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Cells
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Hypoxia and Cancer: Mechanisms of Resistance and Metastasis
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Hypoxia and Cancer: Mechanisms of Resistance and Metastasis

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

Deadline for manuscript submissions: closed (15 January 2022) | Viewed by 52689

Special Issue Editor

Dr. Daniele M. Gilkes

E-Mail Website
Guest Editor
Department of Oncology, The Johns Hopkins University School of Medicine, Baltimore, MD, USA
Interests: metastasis; breast cancer; extracellular-matrix proteins; hypoxia; HIFs

Special Issue Information

Dear Colleagues,

Hypoxia, or inadequate oxygenation of a solid tumor, leads to tumor progression. Tumor hypoxia also negatively affects therapeutic outcomes in part by inducing genetic changes in neoplastic cells that promote cancer cell survival. Hypoxia-inducible factors (HIFs) and their target gene products are highly active in cancer and have been shown to contribute to chemotherapeutic resistance. Consequently, alleviating hypoxia in solid tumors is considered a promising target for improving the efficacy of anti-cancer therapeutics. The precise contribution of hypoxia in altering the cellular composition, non-cellular composition and cell phenotypes is emerging and will be important to consider when developing novel therapies for cancer patients.

This current volume aims to present new ideas and novel findings on how hypoxia influences

  • the immune landscape in cancer;
  • the cancer stem cell phenotype;
  • metastasis;
  • resistance to therapy;
  • invasion of epithelial cells into the connective tissue;
  • the epithelial-to-mesenchymal transition; and
  • new tools that can provide a quantitative insight into the O2 levels in human tumors, experimental tumors and organoids.

Dr. Daniele M. Gilkes
Guest Editor

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
  • hypoxia-inducible factors
  • metastasis
  • cancer
  • immune evasion

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Published Papers (6 papers)

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Research

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14 pages, 2491 KiB  
Article
Stabilization of PIM Kinases in Hypoxia Is Mediated by the Deubiquitinase USP28
by Rachel K. Toth, Regina Solomon and Noel A. Warfel
Cells 2022, 11(6), 1006; https://doi.org/10.3390/cells11061006 - 16 Mar 2022
Cited by 8 | Viewed by 2960
Abstract
Proviral integration sites for Moloney murine leukemia virus (PIM) kinases are upregulated at the protein level in response to hypoxia and have multiple protumorigenic functions, promoting cell growth, survival, and angiogenesis. However, the mechanism responsible for the induction of PIM in hypoxia remains [...] Read more.
Proviral integration sites for Moloney murine leukemia virus (PIM) kinases are upregulated at the protein level in response to hypoxia and have multiple protumorigenic functions, promoting cell growth, survival, and angiogenesis. However, the mechanism responsible for the induction of PIM in hypoxia remains unknown. Here, we examined factors affecting PIM kinase stability in normoxia and hypoxia. We found that PIM kinases were upregulated in hypoxia at the protein level but not at the mRNA level, confirming that PIMs were upregulated in hypoxia in a hypoxia inducible factor 1-independent manner. PIM kinases were less ubiquitinated in hypoxia than in normoxia, indicating that hypoxia reduced their proteasomal degradation. We identified the deubiquitinase ubiquitin-specific protease 28 (USP28) as a key regulator of PIM1 and PIM2 stability. The overexpression of USP28 increased PIM protein stability and total levels in both normoxia and hypoxia, and USP28-knockdown significantly increased the ubiquitination of PIM1 and PIM2. Interestingly, coimmunoprecipitation assays showed an increased interaction between PIM1/2 and USP28 in response to hypoxia, which correlated with reduced ubiquitination and increased protein stability. In a xenograft model, USP28-knockdown tumors grew more slowly than control tumors and showed significantly lower levels of PIM1 in vivo. In conclusion, USP28 blocked the ubiquitination and increased the stability of PIM1/2, particularly in hypoxia. These data provide the first insight into proteins responsible for controlling PIM protein degradation and identify USP28 as an important upstream regulator of this hypoxia-induced, protumorigenic signaling pathway. Full article
(This article belongs to the Special Issue Hypoxia and Cancer: Mechanisms of Resistance and Metastasis)
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18 pages, 3771 KiB  
Article
Treatment of Pheochromocytoma Cells with Recurrent Cycles of Hypoxia: A New Pseudohypoxic In Vitro Model
by Jana Helm, Stephan Drukewitz, Isabel Poser, Susan Richter, Markus Friedemann, Doreen William, Hermine Mohr, Svenja Nölting, Mercedes Robledo, Stefan R. Bornstein, Graeme Eisenhofer and Nicole Bechmann
Cells 2022, 11(3), 560; https://doi.org/10.3390/cells11030560 - 5 Feb 2022
Cited by 3 | Viewed by 3081
Abstract
Continuous activation of hypoxia pathways in pheochromocytomas and paragangliomas (PPGLs) is associated with higher disease aggressiveness, for which effective treatment strategies are still missing. Most of the commonly used in vitro models lack characteristics of these pseudohypoxic tumors, including elevated expression of hypoxia-inducible [...] Read more.
Continuous activation of hypoxia pathways in pheochromocytomas and paragangliomas (PPGLs) is associated with higher disease aggressiveness, for which effective treatment strategies are still missing. Most of the commonly used in vitro models lack characteristics of these pseudohypoxic tumors, including elevated expression of hypoxia-inducible factor (HIF) 2α. To address this shortcoming, we investigated whether recurrent hypoxia cycles lead to continuous activation of hypoxia pathways under normoxic conditions and whether this pseudohypoxia is associated with increased cellular aggressiveness. Rat pheochromocytoma cells (PC12) were incubated under hypoxia for 24 h every 3–4 days, up to 20 hypoxia–reoxygenation cycles, resulting in PC12 Z20 cells. PC12 Z20 control cells were obtained by synchronous cultivation under normoxia. RNA sequencing revealed upregulation of HIF2α in PC12 Z20 cells and a pseudohypoxic gene signature that overlapped with the gene signature of pseudohypoxic PPGLs. PC12 Z20 cells showed a higher growth rate, and the migration and adhesion capacity were significantly increased compared with control cells. Changes in global methylation, together with the pseudohypoxic conditions, may be responsible for the increased aggressiveness of this new model. The established sub-cell line with characteristics of pseudohypoxic PPGLs represent a complementary model for further investigations, for example, with regard to new therapeutic approaches. Full article
(This article belongs to the Special Issue Hypoxia and Cancer: Mechanisms of Resistance and Metastasis)
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Review

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22 pages, 1085 KiB  
Review
Detection of Hypoxia in Cancer Models: Significance, Challenges, and Advances
by Inês Godet, Steven Doctorman, Fan Wu and Daniele M. Gilkes
Cells 2022, 11(4), 686; https://doi.org/10.3390/cells11040686 - 16 Feb 2022
Cited by 58 | Viewed by 10491
Abstract
The rapid proliferation of cancer cells combined with deficient vessels cause regions of nutrient and O2 deprivation in solid tumors. Some cancer cells can adapt to these extreme hypoxic conditions and persist to promote cancer progression. Intratumoral hypoxia has been consistently associated [...] Read more.
The rapid proliferation of cancer cells combined with deficient vessels cause regions of nutrient and O2 deprivation in solid tumors. Some cancer cells can adapt to these extreme hypoxic conditions and persist to promote cancer progression. Intratumoral hypoxia has been consistently associated with a worse patient prognosis. In vitro, 3D models of spheroids or organoids can recapitulate spontaneous O2 gradients in solid tumors. Likewise, in vivo murine models of cancer reproduce the physiological levels of hypoxia that have been measured in human tumors. Given the potential clinical importance of hypoxia in cancer progression, there is an increasing need to design methods to measure O2 concentrations. O2 levels can be directly measured with needle-type probes, both optical and electrochemical. Alternatively, indirect, noninvasive approaches have been optimized, and include immunolabeling endogenous or exogenous markers. Fluorescent, phosphorescent, and luminescent reporters have also been employed experimentally to provide dynamic measurements of O2 in live cells or tumors. In medical imaging, modalities such as MRI and PET are often the method of choice. This review provides a comparative overview of the main methods utilized to detect hypoxia in cell culture and preclinical models of cancer. Full article
(This article belongs to the Special Issue Hypoxia and Cancer: Mechanisms of Resistance and Metastasis)
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18 pages, 2238 KiB  
Review
Hypoxia, Metabolic Reprogramming, and Drug Resistance in Liver Cancer
by Macus Hao-Ran Bao and Carmen Chak-Lui Wong
Cells 2021, 10(7), 1715; https://doi.org/10.3390/cells10071715 - 6 Jul 2021
Cited by 174 | Viewed by 13175
Abstract
Hypoxia, low oxygen (O2) level, is a hallmark of solid cancers, especially hepatocellular carcinoma (HCC), one of the most common and fatal cancers worldwide. Hypoxia contributes to drug resistance in cancer through various molecular mechanisms. In this review, we particularly focus [...] Read more.
Hypoxia, low oxygen (O2) level, is a hallmark of solid cancers, especially hepatocellular carcinoma (HCC), one of the most common and fatal cancers worldwide. Hypoxia contributes to drug resistance in cancer through various molecular mechanisms. In this review, we particularly focus on the roles of hypoxia-inducible factor (HIF)-mediated metabolic reprogramming in drug resistance in HCC. Combination therapies targeting hypoxia-induced metabolic enzymes to overcome drug resistance will also be summarized. Acquisition of drug resistance is the major cause of unsatisfactory clinical outcomes of existing HCC treatments. Extra efforts to identify novel mechanisms to combat refractory hypoxic HCC are warranted for the development of more effective treatment regimens for HCC patients. Full article
(This article belongs to the Special Issue Hypoxia and Cancer: Mechanisms of Resistance and Metastasis)
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26 pages, 2488 KiB  
Review
Hypoxia-Driven Effects in Cancer: Characterization, Mechanisms, and Therapeutic Implications
by Rachel Shi, Chengheng Liao and Qing Zhang
Cells 2021, 10(3), 678; https://doi.org/10.3390/cells10030678 - 19 Mar 2021
Cited by 71 | Viewed by 13974
Abstract
Hypoxia, a common feature of solid tumors, greatly hinders the efficacy of conventional cancer treatments such as chemo-, radio-, and immunotherapy. The depletion of oxygen in proliferating and advanced tumors causes an array of genetic, transcriptional, and metabolic adaptations that promote survival, metastasis, [...] Read more.
Hypoxia, a common feature of solid tumors, greatly hinders the efficacy of conventional cancer treatments such as chemo-, radio-, and immunotherapy. The depletion of oxygen in proliferating and advanced tumors causes an array of genetic, transcriptional, and metabolic adaptations that promote survival, metastasis, and a clinically malignant phenotype. At the nexus of these interconnected pathways are hypoxia-inducible factors (HIFs) which orchestrate transcriptional responses under hypoxia. The following review summarizes current literature regarding effects of hypoxia on DNA repair, metastasis, epithelial-to-mesenchymal transition, the cancer stem cell phenotype, and therapy resistance. We also discuss mechanisms and pathways, such as HIF signaling, mitochondrial dynamics, exosomes, and the unfolded protein response, that contribute to hypoxia-induced phenotypic changes. Finally, novel therapeutics that target the hypoxic tumor microenvironment or interfere with hypoxia-induced pathways are reviewed. Full article
(This article belongs to the Special Issue Hypoxia and Cancer: Mechanisms of Resistance and Metastasis)
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23 pages, 3308 KiB  
Review
Mimicking Tumor Hypoxia in Non-Small Cell Lung Cancer Employing Three-Dimensional In Vitro Models
by Iwona Ziółkowska-Suchanek
Cells 2021, 10(1), 141; https://doi.org/10.3390/cells10010141 - 12 Jan 2021
Cited by 32 | Viewed by 7804
Abstract
Hypoxia is the most common microenvironment feature of lung cancer tumors, which affects cancer progression, metastasis and metabolism. Oxygen induces both proteomic and genomic changes within tumor cells, which cause many alternations in the tumor microenvironment (TME). This review defines current knowledge in [...] Read more.
Hypoxia is the most common microenvironment feature of lung cancer tumors, which affects cancer progression, metastasis and metabolism. Oxygen induces both proteomic and genomic changes within tumor cells, which cause many alternations in the tumor microenvironment (TME). This review defines current knowledge in the field of tumor hypoxia in non-small cell lung cancer (NSCLC), including biology, biomarkers, in vitro and in vivo studies and also hypoxia imaging and detection. While classic two-dimensional (2D) in vitro research models reveal some hypoxia dependent manifestations, three-dimensional (3D) cell culture models more accurately replicate the hypoxic TME. In this study, a systematic review of the current NSCLC 3D models that have been able to mimic the hypoxic TME is presented. The multicellular tumor spheroid, organoids, scaffolds, microfluidic devices and 3D bioprinting currently being utilized in NSCLC hypoxia studies are reviewed. Additionally, the utilization of 3D in vitro models for exploring biological and therapeutic parameters in the future is described. Full article
(This article belongs to the Special Issue Hypoxia and Cancer: Mechanisms of Resistance and Metastasis)
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