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Hypoxia and Cancer: New Aspects
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Hypoxia and Cancer: New Aspects

A special issue of Cells (ISSN 2073-4409). This special issue belongs to the section "Cellular Pathology".

Deadline for manuscript submissions: closed (30 June 2021) | Viewed by 50882

Special Issue Editors

Prof. Dr. Adrian Harris

E-Mail Website
Guest Editor
Weatherall Institute of Molecular Medicine, Oxford, UK
Interests: tumour angiogenesis; notch signalling; hypoxia biology
Prof. Dr. Francesco Pezzella

E-Mail Website
Guest Editor
Nuffield Division of Clinical Laboratory Science, Nuffield Department of Medicine, University of Oxford, John Radcliffe Hospital, Oxford OX3 9DU, UK
Interests: relationship between cancer cells and blood vessels
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Recent advances in the biology of hypoxia and its role in cancer have revealed several added layers of complexity. In the last three decades, a model of cancer growth and progression emerged in which, as a neoplastic lesion expands and outgrows the vascular supply, the cells become hypoxic. Hypoxia then activates pathways which lead to the triggering of new vessel formation (i.e., angiogenesis), which supply the tumour with essential blood flow. This allows the tumour to keep growing and to disseminate metastatic cells. However, there is now growing evidence that as a tumour grows and becomes hypoxic, angiogenesis does not necessarily follow, as some neoplasia grow in its absence by co-opting and exploiting pre-existing tumours. As general rule these non-angiogenic tumours also display increased proliferation, epithelial–mesenchymal transition, invasiveness and motility, leading to an aggressive behaviour. Furthermore, some antiangiogenic drugs, such as those inhibiting the VEGF pathway, can in some patients improve the response but in others lead to proliferation and invasiveness. On the other hand, some cancer cells are able to nest by the vessels, in the so called “perivascular niche” and remain dormant in the complete absence of proliferation. In this Special Issue we aim to provide an update in this field and call for publications providing new information to help us better understand this biological crossroads facing the tumour cell. 

Prof. Dr. Adrian Harris
Prof. Francesco Pezzella
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Cells is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2700 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • Hypoxia in other organism and its evolution
  • Hypoxia in Zebra fish model
  • Basic regulation in human
  • Hypoxia and Immunology
  • Hypoxia and inflammation
  • Development of hypoxia molecular signatures
  • Hypoxia and metastases
  • Development of new treatments targeting hypocia pathways
  • Predictive markers for radiotherapy
  • Radiotherapy and hypoxia

Published Papers (10 papers)

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Research

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16 pages, 2980 KiB  
Article
PBRM1 Cooperates with YTHDF2 to Control HIF-1α Protein Translation
by Alena Shmakova, Mark Frost, Michael Batie, Niall S. Kenneth and Sonia Rocha
Cells 2021, 10(6), 1425; https://doi.org/10.3390/cells10061425 - 08 Jun 2021
Cited by 11 | Viewed by 4013
Abstract
PBRM1, a component of the chromatin remodeller SWI/SNF, is often deleted or mutated in human cancers, most prominently in renal cancers. Core components of the SWI/SNF complex have been shown to be important for the cellular response to hypoxia. Here, we investigated how [...] Read more.
PBRM1, a component of the chromatin remodeller SWI/SNF, is often deleted or mutated in human cancers, most prominently in renal cancers. Core components of the SWI/SNF complex have been shown to be important for the cellular response to hypoxia. Here, we investigated how PBRM1 controls HIF-1α activity. We found that PBRM1 is required for HIF-1α transcriptional activity and protein levels. Mechanistically, PBRM1 is important for HIF-1α mRNA translation, as absence of PBRM1 results in reduced actively translating HIF-1α mRNA. Interestingly, we found that PBRM1, but not BRG1, interacts with the m6A reader protein YTHDF2. HIF-1α mRNA is m6A-modified, bound by PBRM1 and YTHDF2. PBRM1 is necessary for YTHDF2 binding to HIF-1α mRNA and reduction of YTHDF2 results in reduced HIF-1α protein expression in cells. Our results identify a SWI/SNF-independent function for PBRM1, interacting with HIF-1α mRNA and the epitranscriptome machinery. Furthermore, our results suggest that the epitranscriptome-associated proteins play a role in the control of hypoxia signalling pathways. Full article
(This article belongs to the Special Issue Hypoxia and Cancer: New Aspects)
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17 pages, 2203 KiB  
Article
Aquaglyceroporin-3’s Expression and Cellular Localization Is Differentially Modulated by Hypoxia in Prostate Cancer Cell Lines
by Andreia de Almeida, Dimitris Parthimos, Holly Dew, Oliver Smart, Marie Wiltshire and Rachel J. Errington
Cells 2021, 10(4), 838; https://doi.org/10.3390/cells10040838 - 08 Apr 2021
Cited by 6 | Viewed by 2770
Abstract
Aquaporins are required by cells to enable fast adaptation to volume and osmotic changes, as well as microenvironmental metabolic stimuli. Aquaglyceroporins play a crucial role in supplying cancer cells with glycerol for metabolic needs. Here, we show that AQP3 is differentially expressed in [...] Read more.
Aquaporins are required by cells to enable fast adaptation to volume and osmotic changes, as well as microenvironmental metabolic stimuli. Aquaglyceroporins play a crucial role in supplying cancer cells with glycerol for metabolic needs. Here, we show that AQP3 is differentially expressed in cells of a prostate cancer panel. AQP3 is located at the cell membrane and cytoplasm of LNCaP cell while being exclusively expressed in the cytoplasm of Du145 and PC3 cells. LNCaP cells show enhanced hypoxia growth; Du145 and PC3 cells display stress factors, indicating a crucial role for AQP3 at the plasma membrane in adaptation to hypoxia. Hypoxia, both acute and chronic affected AQP3′s cellular localization. These outcomes were validated using a machine learning classification approach of the three cell lines and of the six normoxic or hypoxic conditions. Classifiers trained on morphological features derived from cytoskeletal and nuclear labeling alongside corresponding texture features could uniquely identify each individual cell line and the corresponding hypoxia exposure. Cytoskeletal features were 70–90% accurate, while nuclear features allowed for 55–70% accuracy. Cellular texture features (73.9% accuracy) were a stronger predictor of the hypoxic load than the AQP3 distribution (60.3%). Full article
(This article belongs to the Special Issue Hypoxia and Cancer: New Aspects)
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15 pages, 3827 KiB  
Article
Hypoxia-Induced Reactivity of Tumor-Associated Astrocytes Affects Glioma Cell Properties
by Vasiliki Pantazopoulou, Pauline Jeannot, Rebecca Rosberg, Tracy J. Berg and Alexander Pietras
Cells 2021, 10(3), 613; https://doi.org/10.3390/cells10030613 - 10 Mar 2021
Cited by 9 | Viewed by 3930
Abstract
Glioblastoma is characterized by extensive necrotic areas with surrounding hypoxia. The cancer cell response to hypoxia in these areas is well-described; it involves a metabolic shift and an increase in stem cell-like characteristics. Less is known about the hypoxic response of tumor-associated astrocytes, [...] Read more.
Glioblastoma is characterized by extensive necrotic areas with surrounding hypoxia. The cancer cell response to hypoxia in these areas is well-described; it involves a metabolic shift and an increase in stem cell-like characteristics. Less is known about the hypoxic response of tumor-associated astrocytes, a major component of the glioma tumor microenvironment. Here, we used primary human astrocytes and a genetically engineered glioma mouse model to investigate the response of this stromal cell type to hypoxia. We found that astrocytes became reactive in response to intermediate and severe hypoxia, similarly to irradiated and temozolomide-treated astrocytes. Hypoxic astrocytes displayed a potent hypoxia response that appeared to be driven primarily by hypoxia-inducible factor 2-alpha (HIF-2α). This response involved the activation of classical HIF target genes and the increased production of hypoxia-associated cytokines such as TGF-β1, IL-3, angiogenin, VEGF-A, and IL-1 alpha. In vivo, astrocytes were present in proximity to perinecrotic areas surrounding HIF-2α expressing cells, suggesting that hypoxic astrocytes contribute to the glioma microenvironment. Extracellular matrix derived from hypoxic astrocytes increased the proliferation and drug efflux capability of glioma cells. Together, our findings suggest that hypoxic astrocytes are implicated in tumor growth and potentially stemness maintenance by remodeling the tumor microenvironment. Full article
(This article belongs to the Special Issue Hypoxia and Cancer: New Aspects)
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23 pages, 7442 KiB  
Article
Resistance of Hypoxic Cells to Ionizing Radiation Is Mediated in Part via Hypoxia-Induced Quiescence
by Apostolos Menegakis, Rob Klompmaker, Claire Vennin, Aina Arbusà, Maartje Damen, Bram van den Broek, Daniel Zips, Jacco van Rheenen, Lenno Krenning and René H. Medema
Cells 2021, 10(3), 610; https://doi.org/10.3390/cells10030610 - 10 Mar 2021
Cited by 17 | Viewed by 3599
Abstract
Double strand breaks (DSBs) are highly toxic to a cell, a property that is exploited in radiation therapy. A critical component for the damage induction is cellular oxygen, making hypoxic tumor areas refractory to the efficacy of radiation treatment. During a fractionated radiation [...] Read more.
Double strand breaks (DSBs) are highly toxic to a cell, a property that is exploited in radiation therapy. A critical component for the damage induction is cellular oxygen, making hypoxic tumor areas refractory to the efficacy of radiation treatment. During a fractionated radiation regimen, these hypoxic areas can be re-oxygenated. Nonetheless, hypoxia still constitutes a negative prognostic factor for the patient’s outcome. We hypothesized that this might be attributed to specific hypoxia-induced cellular traits that are maintained upon reoxygenation. Here, we show that reoxygenation of hypoxic non-transformed RPE-1 cells fully restored induction of DSBs but the cells remain radioresistant as a consequence of hypoxia-induced quiescence. With the use of the cell cycle indicators (FUCCI), cell cycle-specific radiation sensitivity, the cell cycle phase duration with live cell imaging, and single cell tracing were assessed. We observed that RPE-1 cells experience a longer G1 phase under hypoxia and retain a large fraction of cells that are non-cycling. Expression of HPV oncoprotein E7 prevents hypoxia-induced quiescence and abolishes the radioprotective effect. In line with this, HPV-negative cancer cell lines retain radioresistance, while HPV-positive cancer cell lines are radiosensitized upon reoxygenation. Quiescence induction in hypoxia and its HPV-driven prevention was observed in 3D multicellular spheroids. Collectively, we identify a new hypoxia-dependent radioprotective phenotype due to hypoxia-induced quiescence that accounts for a global decrease in radiosensitivity that can be retained upon reoxygenation and is absent in cells expressing oncoprotein E7. Full article
(This article belongs to the Special Issue Hypoxia and Cancer: New Aspects)
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21 pages, 4582 KiB  
Article
Calcitriol Suppresses HIF-1 and HIF-2 Transcriptional Activity by Reducing HIF-1/2α Protein Levels via a VDR-Independent Mechanism
by Ioanna-Maria Gkotinakou, Eleni Kechagia, Kalliopi Pazaitou-Panayiotou, Ilias Mylonis, Panagiotis Liakos and Andreas Tsakalof
Cells 2020, 9(11), 2440; https://doi.org/10.3390/cells9112440 - 09 Nov 2020
Cited by 13 | Viewed by 3117
Abstract
Hypoxia-inducible transcription factors 1 and 2 (HIFs) are major mediators of cancer development and progression and validated targets for cancer therapy. Although calcitriol, the biologically active metabolite of vitamin D, was attributed with anticancer properties, there is little information on the effect of [...] Read more.
Hypoxia-inducible transcription factors 1 and 2 (HIFs) are major mediators of cancer development and progression and validated targets for cancer therapy. Although calcitriol, the biologically active metabolite of vitamin D, was attributed with anticancer properties, there is little information on the effect of calcitriol on HIFs and the mechanism underling this activity. Here, we demonstrate the negative effect of calcitriol on HIF-1/2α protein levels and HIF-1/2 transcriptional activity and elucidate the molecular mechanism of calcitriol action. We also reveal that the suppression of vitamin D receptor (VDR) expression by siRNA does not abrogate the negative regulation of HIF-1α and HIF-2α protein levels and HIF-1/2 transcriptional activity by calcitriol, thus testifying that the mechanism of these actions is VDR independent. At the same time, calcitriol significantly reduces the phosphorylation of Akt protein kinase and its downstream targets and suppresses HIF-1/2α protein synthesis by inhibiting HIF1A and EPAS1 (Endothelial PAS domain-containing protein 1) mRNA translation, without affecting their mRNA levels. On the basis of the acquired data, it can be proposed that calcitriol reduces HIF-1α and HIF-2α protein levels and inhibits HIF-1 and HIF-2 transcriptional activity by a VDR-independent, nongenomic mechanism that involves inhibition of PI3K/Akt signaling pathway and suppression of HIF1A and EPAS1 mRNA translation. Full article
(This article belongs to the Special Issue Hypoxia and Cancer: New Aspects)
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Review

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26 pages, 13758 KiB  
Review
HIF-1-Independent Mechanisms Regulating Metabolic Adaptation in Hypoxic Cancer Cells
by Shen-Han Lee, Monika Golinska and John R. Griffiths
Cells 2021, 10(9), 2371; https://doi.org/10.3390/cells10092371 - 09 Sep 2021
Cited by 48 | Viewed by 10786
Abstract
In solid tumours, cancer cells exist within hypoxic microenvironments, and their metabolic adaptation to this hypoxia is driven by HIF-1 transcription factor, which is overexpressed in a broad range of human cancers. HIF inhibitors are under pre-clinical investigation and clinical trials, but there [...] Read more.
In solid tumours, cancer cells exist within hypoxic microenvironments, and their metabolic adaptation to this hypoxia is driven by HIF-1 transcription factor, which is overexpressed in a broad range of human cancers. HIF inhibitors are under pre-clinical investigation and clinical trials, but there is evidence that hypoxic cancer cells can adapt metabolically to HIF-1 inhibition, which would provide a potential route for drug resistance. Here, we review accumulating evidence of such adaptions in carbohydrate and creatine metabolism and other HIF-1-independent mechanisms that might allow cancers to survive hypoxia despite anti-HIF-1 therapy. These include pathways in glucose, glutamine, and lipid metabolism; epigenetic mechanisms; post-translational protein modifications; spatial reorganization of enzymes; signalling pathways such as Myc, PI3K-Akt, 2-hyxdroxyglutarate and AMP-activated protein kinase (AMPK); and activation of the HIF-2 pathway. All of these should be investigated in future work on hypoxia bypass mechanisms in anti-HIF-1 cancer therapy. In principle, agents targeted toward HIF-1β rather than HIF-1α might be advantageous, as both HIF-1 and HIF-2 require HIF-1β for activation. However, HIF-1β is also the aryl hydrocarbon nuclear transporter (ARNT), which has functions in many tissues, so off-target effects should be expected. In general, cancer therapy by HIF inhibition will need careful attention to potential resistance mechanisms. Full article
(This article belongs to the Special Issue Hypoxia and Cancer: New Aspects)
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16 pages, 1163 KiB  
Review
Regulation of the Hypoxia-Inducible Factor (HIF) by Pro-Inflammatory Cytokines
by Mykyta I. Malkov, Chee Teik Lee and Cormac T. Taylor
Cells 2021, 10(9), 2340; https://doi.org/10.3390/cells10092340 - 07 Sep 2021
Cited by 56 | Viewed by 7935
Abstract
Hypoxia and inflammation are frequently co-incidental features of the tissue microenvironment in a wide range of inflammatory diseases. While the impact of hypoxia on inflammatory pathways in immune cells has been well characterized, less is known about how inflammatory stimuli such as cytokines [...] Read more.
Hypoxia and inflammation are frequently co-incidental features of the tissue microenvironment in a wide range of inflammatory diseases. While the impact of hypoxia on inflammatory pathways in immune cells has been well characterized, less is known about how inflammatory stimuli such as cytokines impact upon the canonical hypoxia-inducible factor (HIF) pathway, the master regulator of the cellular response to hypoxia. In this review, we discuss what is known about the impact of two major pro-inflammatory cytokines, tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β), on the regulation of HIF-dependent signaling at sites of inflammation. We report extensive evidence for these cytokines directly impacting upon HIF signaling through the regulation of HIF at transcriptional and post-translational levels. We conclude that multi-level crosstalk between inflammatory and hypoxic signaling pathways plays an important role in shaping the nature and degree of inflammation occurring at hypoxic sites. Full article
(This article belongs to the Special Issue Hypoxia and Cancer: New Aspects)
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25 pages, 6951 KiB  
Review
Tumour Hypoxia-Mediated Immunosuppression: Mechanisms and Therapeutic Approaches to Improve Cancer Immunotherapy
by Zhe Fu, Alexandra M. Mowday, Jeff B. Smaill, Ian F. Hermans and Adam V. Patterson
Cells 2021, 10(5), 1006; https://doi.org/10.3390/cells10051006 - 24 Apr 2021
Cited by 44 | Viewed by 4916
Abstract
The magnitude of the host immune response can be regulated by either stimulatory or inhibitory immune checkpoint molecules. Receptor-ligand binding between inhibitory molecules is often exploited by tumours to suppress anti-tumour immune responses. Immune checkpoint inhibitors that block these inhibitory interactions can relieve [...] Read more.
The magnitude of the host immune response can be regulated by either stimulatory or inhibitory immune checkpoint molecules. Receptor-ligand binding between inhibitory molecules is often exploited by tumours to suppress anti-tumour immune responses. Immune checkpoint inhibitors that block these inhibitory interactions can relieve T-cells from negative regulation, and have yielded remarkable activity in the clinic. Despite this success, clinical data reveal that durable responses are limited to a minority of patients and malignancies, indicating the presence of underlying resistance mechanisms. Accumulating evidence suggests that tumour hypoxia, a pervasive feature of many solid cancers, is a critical phenomenon involved in suppressing the anti-tumour immune response generated by checkpoint inhibitors. In this review, we discuss the mechanisms associated with hypoxia-mediate immunosuppression and focus on modulating tumour hypoxia as an approach to improve immunotherapy responsiveness. Full article
(This article belongs to the Special Issue Hypoxia and Cancer: New Aspects)
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26 pages, 2094 KiB  
Review
Hypoxia and Extracellular Acidification as Drivers of Melanoma Progression and Drug Resistance
by Ewelina Dratkiewicz, Aleksandra Simiczyjew, Justyna Mazurkiewicz, Marcin Ziętek, Rafał Matkowski and Dorota Nowak
Cells 2021, 10(4), 862; https://doi.org/10.3390/cells10040862 - 09 Apr 2021
Cited by 33 | Viewed by 4071
Abstract
Hypoxia and elevated extracellular acidification are prevalent features of solid tumors and they are often shown to facilitate cancer progression and drug resistance. In this review, we have compiled recent and most relevant research pertaining to the role of hypoxia and acidification in [...] Read more.
Hypoxia and elevated extracellular acidification are prevalent features of solid tumors and they are often shown to facilitate cancer progression and drug resistance. In this review, we have compiled recent and most relevant research pertaining to the role of hypoxia and acidification in melanoma growth, invasiveness, and response to therapy. Melanoma represents a highly aggressive and heterogeneous type of skin cancer. Currently employed treatments, including BRAF V600E inhibitors and immune therapy, often are not effective due to a rapidly developing drug resistance. A variety of intracellular mechanisms impeding the treatment were discovered. However, the tumor microenvironment encompassing stromal and immune cells, extracellular matrix, and physicochemical conditions such as oxygen level or acidity, may also influence the therapy effectiveness. Hypoxia and acidification are able to reprogram the metabolism of melanoma cells, enhance their survival and invasiveness, as well as promote the immunosuppressive environment. For this reason, these physicochemical features of the melanoma niche and signaling pathways related to them emerge as potential therapeutic targets. Full article
(This article belongs to the Special Issue Hypoxia and Cancer: New Aspects)
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14 pages, 858 KiB  
Review
Targeting the Hypoxic and Acidic Tumor Microenvironment with pH-Sensitive Peptides
by Nayanthara U. Dharmaratne, Alanna R. Kaplan and Peter M. Glazer
Cells 2021, 10(3), 541; https://doi.org/10.3390/cells10030541 - 04 Mar 2021
Cited by 31 | Viewed by 4189
Abstract
The delivery of cancer therapeutics can be limited by pharmacological issues such as poor bioavailability and high toxicity to healthy tissue. pH-low insertion peptides (pHLIPs) represent a promising tool to overcome these limitations. pHLIPs allow for the selective delivery of agents to tumors [...] Read more.
The delivery of cancer therapeutics can be limited by pharmacological issues such as poor bioavailability and high toxicity to healthy tissue. pH-low insertion peptides (pHLIPs) represent a promising tool to overcome these limitations. pHLIPs allow for the selective delivery of agents to tumors on the basis of pH, taking advantage of the acidity of the hypoxic tumor microenvironment. This review article highlights the various applications in which pHLIPs have been utilized for targeting and treating diseases in hypoxic environments, including delivery of small molecule inhibitors, toxins, nucleic acid analogs, fluorescent dyes, and nanoparticles. Full article
(This article belongs to the Special Issue Hypoxia and Cancer: New Aspects)
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