Cited by 372Cancer, Hypoxia, and MetabolismAngiogenesis and VEGF in CancerCancer Cells and Metastasis

HIFs, angiogenesis, and metabolism: Elusive enemies in breast cancer

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de Heer, Ellen C., Jalving, Mathilde, Harris, Adrian L.·2020·Journal of Clinical Investigation

Abstract

Hypoxia-inducible factors (HIFs) and the HIF-dependent cancer hallmarks angiogenesis and metabolic rewiring are well-established drivers of breast cancer aggressiveness, therapy resistance, and poor prognosis. Targeting of HIF and its downstream targets in angiogenesis and metabolism has been unsuccessful so far in the breast cancer clinical setting, with major unresolved challenges residing in target selection, development of robust biomarkers for response prediction, and understanding and harnessing of escape mechanisms. This Review discusses the pathophysiological role of HIFs, angiogenesis, and metabolism in breast cancer and the challenges of targeting these features in patients with breast cancer. Rational therapeutic combinations, especially with immunotherapy and endocrine therapy, seem most promising in the clinical exploitation of the intricate interplay of HIFs, angiogenesis, and metabolism in breast cancer cells and the tumor microenvironment.

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Crossref · 10.1172/jci137552

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  • HIFs play critical roles in cancer progression by activating transcription of genes encoding proteins involved in angiogenesis, glucose metabolism, invasion/metastasis, stem cell specification, protumoral inflammatory responses, and tumor immune evasion.

    “Hypoxia-inducible factors (HIFs) play critical roles in cancer progression by activating the transcription of a large battery of genes encoding proteins that play key roles in angiogenesis, glucose metabolism, invasion/metastasis, stem cell specification, protumoral inflammatory responses, and tumor immune evasion (18, 23–27).”
  • Tumors can induce angiogenesis from nearby blood vessels, triggered by hypoxia-induced HIF signaling and VEGF secretion by cancer cells in a growing tumor.

    “In addition, there is crosstalk between (primary) tumors and blood vessels: tumors can induce angiogenesis from nearby blood vessels, which is triggered by hypoxia-induced hypoxia-inducible factor (HIF) signaling and vascular endothelial growth factor (VEGF) secretion by cancer cells in a growing tumor [48,49].”

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Research works printed but not linked: 2

  1. [5]5. Harris AL. Clinical strategies to inhibit tumor vas- cularization. In: Ribatti D, Pezzella F, eds. Tumor Vascularization. Elsevier Science; 2020:147-175.
  2. [19]19. Giatromanolaki A, et al. c-erbB-2 related aggres- siveness in breast cancer is hypoxia inducible factor-1alpha dependent. Clin Cancer Res. 2004;10(23):7972-7977.

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Authors
de Heer, E. C., Jalving, M., & Harris, A. L.
Affiliations
  • University Medical Center Groningen (NL)
  • University of Oxford (GB)
Corresponding author
Harris, Adrian L.
Venue
Journal of Clinical Investigation
Published
2020-10-01
Volume
130
Issue
10
Pages
5074-5087
ISSN
  • 0021-9738 (ISSN-L)
  • 1558-8238
OpenAlex
W3082891477
Cited by
372
References
202
Citations by year
2026: 32 · 2025: 69 · 2024: 83 · 2023: 94 · 2022: 71 · 2021: 22
FWCI
4.79
Type
journal article
Language
en
Open access
Licence
other-oa
Locations
  • Journal of Clinical Investigation (publishedVersion, other-oa)
  • Europe PMC (PubMed Central) (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
  • University of Groningen research database (University of Groningen / Centre for Information Technology) (submittedVersion, cc-by)
Funders
  • Breast Cancer Research Foundation
  • Cancer Research UK (A18974, 18974)
  • University of Oxford
  • KWF Kankerbestrijding (Young Investigator Grant 10913/2017-1, 10913/2017-1)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Angiogenesis and VEGF in Cancer
  • Health Sciences › Medicine › Oncology › Cancer Cells and Metastasis
Keywords
hypoxia-inducible factor, breast cancer, angiogenesis, cancer metabolism, metabolic reprogramming, treatment resistance, tumor microenvironment, combination immunotherapy, endocrine therapy, biomarkers, HIF-targeted therapy
MeSH terms
Animals, Hypoxia, Breast Neoplasms, Female, Humans, Models, Biological, Neovascularization, Pathologic, Prognosis, Biomarkers, Tumor, Signal Transduction, Basic Helix-Loop-Helix Transcription Factors, Basic Helix-Loop-Helix Proteins, Hypoxia-Inducible Factor 1, alpha Subunit, Tumor Microenvironment

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