title: Therapeutic targeting of hypoxia and hypoxia-inducible factors in cancer.
abstract: 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.
authors.affiliation: Translational Cancer Research, Medicon Village 404:C3, Lund University, Lund, Sweden.
authors.forename: Caroline
authors.initials: C
authors.lastname: Wigerup
authors.affiliation: Translational Cancer Research, Medicon Village 404:C3, Lund University, Lund, Sweden. Electronic address: sven.pahlman@med.lu.se.
authors.forename: Sven
authors.initials: S
authors.lastname: Påhlman
authors.affiliation: Translational Cancer Research, Medicon Village 404:C3, Lund University, Lund, Sweden.
authors.forename: Daniel
authors.initials: D
authors.lastname: Bexell
mesh_terms: D017209:Apoptosis / Q000502:physiology; D051792:Basic Helix-Loop-Helix Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D002454:Cell Differentiation / Q000502:physiology; D015687:Cell Hypoxia / Q000502:physiology*; D049109:Cell Proliferation / Q000502:physiology; D019008:Drug Resistance, Neoplasm / Q000502:physiology; D006801:Humans; D051793:Hypoxia-Inducible Factor 1 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D009369:Neoplasms / Q000503:physiopathology*; D009389:Neovascularization, Pathologic / Q000503:physiopathology; D011355:Prodrugs / Q000494:pharmacology; D012333:RNA, Messenger / Q000096:biosynthesis; D015533:Transcriptional Activation; D000099162:Endothelial PAS Domain-Containing Protein 1
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D051793:Hypoxia-Inducible Factor 1; D011355:Prodrugs; D012333:RNA, Messenger; D000099162:Endothelial PAS Domain-Containing Protein 1
keywords: Cancer; Hypoxia; Hypoxia-inducible factor (HIF); Neuroblastoma; Paraganglioma; Pheochromocytoma