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Therapeutic targeting of hypoxia and hypoxia-inducible factors in cancer

Author:
  • Caroline Wigerup
  • Sven Påhlman
  • Daniel Bexell
Publishing year: 2016-08
Language: English
Pages: 152-169
Publication/Series: Pharmacology and Therapeutics
Volume: 164
Document type: Journal article review
Publisher: Elsevier

Abstract english

Insufficient tissue oxygenation, or hypoxia, contributes to tumor aggressiveness and has a profound impact on clinical outcomes in cancer patients. At decreased oxygen tensions, hypoxia-inducible factors (HIFs) 1 and 2 are stabilized and mediate a hypoxic response, primarily by acting as transcription factors. HIFs exert differential effects on tumor growth and affect important cancer hallmarks including cell proliferation, apoptosis, differentiation, vascularization/angiogenesis, genetic instability, tumor metabolism, tumor immune responses, and invasion and metastasis. As a consequence, HIFs mediate resistance to chemo- and radiotherapy and are associated with poor prognosis in cancer patients. Intriguingly, perivascular tumor cells can also express HIF-2α, thereby forming a "pseudohypoxic" phenotype that further contributes to tumor aggressiveness. Therefore, therapeutic targeting of HIFs in cancer has the potential to improve treatment efficacy. Different strategies to target hypoxic cancer cells and/or HIFs include hypoxia-activated prodrugs and inhibition of HIF dimerization, mRNA or protein expression, DNA binding capacity, and transcriptional activity. Here we review the functions of HIFs in the progression and treatment of malignant solid tumors. We also highlight how HIFs may be targeted to improve the management of patients with therapy-resistant and metastatic cancer.

Keywords

  • Cancer and Oncology
  • Cancer
  • Hypoxia
  • Hypoxia-inducible factor (HIF)
  • Neuroblastoma
  • Paraganglioma
  • Pheochromocytoma

Other

Published
  • Molecular Pediatric Oncology
  • ISSN: 0163-7258
Sven Påhlman
E-mail: sven.pahlman [at] med.lu.se

Professor

Division of Translational Cancer Research

+46 46 222 64 21

MV406 312K1

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