<p>The unique invasiveness of glioblastoma and possible drug targets on extracellular matrix</p>

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.

Induction of apoptosis through extrinsic/intrinsic pathways and suppression of ERK/NF‐κB signalling participate in anti‐glioblastoma of imipramine

“…A high expression of tumour progression‐associated proteins, such as MMP‐9, MMP‐2, uPA, VEGF and Cyclin D1, was associated with poor outcomes in high‐grade glioma . MMP‐9, MMP‐2 and uPA promote tumour cell invasion through the digestion of extracellular matrix (ECM) components . Angiogenesis mediated by VEGF is essential for tumour growth and metastasis .…”

<p>Verteporfin-Loaded Anisotropic Poly(Beta-Amino Ester)-Based Micelles Demonstrate Brain Cancer-Selective Cytotoxicity and Enhanced Pharmacokinetics</p>

“…Furthermore, it is known that the highly invasive nature of GBM cells is aided by the degradation of the cancer cell extracellular matrix (ECM) via protease secretions. 46 Reduced ECM surrounding GBM cells compared to astrocytes may enhance the uptake of the micelles into GBM cells. In addition to enhanced uptake into the cancer cells, the YAP-TEAD pathway, the primary target of VP, is activated more in cancer cells compared to healthy cells.…”

A role for caveola‐forming proteins caveolin‐1 and CAVIN1 in the pro‐invasive response of glioblastoma to osmotic and hydrostatic pressure

“…Conversely, matrix proteases such as gelatinases or uPA act through both degradation of the brain extracellular matrix and the activation of pro-migratory signalling. 13 We have previously demonstrated that exposure of GBM adherent cell lines or oncospheres to osmotic and hydrostatic or centrifugal pressure induces an increase in GBM invasive potential in vitro. In the present study, we investigated whether caveolae mediate the pro-invasive response to pressure in GBM cells.…”

“…Several signalling pathways known to be activated in GBM result in increased protease expression. Conversely, matrix proteases such as gelatinases or uPA act through both degradation of the brain extracellular matrix and the activation of pro‐migratory signalling . We have previously demonstrated that exposure of GBM adherent cell lines or oncospheres to osmotic and hydrostatic or centrifugal pressure induces an increase in GBM invasive potential in vitro.…”