Abstract
Glioblastomas are malignant brain tumors with dismal prognosis despite standard treatment with surgery and radio/chemotherapy. These tumors are defined by an important cellular heterogeneity and notably contain a particular subpopulation of Glioblastoma-initiating cells, which recapitulate the heterogeneity of the original Glioblastoma. In order to classify these heterogeneous tumors, genomic profiling has also been undertaken to classify these heterogeneous tumors into several subtypes. Current research focuses on developing therapies, which could take into account this cellular and genomic heterogeneity. Among these targets, integrins are the subject of numerous studies since these extracellular matrix transmembrane receptors notably controls tumor invasion and progression. Moreover, some of these integrins are considered as membrane markers for the Glioblastoma-initiating cells subpopulation. We reviewed here integrin expression according to glioblastoma molecular subtypes and cell heterogeneity. We discussed their roles in glioblastoma invasion, angiogenesis, therapeutic resistance, stemness and microenvironment modulations, and provide an overview of clinical trials investigating integrins in glioblastomas. This review highlights that specific integrins could be identified as selective glioblastoma cells markers and that their targeting represents new diagnostic and/or therapeutic strategies.
Highlights
We reviewed here integrin expression according to glioblastoma molecular subtypes and cell heterogeneity
A major molecular prognostic factor identified in GB is IDH1/2 mutations, a benefic prognosis factor that closely concerns secondary GB, which progress from low-grade diffuse astrocytoma or anaplastic astrocytoma (~5–10% of GB) [1]
Recent studies have highlighted new prognosis factors in GB, such as TERT promoter mutations (~70–75% of de novo GB, worse prognosis factor), histone H3F3A K27 and G34 mutations (~5% of adult GB), ATRX mutations and a positive gliomaCpG island methylator phenotype (G-CIMP), a benefic prognosis factor closely associated to secondary IDH mutant GB [4, 5]
Summary
Glioblastomas (GB), classified by the World Health Organization as Grade IV-Diffuse Glioma [1], are the most frequent and lethal malignant primary adult brain tumor [2]. Regarding the correlation of GIC subtypes with survival prognosis in GB patients or in xenografted-mice, no clear trend could be defined since opposite results were obtained according to the studies, with a worse survival either for Mesenchymal GIC [56, 117] or for Pro-Neural GIC [115, 116] This molecular and functional heterogeneity between GIC clones/cell lines was shown to be associated with differential integrin expression between GIC subgroups. Cell membrane-expressed integrins can interact and modulate GB specific microenvironment via pro-migratory and pro-invasive properties (previously reviewed [24] and described above), hypoxic signalling/conditions, growth factor pathways, immune system and GIC maintenance within their niches These mechanisms are detailed below and Figure 5. Colon cancer, GB, melanoma, refractory advanced solid tumours, AML Melanoma, prostate/colon/ thyroid cancer Renal cell carcinoma, melanoma, NSCLC, pancreatic cancer Solid tumours
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