The unique invasiveness of glioblastoma and possible drug targets on extracellular matrix

Abstract

Glioblastoma, or glioblastoma multiforme (GBM), is described as one of the most invasive cancer types. Although GBM is a rare disease, with a global incidence of <10 per 100,000 people, its prognosis is extremely poor. Patient survival without treatment is ~6 months, which can be extended to around 15 months with the standard treatment protocol. Given the propensity of GBM cells to show widespread local invasion, beyond the margins seen through the best current imaging techniques, tumor margins cannot be clearly defined. Recurrence is inevitable, as the highly invasive nature of GBM means complete surgical resection of the tumor is near impossible without extensive damage to healthy surrounding brain tissue. Here, we outline GBM cell invasion in the unique environment of the brain extracellular matrix (ECM), as well as a deeper exploration of the specific mechanisms upregulated in GBMs to promote the characteristic highly invasive phenotype. Among these is the secretion of proteolytic enzymes for the destruction of the ECM, as well as discussion of a novel theory of amoeboid invasion, termed the “hydrodynamic mode of invasion”. The vast heterogeneity of GBM means that there are significant redundancies in invasive pathways, which pose challenges to the development of new treatments. In the past few decades, only one major advancement has been made in GBM treatment, namely the discovery of temozolomide. Future research should look to elucidate novel strategies for the specific targeting of the invasive cells of the tumor, to reduce recurrence rates and improve patient overall survival.