Regulation of HIFs in Cancer Cells

A special issue of Cancers (ISSN 2072-6694). This special issue belongs to the section "Tumor Microenvironment".

Deadline for manuscript submissions: 30 April 2024 | Viewed by 2617

Special Issue Editors

Laboratory of Biochemistry, Faculty of Medicine, University of Thessaly, Panepistimiou 3, BIOPOLIS, 41500 Larissa, Greece
Interests: Hypoxia; Hypoxia-inducible Factors (HIFs); HIF-2 regulation and post-translational modifications; cell signaling in cancer cells; oxidative stress; endothelium; angiogenesis
Laboratory of Biochemistry, Faculty of Medicine, University of Thessaly, Panepistimiou 3, BIOPOLIS, 41500 Larissa, Greece
Interests: Hypoxia; Hypoxia-inducible factor-1 (HIF-1); regulation of gene expression; cell signaling and cancer; nucleocytoplasmic transport; nuclear structure and function; regulation of lipid metabolism
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Special Issue Information

Dear Colleagues,

Hypoxia, a condition in which cells are exposed to reduced oxygen levels, is implicated in physiological processes, such as life in high altitude and intense exercise, but also in pathologic conditions, including ischemia, inflammatory disorders, pulmonary diseases, renal diseases, and cancer. Cancer cells under hypoxia exhibit significant changes in gene expression patterns in order to facilitate their adaptation under the hypoxic microenvironment. This transcriptional reprogramming is mainly coordinated by Hypoxia-Inducible transcription Factors (HIF) and allows cells to alter their metabolism, proliferate, and acquire resistance to death. However, it also facilitates processes such as angiogenesis and vascularization of the tumor, invasion, and metastasis.

HIFs are a small family of heterodimeric transcription factors comprising three distinct isoforms (HIF-1, HIF-2, HIF-3), and consist of an oxygen-regulated HIF-α subunit and a stably expressed HIF-β subunit or ARNT (Aryl hydrocarbon Receptor Nuclear Translocator). HIF-α oxygen-regulated subunits are often overexpressed in human cancers, not only by local hypoxia but also by oncogenic mutations (as in VHL) or overactivation of signaling pathways such as PI3K/AKT/mTOR or Ras/ERK1/2 that stimulate HIF-α expression and/or HIF transcriptional activity. In addition, the overexpression of HIF-α is observed in many cancers and is strongly correlated with poor patient prognosis and resistance to conventional therapy.

Thus, HIFs represent an attractive target for anticancer therapy and a global effort is underway to find strategies to control and modulate HIF activity for therapeutic purposes. Recent preclinical models and clinical studies have shown the prospects of inhibiting HIF in poorly oxygenated cancer cells; however, the full potential of HIF inhibition may be revealed when it is combined with other treatments as a tool to fight cancer.

Therefore, in order to develop new tools that effectively impact hypoxic cancer cells and limit tumor growth, it is important to elucidate the mechanistic details of HIF regulation in cancer cells and gain new knowledge on the contribution of various HIF isoforms in different types of cancer.

Dr. Panagiotis Liakos
Dr. Ilias Mylonis
Guest Editors

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Keywords

  • Hypoxia
  • Hypoxia-inducible Factors (HIFs)
  • tumor microenvironment
  • cancer
  • oxygen
  • transcription
  • post-translational modifications
  • mRNA synthesis

Published Papers (2 papers)

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Research

14 pages, 4026 KiB  
Article
Non-Contrast-Enhanced Multiparametric MRI of the Hypoxic Tumor Microenvironment Allows Molecular Subtyping of Breast Cancer: A Pilot Study
by Silvester J. Bartsch, Klára Brožová, Viktoria Ehret, Joachim Friske, Christoph Fürböck, Lukas Kenner, Daniela Laimer-Gruber, Thomas H. Helbich and Katja Pinker
Cancers 2024, 16(2), 375; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers16020375 - 16 Jan 2024
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Abstract
Tumor neoangiogenesis is an important hallmark of cancer progression, triggered by alternating selective pressures from the hypoxic tumor microenvironment. Non-invasive, non-contrast-enhanced multiparametric MRI combining blood-oxygen-level-dependent (BOLD) MRI, which depicts blood oxygen saturation, and intravoxel-incoherent-motion (IVIM) MRI, which captures intravascular and extravascular diffusion, can [...] Read more.
Tumor neoangiogenesis is an important hallmark of cancer progression, triggered by alternating selective pressures from the hypoxic tumor microenvironment. Non-invasive, non-contrast-enhanced multiparametric MRI combining blood-oxygen-level-dependent (BOLD) MRI, which depicts blood oxygen saturation, and intravoxel-incoherent-motion (IVIM) MRI, which captures intravascular and extravascular diffusion, can provide insights into tumor oxygenation and neovascularization simultaneously. Our objective was to identify imaging markers that can predict hypoxia-induced angiogenesis and to validate our findings using multiplexed immunohistochemical analyses. We present an in vivo study involving 36 female athymic nude mice inoculated with luminal A, Her2+, and triple-negative breast cancer cells. We used a high-field 9.4-tesla MRI system for imaging and subsequently analyzed the tumors using multiplex immunohistochemistry for CD-31, PDGFR-β, and Hif1-α. We found that the hyperoxic-BOLD-MRI-derived parameter ΔR2* discriminated luminal A from Her2+ and triple-negative breast cancers, while the IVIM-derived parameter fIVIM discriminated luminal A and Her2+ from triple-negative breast cancers. A comprehensive analysis using principal-component analysis of both multiparametric MRI- and mpIHC-derived data highlighted the differences between triple-negative and luminal A breast cancers. We conclude that multiparametric MRI combining hyperoxic BOLD MRI and IVIM MRI, without the need for contrast agents, offers promising non-invasive markers for evaluating hypoxia-induced angiogenesis. Full article
(This article belongs to the Special Issue Regulation of HIFs in Cancer Cells)
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17 pages, 3835 KiB  
Article
Influence of the Hypoxia-Activated Prodrug Evofosfamide (TH-302) on Glycolytic Metabolism of Canine Glioma: A Potential Improvement in Cancer Metabolism
by Hiroki Yamazaki, Seio Onoyama, Shunichi Gotani, Tatsuya Deguchi, Masahiro Tamura, Hiroshi Ohta, Hidetomo Iwano, Hidetaka Nishida, Peter J. Dickinson and Hideo Akiyoshi
Cancers 2023, 15(23), 5537; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers15235537 - 22 Nov 2023
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Abstract
The transcription factor hypoxia-inducible factor 1α (HIF-1α) drives metabolic reprogramming in gliomas (GLs) under hypoxic conditions, promoting glycolysis for tumor development. Evofosfamide (EVO) releases a DNA-alkylating agent within hypoxic regions, indicating that it may serve as a hypoxia-targeted therapy. The aim of this [...] Read more.
The transcription factor hypoxia-inducible factor 1α (HIF-1α) drives metabolic reprogramming in gliomas (GLs) under hypoxic conditions, promoting glycolysis for tumor development. Evofosfamide (EVO) releases a DNA-alkylating agent within hypoxic regions, indicating that it may serve as a hypoxia-targeted therapy. The aim of this study was to investigate the glycolytic metabolism and antitumor effects of EVO in a canine GL model. Our clinical data showed that overall survival was significantly decreased in GL dog patients with higher HIF-1α expression compared to that of those with lower HIF-1α expression, and there was a positive correlation between HIF-1α and pyruvate dehydrogenase kinase 1 (PDK1) expression, suggesting that glycolytic activity under hypoxia conditions may contribute to poor outcomes in canine GL. Our glycolysis assay tests showed that the glycolytic ATP level was higher than the mitochondrial ATP level in three types of canine GL cell lines by activating the HIF-1 signal pathway under hypoxia conditions, resulting in an overall increase in total cellular ATP production. However, treatment with EVO inhibited the glycolytic ATP level in the GL cell lines under hypoxia conditions by targeting HIF-1α-positive cells, leading to decrease in total cellular ATP production. Our in vivo tests showed that EVO significantly reduced tumor development compared to controls and temozolomide in murine GL models. A metabolic analysis demonstrated that EVO effectively suppressed glycolytic metabolism by eliminating HIF-1α-positive cells, suggesting that it may restore metabolism in canine GLs. The evidence presented here supports the favorable preclinical evaluation of EVO as a potential improvement in cancer metabolism. Full article
(This article belongs to the Special Issue Regulation of HIFs in Cancer Cells)
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