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Therapeutic targeting of hypoxia and hypoxia-inducible factors in cancer

Wigerup, Caroline LU ; Påhlman, Sven LU and Bexell, Daniel LU (2016) In Pharmacology and Therapeutics 164. p.152-169
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... (More)

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.

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organization
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type
Contribution to journal
publication status
published
subject
keywords
Cancer, Hypoxia, Hypoxia-inducible factor (HIF), Neuroblastoma, Paraganglioma, Pheochromocytoma
in
Pharmacology and Therapeutics
volume
164
pages
152 - 169
publisher
Elsevier
external identifiers
  • Scopus:84971645609
ISSN
0163-7258
DOI
10.1016/j.pharmthera.2016.04.009
language
English
LU publication?
yes
id
87d4ad42-163f-4d00-bdf2-95733a7d99e7
date added to LUP
2016-06-15 12:40:10
date last changed
2017-02-05 04:50:47
@article{87d4ad42-163f-4d00-bdf2-95733a7d99e7,
  abstract     = {<p>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.</p>},
  author       = {Wigerup, Caroline and Påhlman, Sven and Bexell, Daniel},
  issn         = {0163-7258},
  keyword      = {Cancer,Hypoxia,Hypoxia-inducible factor (HIF),Neuroblastoma,Paraganglioma,Pheochromocytoma},
  language     = {eng},
  pages        = {152--169},
  publisher    = {Elsevier},
  series       = {Pharmacology and Therapeutics},
  title        = {Therapeutic targeting of hypoxia and hypoxia-inducible factors in cancer},
  url          = {http://dx.doi.org/10.1016/j.pharmthera.2016.04.009},
  volume       = {164},
  year         = {2016},
}