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Hypoxia and Cancer: Mechanism of Action and Potential Therapeutic Approaches...
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Hypoxia and Cancer: Mechanism of Action and Potential Therapeutic Approaches

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Oncology".

Deadline for manuscript submissions: closed (31 March 2021) | Viewed by 9217

Special Issue Editors

Prof. Dr. Massimo Nabissi

E-Mail Website
Guest Editor
1. School of Pharmacy, University of Camerino, 62032 Camerino, Italy
2. Integrative Therapy Discovery Lab, School of Pharmacy, University of Camerino, 62032 Camerino, Italy
Interests: oncology; immunotherapy; cannabinoids; chemotherapy
Special Issues, Collections and Topics in MDPI journals
Dr. Oliviero Marinelli

E-Mail Website
Guest Editor
Immunopathology Laboratory, School of Pharmacy, University of Camerino, 62032 Camerino, Italy
Interests: oncology; immunotherapy; cannabinoids; chemotherapy
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Hypoxia is one of the major stressors involved in carcinogenesis, and tumor hypoxia is one of the well-described factors that can lead to resistance to conventional chemo- and radiotherapy. The well-known mechanism of response to hypoxia involves hypoxia-inducible factors (HIFs), which are stabilized by low oxygen availability and control the expression of a large number of genes, such as those involved in cell survival, angiogenesis, glycolysis, and invasion/metastasis. An important question is how cells sense oxygen levels to coordinate different biological process during hypoxia and how these processes can be regulated to reduce the benefits that cancer obtains in a hypoxic environment. Different reports evidenced as cancer cells under a hypoxia condition activate survival pathways, DNA damage repair pathways, and developmental pathways, decreasing the efficacy of therapies. Since hypoxia is known to be a negative prognostic and predictive factor, and it is generally accepted as a major limitation for tumor control in conventional therapy resulting in a poor clinical outcome, this Special Issue will be dedicated to all those studies that will help to clarify the mechanism of hypoxia in cancer and to new potential therapeutic approaches for reducing hypoxia.

Prof. M. Ivan Nabissi
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. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. 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
  • Chemoresistance
  • Radioresistance
  • Angiogenesis
  • Invasion/metastasis
  • Tumor microenvironment

Published Papers (3 papers)

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Research

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10 pages, 1129 KiB  
Communication
Hypoxia Promotes Prostate Cancer Aggressiveness by Upregulating EMT-Activator Zeb1 and SK3 Channel Expression
by Fanny Bery, Sandy Figiel, Sana Kouba, Delphine Fontaine, Maxime Guéguinou, Marie Potier-Cartereau, Christophe Vandier, Roseline Guibon, Franck Bruyère, Gaëlle Fromont and Karine Mahéo
Int. J. Mol. Sci. 2020, 21(13), 4786; https://doi.org/10.3390/ijms21134786 - 06 Jul 2020
Cited by 19 | Viewed by 2685
Abstract
Hypoxia is a well-established feature of prostate cancer (PCa) and is associated with disease aggressiveness. The hypoxic microenvironment initiates multiple adaptive responses including epithelial-to-mesenchymal transition (EMT) and a remodeling of calcium homeostasis involved in cancer progression. In the present study, we identified a [...] Read more.
Hypoxia is a well-established feature of prostate cancer (PCa) and is associated with disease aggressiveness. The hypoxic microenvironment initiates multiple adaptive responses including epithelial-to-mesenchymal transition (EMT) and a remodeling of calcium homeostasis involved in cancer progression. In the present study, we identified a new hypoxia signaling pathway with a positive feedback loop between the EMT transcription factor Zeb1 and SK3, a Ca2+-activated K+ channel, which leads to amplifying store-operated Ca2+ entry. Zeb1 and SK3 channel were strongly upregulated by hypoxia both in vitro and ex vivo in organotypic cultures of human PCa. Taking into account the sensitivity of the SK3 channel to the membrane lipid composition, we identified lipids such as Ohmline (an alkyl ether lipid and SK3 inhibitor), linoleic acid (LA) and eicosapentaenoic acid (EPA) (fatty acids associated with indolent PCa), which were able to completely abrogate the hypoxia-induced changes in Zeb1 expression. Ultimately, better understanding of this new hypoxia-induced EMT pathway may allow to develop adjuvant therapeutic strategies, in order to control PCa aggressiveness and improve treatment outcomes. Full article
(This article belongs to the Special Issue Hypoxia and Cancer: Mechanism of Action and Potential Therapeutic Approaches )
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17 pages, 3745 KiB  
Article
Hypoxia-Induced miR-675-5p Supports β-Catenin Nuclear Localization by Regulating GSK3-β  Activity in Colorectal Cancer Cell Lines
by Laura Saieva, Maria Magdalena Barreca, Chiara Zichittella, Maria Giulia Prado, Marco Tripodi, Riccardo Alessandro and Alice Conigliaro
Int. J. Mol. Sci. 2020, 21(11), 3832; https://doi.org/10.3390/ijms21113832 - 28 May 2020
Cited by 17 | Viewed by 2488
Abstract
The reduction of oxygen partial pressure in growing tumors triggers numerous survival strategies driven by the transcription factor complex HIF1 (Hypoxia Inducible Factor-1). Recent evidence revealed that HIF1 promotes rapid and effective phenotypic changes through the induction of non-coding RNAs, whose contribution has [...] Read more.
The reduction of oxygen partial pressure in growing tumors triggers numerous survival strategies driven by the transcription factor complex HIF1 (Hypoxia Inducible Factor-1). Recent evidence revealed that HIF1 promotes rapid and effective phenotypic changes through the induction of non-coding RNAs, whose contribution has not yet been fully described. Here we investigated the role of the hypoxia-induced, long non-coding RNA H19 (lncH19) and its intragenic miRNA (miR-675-5p) into HIF1-Wnt crosstalk. During hypoxic stimulation, colorectal cancer cell lines up-regulated the levels of both the lncH19 and its intragenic miR-675-5p. Loss of expression experiments revealed that miR-675-5p inhibition, in hypoxic cells, hampered β-catenin nuclear localization and its transcriptional activity, while lncH19 silencing did not induce the same effects. Interestingly, our data revealed that miRNA inhibition in hypoxic cells restored the activity of Glycogen Synthase Kinase 3β (GSK-3β) reducing the amount of P-Ser9 kinase, thus unveiling a role of the miR-675-5p in controlling GSK-3β activity. Bioinformatics analyses highlighted the serine/threonine-protein phosphatases PPP2CA, responsible for GSK-3β activation, among the miR-675-5p targets, thus indicating the molecular mediator through which miR-675-5p may control β-catenin nuclear localization. In conclusion, here we demonstrated that the inhibition of the hypoxia-induced non-coding RNA miR-675-5p hampered the nuclear localization of β-catenin by regulating GSK-3β activity, thus proposing the miR-675-5p as a new therapeutic target for the treatment of colorectal cancer. Full article
(This article belongs to the Special Issue Hypoxia and Cancer: Mechanism of Action and Potential Therapeutic Approaches )
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Review

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31 pages, 3095 KiB  
Review
Hypoxia-Mediated Decrease of Ovarian Cancer Cells Reaction to Treatment: Significance for Chemo- and Immunotherapies
by Aleksandra Klemba, Lubomir Bodnar, Halina Was, Klaudia K. Brodaczewska, Gabriel Wcislo, Cezary A. Szczylik and Claudine Kieda
Int. J. Mol. Sci. 2020, 21(24), 9492; https://doi.org/10.3390/ijms21249492 - 14 Dec 2020
Cited by 24 | Viewed by 3538
Abstract
Hypoxia, a common factor ruling the microenvironment composition, leads to tumor progression. In this hypoxic context, cytokines and cells cooperate to favor cancer development and metastasis. Tumor hypoxia is heterogeneously distributed. Oxygen gradients depend on the vicinity, functionality of blood vessels, and oxygen [...] Read more.
Hypoxia, a common factor ruling the microenvironment composition, leads to tumor progression. In this hypoxic context, cytokines and cells cooperate to favor cancer development and metastasis. Tumor hypoxia is heterogeneously distributed. Oxygen gradients depend on the vicinity, functionality of blood vessels, and oxygen ability to diffuse into surrounding tissues. Thus, the vasculature state modulates the microenvironment of the tumor cells. Cells sense and react to small variations in oxygen tension, which explains the lack of tumor cells’ unicity in their reaction to drugs. Ovarian cancers are highly hypoxia-dependent, ascites worsening the access to oxygen, in their reactions to both chemotherapy and new immunotherapy. Consequently, hypoxia affects the results of immunotherapy, and is thus, crucial for the design of treatments. Controlling key immunosuppressive factors and receptors, as well as immune checkpoint molecule expression on tumor, immune and stromal cells, hypoxia induces immunosuppression. Consequently, new approaches to alleviate hypoxia in the tumor microenvironment bring promises for ovarian cancer immunotherapeutic strategies. This review focuses on the effects of hypoxia in the microenvironment and its consequences on tumor treatments. This opens the way to innovative combined treatments to the advantage of immunotherapy outcome in ovarian cancers. Full article
(This article belongs to the Special Issue Hypoxia and Cancer: Mechanism of Action and Potential Therapeutic Approaches )
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