Targeting Glioma Cell Invasion

Glioblastoma (GBM) is the most aggressive brain tumor for which no curative treatment is currently available. The 5-year survival rate of patients affected with GBM is less than 10%, the majority of patients die within the first year of diagnosis (Weller et al., 2012). Even lower grade gliomas (grade II and III) must be considered as aggressive tumors as they eventually all progress to GBM and lead to fatal recurrence.
The potent infiltrative capacity of gliomas has long been recognized as a major clinical challenge precluding complete surgical removal of the tumor (Scherer, 1940) (Vehlow and Cordes, 2013). Despite advancements in neurosurgical practice, in radio- and chemotherapy, the highly invasive tumor cells have not been tackled efficiently. Invasive cells migrate preferentially along preexisting anatomical structures such as blood vessels, axonal fiber tracts and the subependymal space, thereby widely invading surrounding brain tissue.
The migration along blood vessels, also termed vessel co-option, also allows to satisfy the early oxygen demands of the tumor. Over time the rapid growth of GBM results in focal ischemia and hypoxia, which triggers the formation of abnormal and leaky blood vessels through the process of angiogenesis (Hardee and Zagzag, 2012). Thus during glioma development glioma cells can adopt a purely infiltrative or an angiogenesis dependent growth pattern. Interestingly, we and others have recently shown that anti-angiogenic treatment of GBM increases the invasive behaviour of tumor cells (Keunen et al., 2011), indicating that combinatorial treatment strategies are required that target angiogenesis AND invasion.
Thus, controlling the diffuse infiltrative component of GBMs remains the major challenge in GBM treatment and a pre-requisite for improved patient management. Therefore a better understanding of the underlying mechanisms of invasion and angiogenesis and the capacity of GBM to switch between these two phenotypes is mandatory. Here we propose to identify novel therapeutic targets and treatment paradigms against glioma invasion by using clinically relevant brain tumor models that display a typical invasive growth pattern in vivo.