title: GBM's multifaceted landscape: highlighting regional and microenvironmental heterogeneity.
abstract: Gliomas are a heterogeneous group of tumors that show variable proliferative potential, invasiveness, aggressiveness, histological grading, and clinical behavior. In this review, we focus on glioblastoma multiforme (GBM), a grade IV glioma, which is the most common and malignant of primary adult brain tumors. Research over the past several decades has revealed the existence of extensive cellular, molecular, genetic, epigenetic, and metabolic heterogeneity among tumors of the same grade and even within individual tumors. Evaluation of different tumor types has shown that tumors with advanced grade and clinical aggressiveness also display enhanced molecular, cellular, and microenvironmental heterogeneity. From a therapeutic standpoint, this heterogeneity is a major clinical hurdle for devising effective therapeutic strategies for patients and challenges personalized medicine. In this review, we will highlight key aspects of GBM heterogeneity, directing special attention to regional heterogeneity, hypoxia, genomic heterogeneity, tumor-specific metabolic reprogramming, neovascularization or angiogenesis, and stromal immune cells. We will further discuss the clinical implications of GBM heterogeneity in the context of therapy.
authors.affiliation: The Arthur and Sonia Labatt Brain Tumor Research Centre, Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada (A.V., S.K.S., S.A., S.J., K.B., G.Z.); Division of Neurosurgery, Toronto Western Hospital, University of Toronto, Toronto, Ontario, Canada (G.Z.); Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas (K.D.A.).
authors.forename: Alenoush
authors.initials: A
authors.lastname: Vartanian
authors.affiliation: The Arthur and Sonia Labatt Brain Tumor Research Centre, Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada (A.V., S.K.S., S.A., S.J., K.B., G.Z.); Division of Neurosurgery, Toronto Western Hospital, University of Toronto, Toronto, Ontario, Canada (G.Z.); Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas (K.D.A.).
authors.forename: Sanjay K
authors.initials: SK
authors.lastname: Singh
authors.affiliation: The Arthur and Sonia Labatt Brain Tumor Research Centre, Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada (A.V., S.K.S., S.A., S.J., K.B., G.Z.); Division of Neurosurgery, Toronto Western Hospital, University of Toronto, Toronto, Ontario, Canada (G.Z.); Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas (K.D.A.).
authors.forename: Sameer
authors.initials: S
authors.lastname: Agnihotri
authors.affiliation: The Arthur and Sonia Labatt Brain Tumor Research Centre, Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada (A.V., S.K.S., S.A., S.J., K.B., G.Z.); Division of Neurosurgery, Toronto Western Hospital, University of Toronto, Toronto, Ontario, Canada (G.Z.); Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas (K.D.A.).
authors.forename: Shahrzad
authors.initials: S
authors.lastname: Jalali
authors.affiliation: The Arthur and Sonia Labatt Brain Tumor Research Centre, Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada (A.V., S.K.S., S.A., S.J., K.B., G.Z.); Division of Neurosurgery, Toronto Western Hospital, University of Toronto, Toronto, Ontario, Canada (G.Z.); Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas (K.D.A.).
authors.forename: Kelly
authors.initials: K
authors.lastname: Burrell
authors.affiliation: The Arthur and Sonia Labatt Brain Tumor Research Centre, Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada (A.V., S.K.S., S.A., S.J., K.B., G.Z.); Division of Neurosurgery, Toronto Western Hospital, University of Toronto, Toronto, Ontario, Canada (G.Z.); Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas (K.D.A.).
authors.forename: Kenneth D
authors.initials: KD
authors.lastname: Aldape
authors.affiliation: The Arthur and Sonia Labatt Brain Tumor Research Centre, Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada (A.V., S.K.S., S.A., S.J., K.B., G.Z.); Division of Neurosurgery, Toronto Western Hospital, University of Toronto, Toronto, Ontario, Canada (G.Z.); Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas (K.D.A.).
authors.forename: Gelareh
authors.initials: G
authors.lastname: Zadeh
mesh_terms: D000328:Adult; D001921:Brain / Q000098:blood supply / Q000503:physiopathology; D001932:Brain Neoplasms / Q000150:complications / Q000378:metabolism / Q000503:physiopathology*; D049109:Cell Proliferation; D005909:Glioblastoma / Q000150:complications / Q000378:metabolism / Q000503:physiopathology*; D006801:Humans; D002534:Hypoxia, Brain / Q000150:complications; D009389:Neovascularization, Pathologic; D059016:Tumor Microenvironment
keywords: angiogenesis; glioblastoma; hypoxia; metabolism