The Molecular and Phenotypic Basis of the Glioma Invasive Perivascular Niche

Abstract

Gliomas are devastating brain cancers that have poor prognostic outcomes for their patients. Short overall patient survival is due to a lack of durable, efficacious treatment options. Such therapeutic difficulties exist, in part, due to several glioma survival adaptations and mechanisms, which allow glioma cells to repurpose paracrine signalling pathways and ion channels within discreet microenvironments. These Darwinian adaptations facilitate invasion into brain parenchyma and perivascular space or promote evasion from anti-cancer defence mechanisms. Ultimately, this culminates in glioma repopulation and migration at distances beyond the original tumour site, which is a considerable obstacle for effective treatment. After an era of failed phase II trials targeting individual signalling pathways, coupled to our increasing knowledge of glioma sub-clonal divergence, combinatorial therapeutic approaches which target multiple molecular pathways and mechanisms will be necessary for better treatment outcomes in treating malignant gliomas. Furthermore, next-generation therapy which focuses on infiltrative tumour phenotypes and disruption of the vascular and perivascular microenvironments harbouring residual disease cells offers optimism for the localised control of malignant gliomas.

Conventional Anti-glioblastoma Chemotherapy Affects Proteoglycan Composition of Brain Extracellular Matrix in Rat Experimental Model in vivo

“…However, being concentrated to destroy the glioblastoma cells, one can overlook a danger coming from a significant impairment of the surrounding normal brain tissue during the adjuvant therapy. In fact, the most dangerous trait of glioblastoma is its’ active invasion into the surrounding healthy brain tissue ( Paw et al, 2015 ; Diksin et al, 2017 ), and the invasiveness of GBM cells and tumour development depend on not only migration capabilities of the proliferating glioblastoma cells but also structure of the surrounding normal brain tissue ( Song and Dityatev, 2017 ; Manini et al, 2018 ). One of the key invasion-related component of normal brain tissue is extracellular matrix (ECM) which occupies near 20% of its volume and serve as a main basic element of tissue structure and physiology ( Nicholson and Hrabětová, 2017 ).…”

Kinins in Glioblastoma Microenvironment

“…Migrating cells form protrusions, such as invadopodia and other extensions including ruffles or spikes, all containing filamentous actin, and lead to dynamic interactions with ECM substrates [107]. The regulation in myosin-actin contractions is also under the calcium oscillations control [108] which, as mentioned above, are regulated by kinin receptors and have been proven as crucial for glioma invasion [109,110]. BK also induced expression of smooth muscle actin in human MSCs [111].…”

Satellitosis, a Crosstalk between Neurons, Vascular Structures and Neoplastic Cells in Brain Tumours; Early Manifestation of Invasive Behaviour

“…In glioma, the term perivascular satellitosis is used to refer to a non-vasculogenic process whereby blood vessels hijack glioma cells to migrate towards pre-existing vasculature ( Figure 3 and Figure 6 ) [ 77 ]. This feature has commonly been found in both high and low-grade glioma [ 15 ].…”