. More than 50% of all cancer patients receive radiotherapy during their course of disease. Therefore, improvements of this therapy modality significantly impact the quality of life of cancer patients. We attempted to systematically investigate the molecular mechanism governing tumor resistance to radiotherapy using the wellestablished integrative high-through put molecular biology platforms established in our laboratory. The result of this investigation was that tumor endothelium is a critical target of radiotherapy and tumor-vessel interface plays a central role in tumor radiosensitivity. We found that paracrine growth factor release by the tumor/stroma and the corresponding receptor upregulation in the endothelium represent a coordinated mechanism by which radiochemotherapy induced endothelial cell death is effectively evaded. Based on compensatory mechanism identified in tumor- and stroma-vessel interfaces we further postulated that inhibition of these pathways may enhance radiotherapy effects via resensitizing tumor endothelium. We could validate this concept for different key angiogenic and tumorstroma modulating pathways and successfully published these data. Moreover, within the past 6 years a number of these rationally designed multimodal therapy concepts were successfully translated in clinical phase I- III trials. We further uncovered the molecular mechanisms of action of the two key endogenous angiogenesis inhibitors, endostatin and angiostatin, repectively. Moreover, novel mechanisms of evasive tumor resistance to both angiogenesis inhibitors were discovered. Of note, is the discovery of fibronectin/VEGF binding as key mediators of antiangiogenesis by oligomeric- but not monomeric endostatin fragments. Downregulation of fibronectin as well as compensatory upregulationn of CCL2 and IGF1R pathways were further identified as tumor resistant mechanisms against prolonged antiangiogenic treatment with fc-endostatin. Another key finding of the second funding period was the unexpected crosstalk between the redoxsystem, the metabolome and endogenous antiangiogenesis. We found that angiostatin exerts its antiangiogenic effects via inhibition of mitochondrial oxidative phosphorylation/respiration and increase of intracellular ROS levels. These pathways may provide novel targets for antiangiogenic therapy.
