Editorial

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Open AccessEditorial

Hypoxia and Cancer: From Bench to Bedside

by Lingzhi Wang and Qingyu Zhou

Cancers 2023, 15(9), 2478; https://doi.org/10.3390/cancers15092478 - 26 Apr 2023

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This Special Issue of Cancers (two original articles, five reviews), presented by international experts in tumor hypoxia, focuses on the role of hypoxia, or low oxygen levels, in the development and progression of cancer [...] Full article

(This article belongs to the Special Issue Hypoxia and Cancer: From Bench to Bedside)

Research

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16 pages, 3155 KiB

Open AccessFeature PaperArticle

Post-Hypoxic Cells Promote Metastatic Recurrence after Chemotherapy Treatment in TNBC

by Inês Godet, Mahelet Mamo, Andrea Thurnheer, D. Marc Rosen and Daniele M. Gilkes

Cancers 2021, 13(21), 5509; https://doi.org/10.3390/cancers13215509 - 02 Nov 2021

Cited by 11 | Viewed by 3047

Abstract

Hypoxia occurs in 90% of solid tumors and is associated with treatment failure, relapse, and mortality. HIF-1α signaling promotes resistance to chemotherapy in cancer cell lines and murine models via multiple mechanisms including the enrichment of breast cancer stem cells (BCSCs). In this [...] Read more.

Hypoxia occurs in 90% of solid tumors and is associated with treatment failure, relapse, and mortality. HIF-1α signaling promotes resistance to chemotherapy in cancer cell lines and murine models via multiple mechanisms including the enrichment of breast cancer stem cells (BCSCs). In this work, we utilize a hypoxia fate-mapping system to determine whether triple-negative breast cancer (TNBC) cells that experience hypoxia in the primary tumor are resistant to chemotherapy at sites of metastasis. Using two orthotopic mouse models of TNBC, we demonstrate that cells that experience intratumoral hypoxia and metastasize to the lung and liver have decreased sensitivity to doxorubicin and paclitaxel but not cisplatin or 5-FU. Resistance to therapy leads to metastatic recurrence caused by post-hypoxic cells. We further determined that the post-hypoxic cells that metastasize are enriched in pathways related to cancer stem cell gene expression. Overall, our results show that even when hypoxic cancer cells are reoxygenated in the bloodstream they retain a hypoxia-induced cancer stem cell-like phenotype that persists and promotes resistance and eventually recurrence. Full article

(This article belongs to the Special Issue Hypoxia and Cancer: From Bench to Bedside)

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18 pages, 1832 KiB

Open AccessArticle

Impact of Hypoxia on Relative Biological Effectiveness and Oxygen Enhancement Ratio for a 62-MeV Therapeutic Proton Beam

by Chun-Chieh Chan, Fang-Hsin Chen and Ya-Yun Hsiao

Cancers 2021, 13(12), 2997; https://doi.org/10.3390/cancers13122997 - 15 Jun 2021

Cited by 8 | Viewed by 2247

Abstract

This study uses the yields of double-strand breaks (DSBs) to determine the relative biological effectiveness (RBE) of proton beams, using cell survival as a biological endpoint. DSB induction is determined when cells locate at different depths (6 positions) along the track of 62 [...] Read more.

This study uses the yields of double-strand breaks (DSBs) to determine the relative biological effectiveness (RBE) of proton beams, using cell survival as a biological endpoint. DSB induction is determined when cells locate at different depths (6 positions) along the track of 62 MeV proton beams. The DNA damage yields are estimated using Monte Carlo Damage Simulation (MCDS) software. The repair outcomes are estimated using Monte Carlo excision repair (MCER) simulations. The RBE for cell survival at different oxygen concentrations is calculated using the repair-misrepair-fixation (RMF) model. Using ⁶⁰Co γ-rays (linear energy transfer (LET) = 2.4 keV/μm) as the reference radiation, the RBE for DSB induction and enzymatic DSB under aerobic condition (21% O₂) are in the range 1.0–1.5 and 1.0–1.6 along the track depth, respectively. In accord with RBE obtained from experimental data, RMF model-derived RBE values for cell survival are in the range of 1.0–3.0. The oxygen enhancement ratio (OER) for cell survival (10%) decreases from 3.0 to 2.5 as LET increases from 1.1 to 22.6 keV/μm. The RBE values for severe hypoxia (0.1% O₂) are in the range of 1.1–4.4 as LET increases, indicating greater contributions of direct effects for protons. Compared with photon therapy, the overall effect of 62 MeV proton beams results in greater cell death and is further intensified under hypoxic conditions. Full article

(This article belongs to the Special Issue Hypoxia and Cancer: From Bench to Bedside)

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Review

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26 pages, 2938 KiB

Open AccessReview

Significance of Specific Oxidoreductases in the Design of Hypoxia-Activated Prodrugs and Fluorescent Turn off–on Probes for Hypoxia Imaging

by Ewelina Janczy-Cempa, Olga Mazuryk, Agnieszka Kania and Małgorzata Brindell

Cancers 2022, 14(11), 2686; https://doi.org/10.3390/cancers14112686 - 29 May 2022

Cited by 10 | Viewed by 2784

Abstract

Hypoxia is one of the hallmarks of the tumor microenvironment and can be used in the design of targeted therapies. Cellular adaptation to hypoxic stress is regulated by hypoxia-inducible factor 1 (HIF-1). Hypoxia is responsible for the modification of cellular metabolism that can [...] Read more.

Hypoxia is one of the hallmarks of the tumor microenvironment and can be used in the design of targeted therapies. Cellular adaptation to hypoxic stress is regulated by hypoxia-inducible factor 1 (HIF-1). Hypoxia is responsible for the modification of cellular metabolism that can result in the development of more aggressive tumor phenotypes. Reduced oxygen concentration in hypoxic tumor cells leads to an increase in oxidoreductase activity that, in turn, leads to the activation of hypoxia-activated prodrugs (HAPs). The same conditions can convert a non-fluorescent compound into a fluorescent one (fluorescent turn off–on probes), and such probes can be designed to specifically image hypoxic cancer cells. This review focuses on the current knowledge about the expression and activity of oxidoreductases, which are relevant in the activation of HAPs and fluorescent imaging probes. The current clinical status of HAPs, their limitations, and ways to improve their efficacy are briefly discussed. The fluorescence probes triggered by reduction with specific oxidoreductase are briefly presented, with particular emphasis placed on those for which the correlation between the signal and enzyme expression determined with biochemical methods is achievable. Full article

(This article belongs to the Special Issue Hypoxia and Cancer: From Bench to Bedside)

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25 pages, 3934 KiB

Open AccessReview

Vitamin D and Hypoxia: Points of Interplay in Cancer

by Ioanna-Maria Gkotinakou, Ilias Mylonis and Andreas Tsakalof

Cancers 2022, 14(7), 1791; https://doi.org/10.3390/cancers14071791 - 31 Mar 2022

Cited by 3 | Viewed by 3034

Abstract

Vitamin D is a hormone that, through its action, elicits a broad spectrum of physiological responses ranging from classic to nonclassical actions such as bone morphogenesis and immune function. In parallel, many studies describe the antiproliferative, proapoptotic, antiangiogenic effects of calcitriol (the active [...] Read more.

Vitamin D is a hormone that, through its action, elicits a broad spectrum of physiological responses ranging from classic to nonclassical actions such as bone morphogenesis and immune function. In parallel, many studies describe the antiproliferative, proapoptotic, antiangiogenic effects of calcitriol (the active hormonal form) that contribute to its anticancer activity. Additionally, epidemiological data signify the inverse correlation between vitamin D levels and cancer risk. On the contrary, tumors possess several adaptive mechanisms that enable them to evade the anticancer effects of calcitriol. Such maladaptive processes are often a characteristic of the cancer microenvironment, which in solid tumors is frequently hypoxic and elicits the overexpression of Hypoxia-Inducible Factors (HIFs). HIF-mediated signaling not only contributes to cancer cell survival and proliferation but also confers resistance to anticancer agents. Taking into consideration that calcitriol intertwines with signaling events elicited by the hypoxic status cells, this review examines their interplay in cellular signaling to give the opportunity to better understand their relationship in cancer development and their prospect for the treatment of cancer. Full article

(This article belongs to the Special Issue Hypoxia and Cancer: From Bench to Bedside)

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29 pages, 1267 KiB

Open AccessEditor’s ChoiceReview

Targeting HIF-2α in the Tumor Microenvironment: Redefining the Role of HIF-2α for Solid Cancer Therapy

by Leah Davis, Matthias Recktenwald, Evan Hutt, Schuyler Fuller, Madison Briggs, Arnav Goel and Nichole Daringer

Cancers 2022, 14(5), 1259; https://doi.org/10.3390/cancers14051259 - 28 Feb 2022

Cited by 28 | Viewed by 6393

Abstract

Inadequate oxygen supply, or hypoxia, is characteristic of the tumor microenvironment and correlates with poor prognosis and therapeutic resistance. Hypoxia leads to the activation of the hypoxia-inducible factor (HIF) signaling pathway and stabilization of the HIF-α subunit, driving tumor progression. The homologous alpha [...] Read more.

Inadequate oxygen supply, or hypoxia, is characteristic of the tumor microenvironment and correlates with poor prognosis and therapeutic resistance. Hypoxia leads to the activation of the hypoxia-inducible factor (HIF) signaling pathway and stabilization of the HIF-α subunit, driving tumor progression. The homologous alpha subunits, HIF-1α and HIF-2α, are responsible for mediating the transcription of a multitude of critical proteins that control proliferation, angiogenic signaling, metastasis, and other oncogenic factors, both differentially and sequentially regulating the hypoxic response. Post-translational modifications of HIF play a central role in its behavior as a mediator of transcription, as well as the temporal transition from HIF-1α to HIF-2α that occurs in response to chronic hypoxia. While it is evident that HIF-α is highly dynamic, HIF-2α remains vastly under-considered. HIF-2α can intensify the behaviors of the most aggressive tumors by adapting the cell to oxidative stress, thereby promoting metastasis, tissue remodeling, angiogenesis, and upregulating cancer stem cell factors. The structure, function, hypoxic response, spatiotemporal dynamics, and roles in the progression and persistence of cancer of this HIF-2α molecule and its EPAS1 gene are highlighted in this review, alongside a discussion of current therapeutics and future directions. Full article

(This article belongs to the Special Issue Hypoxia and Cancer: From Bench to Bedside)

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20 pages, 1881 KiB

Open AccessReview

Current Understanding of Hypoxia in Glioblastoma Multiforme and Its Response to Immunotherapy

by Jang Hyun Park and Heung Kyu Lee

Cancers 2022, 14(5), 1176; https://doi.org/10.3390/cancers14051176 - 24 Feb 2022

Cited by 25 | Viewed by 4827

Abstract

Hypoxia is a hallmark of glioblastoma multiforme (GBM), the most aggressive cancer of the central nervous system, and is associated with multiple aspects of tumor pathogenesis. For example, hypoxia induces resistance to conventional cancer therapies and inhibits antitumor immune responses. Thus, targeting hypoxia [...] Read more.

Hypoxia is a hallmark of glioblastoma multiforme (GBM), the most aggressive cancer of the central nervous system, and is associated with multiple aspects of tumor pathogenesis. For example, hypoxia induces resistance to conventional cancer therapies and inhibits antitumor immune responses. Thus, targeting hypoxia is an attractive strategy for GBM therapy. However, traditional studies on hypoxia have largely excluded the immune system. Recently, the critical role of the immune system in the defense against multiple tumors has become apparent, leading to the development of effective immunotherapies targeting numerous cancer types. Critically, however, GBM is classified as a “cold tumor” due to poor immune responses. Thus, to improve GBM responsiveness against immunotherapies, an improved understanding of both immune function in GBM and the role of hypoxia in mediating immune responses within the GBM microenvironment is needed. In this review, we discuss the role of hypoxia in GBM from a clinical, pathological, and immunological perspective. Full article

(This article belongs to the Special Issue Hypoxia and Cancer: From Bench to Bedside)

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Other

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7 pages, 529 KiB

Open AccessCommentary

Cancer Therapeutic Targeting of Hypoxia Induced Carbonic Anhydrase IX: From Bench to Bedside

by Paul C. McDonald, Shawn C. Chafe, Claudiu T. Supuran and Shoukat Dedhar

Cancers 2022, 14(14), 3297; https://doi.org/10.3390/cancers14143297 - 06 Jul 2022

Cited by 47 | Viewed by 3050

Abstract

Carbonic Anhydrase IX (CAIX) is a major metabolic effector of tumor hypoxia and regulates intra- and extracellular pH and acidosis. Significant advances have been made recently in the development of therapeutic targeting of CAIX. These approaches include antibody-based immunotherapy, as well as use [...] Read more.

Carbonic Anhydrase IX (CAIX) is a major metabolic effector of tumor hypoxia and regulates intra- and extracellular pH and acidosis. Significant advances have been made recently in the development of therapeutic targeting of CAIX. These approaches include antibody-based immunotherapy, as well as use of antibodies to deliver toxic and radioactive payloads. In addition, a large number of small molecule inhibitors which inhibit the enzymatic activity of CAIX have been described. In this commentary, we highlight the current status of strategies targeting CAIX in both the pre-clinical and clinical space, and discuss future perspectives that leverage inhibition of CAIX in combination with additional targeted therapies to enable effective, durable approaches for cancer therapy. Full article

(This article belongs to the Special Issue Hypoxia and Cancer: From Bench to Bedside)

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