Hypoxia-Mediated Mechanisms Associated with Antiangiogenic Treatment Resistance in Glioblastomas.

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.

The American journal of pathology. 2017 Mar 08 [Epub ahead of print]

Sean Mahase, Rachel N Rattenni, Pieter Wesseling, William Leenders, Clarissa Baldotto, Rajan Jain, David Zagzag

Microvascular and Molecular Neuro-Oncology Laboratory, New York University School of Medicine, New York, New York., 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., Department of Pathology, Radboud University Medical Center, Nijmegen, the Netherlands., Medical Oncology, Instituto Nacionale de Cancer, INCA, Brazil., Department of Radiology, New York University School of Medicine, New York, New York., Microvascular and Molecular Neuro-Oncology Laboratory, 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; Department of Neurosurgery, 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: This email address is being protected from spambots. You need JavaScript enabled to view it..