title: Hypoxia-Mediated Mechanisms Associated with Antiangiogenic Treatment Resistance in Glioblastomas.
abstract: Glioblastomas (GBMs) are malignant tumors characterized by their vascularity and invasive capabilities. Antiangiogenic therapy (AAT) is a treatment option that targets GBM-associated vasculature to mitigate the growth of GBMs. However, AAT demonstrates transient effects because many patients eventually develop resistance to this treatment. Several recent studies attempt to explain the molecular and biochemical basis of resistance to AAT in GBM patients. Experimental investigations suggest that the induction of extensive intratumoral hypoxia plays a key role in GBM escape from AAT. In this review, we examine AAT resistance in GBMs, with an emphasis on six potential hypoxia-mediated mechanisms: enhanced invasion and migration, including increased expression of matrix metalloproteinases and activation of the c-MET tyrosine kinase pathway; shifts in cellular metabolism, including up-regulation of hypoxia inducible factor-1α's downstream processes and the Warburg effect; induction of autophagy; augmentation of GBM stem cell self-renewal; possible implications of GBM-endothelial cell transdifferentiation; and vasoformative responses, including vasculogenesis, alternative angiogenic pathways, and vascular mimicry. Juxtaposing recent studies on well-established resistance pathways with that of emerging mechanisms highlights the overall complexity of GBM treatment resistance while also providing direction for further investigation.
authors.affiliation: Microvascular and Molecular Neuro-Oncology Laboratory, New York University School of Medicine, New York, New York.
authors.forename: Sean
authors.initials: S
authors.lastname: Mahase
authors.affiliation: Microvascular and Molecular Neuro-Oncology Laboratory, New York University School of Medicine, New York, New York.
authors.forename: Rachel N
authors.initials: RN
authors.lastname: Rattenni
authors.affiliation: Department of Pathology, VU University Medical Center, Amsterdam, the Netherlands; Department of Pathology, Princess Máxima Center for Pediatric Oncology and University Medical Center, Utrecht, the Netherlands.
authors.forename: Pieter
authors.initials: P
authors.lastname: Wesseling
authors.affiliation: Department of Pathology, Radboud University Medical Center, Nijmegen, the Netherlands.
authors.forename: William
authors.initials: W
authors.lastname: Leenders
authors.affiliation: Medical Oncology, Instituto Nacionale de Cancer, Rio de Janeiro, Brazil.
authors.forename: Clarissa
authors.initials: C
authors.lastname: Baldotto
authors.affiliation: Department of Radiology, New York University School of Medicine, New York, New York; Department of Neurosurgery, New York University School of Medicine, New York, New York.
authors.forename: Rajan
authors.initials: R
authors.lastname: Jain
authors.affiliation: Microvascular and Molecular Neuro-Oncology Laboratory, New York University School of Medicine, New York, New York; Department of Neurosurgery, New York University School of Medicine, New York, New York; Division of Neuropathology, Department of Pathology, New York University School of Medicine, New York, New York; Laura and Isaac Perlmutter Cancer Center, New York University School of Medicine, New York, New York. Electronic address: david.zagzag@nyumc.org.
authors.forename: David
authors.initials: D
authors.lastname: Zagzag
mesh_terms: D020533:Angiogenesis Inhibitors / Q000627:therapeutic use*; D001343:Autophagy / Q000187:drug effects / Q000502:physiology; D000068258:Bevacizumab / Q000627:therapeutic use; D001921:Brain / Q000378:metabolism; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D015687:Cell Hypoxia / Q000187:drug effects; D002471:Cell Transformation, Neoplastic / Q000187:drug effects; D019008:Drug Resistance, Neoplasm; D005909:Glioblastoma / Q000188:drug therapy* / Q000378:metabolism; D006801:Humans; D009361:Neoplasm Invasiveness; D014411:Neoplastic Stem Cells / Q000502:physiology; D009389:Neovascularization, Pathologic / Q000517:prevention & control; D010766:Phosphorylation / Q000502:physiology; D020794:Receptor Protein-Tyrosine Kinases / Q000378:metabolism; D000072258:Tumor Hypoxia
chemical_list: D020533:Angiogenesis Inhibitors; D000068258:Bevacizumab; C080835:RON protein; D020794:Receptor Protein-Tyrosine Kinases