Vessel cooption in malignant pleural mesothelioma

Malignant pleural mesothelioma (MPM) is an aggressive chest malignancy. Angiogenesis (the formation of new blood vessels) has long been regarded as critical for malignant tumor growth. Drugs targeting the tumor blood vasculature (i.e. antiangiogenic therapies) are today well established in oncology; however, despite early optimism, the clinical results are both encouraging and disappointing. Resistance to antiangiogenic drugs arises through a range of mechanisms, but one of the clinically most relevant is being non-angiogenic tumor growth (i.e. vessel co-option, a process whereby tumor cells recruit existing blood vessels by invasion into the normal tissue of the host organ). Another emerging resistance mechanism is related to the connective tissue structure of malignant tumors: Non-functional blood capillaries and irregular blood perfusion result in inadequate antiangiogenic and chemotherapeutic tumor tissue drug distribution. Thus, blood vessel cells and cancer cells distant from functional capillaries are exposed to suboptimal drug concentrations, resulting in therapeutic resistance. The current proposal will hopefully not only help to better understand these resistance mechanisms, but will also open the door for the development of more effective therapies for patients with such a devastating disease as MPM.