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The Emerging Hallmarks of Cancer Metabolism for Precision Oncology Applications

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A special issue of Cancers (ISSN 2072-6694). This special issue belongs to the section "Molecular Cancer Biology".

Deadline for manuscript submissions: closed (31 December 2021) | Viewed by 19070

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Special Issue Editors

Prof. Dr. Anna Dubrovska

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Guest Editor

1. OncoRay - National Center for Radiation Research in Oncology, Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, Helmholtz-Zentrum Dresden - Rossendorf, Institute of Radiooncology - OncoRay, German Cancer Research Center (DKFZ), Heidelberg, Germany
2. German Cancer Consortium (DKTK), Partner Site Dresden, Germany, 01309 Dresden, Germany
Interests: biomarkers for the individualized radiotherapy; metabolic biomarkers for cancers; cancer stem cells; molecular mechanisms of cancer radioresistance; therapy-induced tumor reprogramming; tumor radiosensitization

Prof. Dr. Verena Jendrossek

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Guest Editor

Institute of Cell Biology (Cancer Research), University Hospital Essen, Virchowstrasse 173, 45122 Essen, Germany
Interests: intrinsic and microenvironment-mediated radiation resistance; cell and tissue responses to ionizing radiation; stress-induced metabolic reprogramming; biomarkers for radiosensitivity; combinatorial treatments for tumor radiosensitization and normal tissue protection
Special Issues, Collections and Topics in MDPI journals

Prof. Dr. Leoni Kunz-Schughart

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Guest Editor

OncoRay—National Center for Radiation Research in Oncology, Faculty of Medicine and University Hospital Carl Gustav Carus, TU Dresden and Helmholtz-Zentrum Dresden–Rossendorf, Dresden, Germany, and National Center for Tumor Diseases (NCT), Dresden site, Germany
Interests: tumor pathophysiology; tumor micromilieu and cellular environment; tumor cell metabolism; metabolic targeting and co-targeting; 3-D assays; photon and proton therapy

Special Issue Information

Dear Colleagues,

The ultimate goal of precision oncology is a more tailored and individualized treatment for cancer patients. However, reliable predictive biomarkers of therapy response along with effective treatments with low toxicity are still rare for many types of tumors. Thus, new strategies for personalized medicine including biomarkers for patient stratification, as well as novel targets for combinatorial treatment regimes need to be developed for improving the prognosis of cancer patients suffering from common cancer types with high rates of local recurrence or metastasis. Reprogramming of cellular metabolism is one of the major hallmarks of cancer cells that plays an important role in tumor initiation and progression, as well as in therapy resistance and tumor immune escape. Thus, biochemical and molecular metabolic features of tumors might serve as specific biomarkers for identifying patients who will most likely benefit from a given therapy. Furthermore, targeting tumor metabolism emerged as a novel, highly potent avenue to enhance the efficacy of conventional anti-cancer treatments such as radio- and chemotherapy as well as immunotherapy approaches. This Special Issue is aimed at summarizing the emerging hallmarks of cancer metabolism across major tumor types and the prospects for clinical development of anti-metabolic therapy and reliable biomarkers to optimize treatment decisions.

Prof. Dr. Anna Dubrovska
Prof. Dr. Verena Jendrossek
Prof. Dr. Leoni Kunz-Schughart
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. Cancers 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 2900 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

metabolic reprogramming
metabolic immune-adaptations
metabolic co-targeting
metabolic biomarkers

Published Papers (6 papers)

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Research

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19 pages, 2897 KiB

Open AccessArticle

Intracellular Amplifiers of Reactive Oxygen Species Affecting Mitochondria as Radiosensitizers

by Hong-Gui Xu, Viktor Reshetnikov, Marit Wondrak, Lisa Eckhardt, Leoni A. Kunz-Schughart, Christina Janko, Rainer Tietze, Christoph Alexiou, Hannes Borchardt, Achim Aigner, Wenjie Gong, Michael Schmitt, Leopold Sellner, Steffen Daum, Hülya Gizem Özkan and Andriy Mokhir

Cancers 2022, 14(1), 208; https://doi.org/10.3390/cancers14010208 - 31 Dec 2021

Cited by 4 | Viewed by 2501

Abstract

Radiotherapy (RT) efficacy can be improved by using radiosensitizers, i.e., drugs enhancing the effect of ionizing radiation (IR). One of the side effects of RT includes damage of normal tissue in close proximity to the treated tumor. This problem can be solved by applying cancer specific radiosensitizers. N-Alkylaminoferrocene-based (NAAF) prodrugs produce reactive oxygen species (ROS) in cancer cells, but not in normal cells. Therefore, they can potentially act as cancer specific radiosensitizers. However, early NAAF prodrugs did not exhibit this property. Since functional mitochondria are important for RT resistance, we assumed that NAAF prodrugs affecting mitochondria in parallel with increasing intracellular ROS can potentially exhibit synergy with RT. We applied sequential Cu⁺-catalyzed alkyne-azide cycloadditions (CuAAC) to obtain a series of NAAF derivatives with the goal of improving anticancer efficacies over already existing compounds. One of the obtained prodrugs (2c) exhibited high anticancer activity with IC₅₀ values in the range of 5–7.1 µM in human ovarian carcinoma, Burkitt’s lymphoma, pancreatic carcinoma and T-cell leukemia cells retained moderate water solubility and showed cancer specificity. 2c strongly affects mitochondria of cancer cells, leading to the amplification of mitochondrial and total ROS production and thus causing cell death via necrosis and apoptosis. We observed that 2c acts as a radiosensitizer in human head and neck squamous carcinoma cells. This is the first demonstration of a synergy between the radiotherapy and NAAF-based ROS amplifiers. Full article

(This article belongs to the Special Issue The Emerging Hallmarks of Cancer Metabolism for Precision Oncology Applications)

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23 pages, 5836 KiB

Open AccessArticle

Colorectal Cancer Progression Is Potently Reduced by a Glucose-Free, High-Protein Diet: Comparison to Anti-EGFR Therapy

by Kerstin Skibbe, Ann-Kathrin Brethack, Annika Sünderhauf, Mohab Ragab, Annika Raschdorf, Maren Hicken, Heidi Schlichting, Joyce Preira, Jennifer Brandt, Darko Castven, Bandik Föh, René Pagel, Jens U. Marquardt, Christian Sina and Stefanie Derer

Cancers 2021, 13(22), 5817; https://doi.org/10.3390/cancers13225817 - 19 Nov 2021

Cited by 4 | Viewed by 2607

Abstract

To enable rapid proliferation, colorectal tumor cells up-regulate epidermal growth factor receptor (EGFR) signaling and aerobic glycolysis, resulting in substantial lactate release into the tumor microenvironment and impaired anti-tumor immune responses. We hypothesized that a nutritional intervention designed to reduce aerobic glycolysis may boost the EGFR-directed antibody (Ab)-based therapy of pre-existing colitis-driven colorectal carcinoma (CRC). CRC development was induced by azoxymethane (AOM) and dextran sodium sulfate (DSS) administration to C57BL/6 mice. AOM/DSS-treated mice were fed a glucose-free, high-protein diet (GFHPD) or an isoenergetic control diet (CD) in the presence or absence of an i.p. injection of an anti-EGFR mIgG2a or respective controls. AOM/DSS-treated mice on a GFHPD displayed a reduced systemic glucose metabolism associated with reduced oxidative phosphorylation (OXPHOS) complex IV expression and diminished tumor loads. Comparable but not additive to an anti-EGFR-Ab therapy, the GFHPD was accompanied by enhanced tumoral goblet cell differentiation and decreased colonic PD-L1 and splenic CD3ε, as well as PD-1 immune checkpoint expression. In vitro, glucose-free, high-amino acid culture conditions reduced proliferation but improved goblet cell differentiation of murine and human CRC cell lines MC-38 and HT29-MTX in combination with down-regulation of PD-L1 expression. We here found GFHPD to systemically dampen glycolysis activity, thereby reducing CRC progression with a similar efficacy to EGFR-directed antibody therapy. Full article

(This article belongs to the Special Issue The Emerging Hallmarks of Cancer Metabolism for Precision Oncology Applications)

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15 pages, 2434 KiB

Open AccessArticle

Targeting Cancer Metabolism Breaks Radioresistance by Impairing the Stress Response

by Melissa Schwab, Katharina Thunborg, Omid Azimzadeh, Christine von Toerne, Caroline Werner, Maxim Shevtsov, Tommaso Di Genio, Masa Zdralevic, Jacques Pouyssegur, Kathrin Renner, Marina Kreutz and Gabriele Multhoff

Cancers 2021, 13(15), 3762; https://doi.org/10.3390/cancers13153762 - 27 Jul 2021

Cited by 16 | Viewed by 3091

Abstract

The heightened energetic demand increases lactate dehydrogenase (LDH) activity, the corresponding oncometabolite lactate, expression of heat shock proteins (HSPs) and thereby promotes therapy resistance in many malignant tumor cell types. Therefore, we assessed the coregulation of LDH and the heat shock response with respect to radiation resistance in different tumor cells (B16F10 murine melanoma and LS174T human colorectal adenocarcinoma). The inhibition of LDH activity by oxamate or GNE-140, glucose deprivation and LDHA/B double knockout (LDH⁻^/⁻) in B16F10 and LS174T cells significantly diminish tumor growth; ROS production and the cytosolic expression of different HSPs, including Hsp90, Hsp70 and Hsp27 concomitant with a reduction of heat shock factor 1 (HSF1)/pHSF1. An altered lipid metabolism mediated by a LDHA/B double knockout results in a decreased presence of the Hsp70-anchoring glycosphingolipid Gb3 on the cell surface of tumor cells, which, in turn, reduces the membrane Hsp70 density and increases the extracellular Hsp70 levels. Vice versa, elevated extracellular lactate/pyruvate concentrations increase the membrane Hsp70 expression in wildtype tumor cells. Functionally, an inhibition of LDH causes a generalized reduction of cytosolic and membrane-bound HSPs in tumor cells and significantly increases the radiosensitivity, which is associated with a G2/M arrest. We demonstrate that targeting of the lactate/pyruvate metabolism breaks the radioresistance by impairing the stress response. Full article

(This article belongs to the Special Issue The Emerging Hallmarks of Cancer Metabolism for Precision Oncology Applications)

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20 pages, 15992 KiB

Open AccessArticle

Identification of Pre-Diagnostic Metabolic Patterns for Glioma Using Subset Analysis of Matched Repeated Time Points

by Pär Jonsson, Henrik Antti, Florentin Späth, Beatrice Melin and Benny Björkblom

Cancers 2020, 12(11), 3349; https://doi.org/10.3390/cancers12113349 - 12 Nov 2020

Cited by 11 | Viewed by 2431

Abstract

Here, we present a strategy for early molecular marker pattern detection—Subset analysis of Matched Repeated Time points (SMART)—used in a mass-spectrometry-based metabolomics study of repeated blood samples from future glioma patients and their matched controls. The outcome from SMART is a predictive time span when disease-related changes are detectable, defined by time to diagnosis and time between longitudinal sampling, and visualization of molecular marker patterns related to future disease. For glioma, we detect significant changes in metabolite levels as early as eight years before diagnosis, with longitudinal follow up within seven years. Elevated blood plasma levels of myo-inositol, cysteine, N-acetylglucosamine, creatinine, glycine, proline, erythronic-, 4-hydroxyphenylacetic-, uric-, and aceturic acid were particularly evident in glioma cases. We use data simulation to ensure non-random events and a separate data set for biomarker validation. The latent biomarker, consisting of 15 interlinked and significantly altered metabolites, shows a strong correlation to oxidative metabolism, glutathione biosynthesis and monosaccharide metabolism, linked to known early events in tumor development. This study highlights the benefits of progression pattern analysis and provide a tool for the discovery of early markers of disease. Full article

(This article belongs to the Special Issue The Emerging Hallmarks of Cancer Metabolism for Precision Oncology Applications)

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17 pages, 3362 KiB

Open AccessArticle

Disruption of Glycogen Utilization Markedly Improves the Efficacy of Carboplatin against Preclinical Models of Clear Cell Ovarian Carcinoma

by Tashbib Khan, Yaowu He, Thomas Kryza, Brittney S. Harrington, Jennifer H. Gunter, Mitchell A. Sullivan, Tahleesa Cuda, Rebecca Rogers, Claire M. Davies, Amy Broomfield, Madeline Gough, Andy C. Wu, Thomas McGann, S. John Weroha, Paul Haluska, Josephine M. Forbes, Jane E. Armes, Sinead C. Barry, Jermaine I. Coward, Nisha Jagasia, Naven Chetty, Cameron E. Snell, Rohan Lourie, Lewis C. Perrin and John D. Hooper Show full author list Hide full author list

Cancers 2020, 12(4), 869; https://doi.org/10.3390/cancers12040869 - 03 Apr 2020

Cited by 5 | Viewed by 4969

Abstract

High stage and recurrent ovarian clear cell carcinoma (OCC) are associated with poor prognosis and resistance to chemotherapy. A distinguishing histological feature of OCC is abundant cytoplasmic stores of glucose, in the form of glycogen, that can be mobilized for cellular metabolism. Here, we report the effect on preclinical models of OCC of disrupting glycogen utilization using the glucose analogue 2-deoxy-D-glucose (2DG). At concentrations significantly lower than previously reported for other cancers, 2DG markedly improves the efficacy in vitro of carboplatin chemotherapy against chemo-sensitive TOV21G and chemo-resistant OVTOKO OCC cell lines, and this is accompanied by the depletion of glycogen. Of note, 2DG doses—of more than 10-fold lower than previously reported for other cancers—significantly improve the efficacy of carboplatin against cell line and patient-derived xenograft models in mice that mimic the chemo-responsiveness of OCC. These findings are encouraging, in that 2DG doses, which are substantially lower than previously reported to cause adverse events in cancer patients, can safely and significantly improve the efficacy of carboplatin against OCC. Our results thus justify clinical trials to evaluate whether low dose 2DG improves the efficacy of carboplatin in OCC patients. Full article

(This article belongs to the Special Issue The Emerging Hallmarks of Cancer Metabolism for Precision Oncology Applications)

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Review

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19 pages, 2389 KiB

Open AccessReview

Methylosystem for Cancer Sieging Strategy

by Shotaro Tatekawa, Ken Ofusa, Ryota Chijimatsu, Andrea Vecchione, Keisuke Tamari, Kazuhiko Ogawa and Hideshi Ishii

Cancers 2021, 13(20), 5088; https://doi.org/10.3390/cancers13205088 - 12 Oct 2021

Cited by 7 | Viewed by 2130

Abstract

As cancer is a genetic disease, methylation defines a biologically malignant phenotype of cancer in the association of one-carbon metabolism-dependent S-adenosylmethionine (SAM) as a methyl donor in each cell. Methylated substances are involved in intracellular metabolism, but via intercellular communication, some of these can also be secreted to affect other substances. Although metabolic analysis at the single-cell level remains challenging, studying the “methylosystem” (i.e., the intercellular and intracellular communications of upstream regulatory factors and/or downstream effectors that affect the epigenetic mechanism involving the transfer of a methyl group from SAM onto the specific positions of nucleotides or other metabolites in the tumor microenvironment) and tracking these metabolic products are important research tasks for understanding spatial heterogeneity. Here, we discuss and highlight the involvement of RNA and nicotinamide, recently emerged targets, in SAM-producing one-carbon metabolism in cancer cells, cancer-associated fibroblasts, and immune cells. Their significance and implications will contribute to the discovery of efficient methods for the diagnosis of and therapeutic approaches to human cancer. Full article

(This article belongs to the Special Issue The Emerging Hallmarks of Cancer Metabolism for Precision Oncology Applications)

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