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Cancers
Special Issues
Metabolic Networks in Cancer
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Metabolic Networks in Cancer

A special issue of Cancers (ISSN 2072-6694). This special issue belongs to the section "Tumor Microenvironment".

Deadline for manuscript submissions: closed (31 December 2021) | Viewed by 15882

Special Issue Editor

Dr. Angela M. Otto

E-Mail Website
Guest Editor
Munich School of Bioengineering, Technical University of Munich, 85748 Garching, Germany
Interests: cancer cell biology; chemotherapeutic drug screening; metabolomics; metabolic imaging; tumor cell models; tumor microenvironment

Special Issue Information

Dear colleagues,

To enhance the translational understanding of the role of metabolic networks in cancer, I would like to invite you to contribute your work to this Special Issue set out to collect new advances in and perspectives on this topic.

Cancer constitutes a system of tumor cells with a high metabolic plasticity in a dynamic microenvironment, including gradients of nutrients, pH, and pO2, as well as the interaction of different cell types. This plasticity requires the modulation of a metabolic network consisting of metabolites, biochemical pathways, and regulatory nodes.

The dynamic interactions of such metabolic modules can occur at different levels—namely, 1) in the extracellular context by tumors and their associated cells, such as immune, stem, and stromal cells, which release, sense, or use specific metabolites in the tumor; 2) at the intracellular level by the modulation of different metabolic pathways of the individual cell through the dynamic interplay of metabolites and enzymes. Within the scope of the cell’s genetic program, the resulting metabolic network regulates the growth, survival, and cellular destiny of specific functions, stemness, or metastatic processes.

Understanding the mechanisms underlying different metabolic networks is thus of translational importance for the tumor prognosis, dietary influences, and chemo-therapeutic responses of cells constituting the tumor. It is also essential for evaluating information obtained with metabolic diagnostics and imaging in the clinical setting.

This Special Issue aims to highlight these aspects at different cellular and preclinical levels. Original papers and reviews based on biochemistry, cell biology, molecular genetics, and modeling applied to cancers with their associated cells and also in a preclinical setting are highly welcomed.

Dr. Angela M. Otto
Guest Editor

Keywords

  • Metabolic heterogeneity in a tumor microenvironment
  • Metabolic crosstalk of different cell types in cancer
  • Cellular metabolomics and metabolic modeling
  • Metabolic imaging techniques of cancers
  • Metabolic interactions with chemotherapeutic drugs

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.

Published Papers (4 papers)

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Research

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26 pages, 4989 KiB  
Article
Conversion of Hyperpolarized [1-13C]Pyruvate in Breast Cancer Cells Depends on Their Malignancy, Metabolic Program and Nutrient Microenvironment
by Martin Grashei, Philipp Biechl, Franz Schilling and Angela M. Otto
Cancers 2022, 14(7), 1845; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers14071845 - 06 Apr 2022
Cited by 9 | Viewed by 2855
Abstract
Hyperpolarized magnetic resonance spectroscopy (MRS) is a technology for characterizing tumors in vivo based on their metabolic activities. The conversion rates (kpl) of hyperpolarized [1-13C]pyruvate to [1-13C]lactate depend on monocarboxylate transporters (MCT) and lactate dehydrogenase (LDH); [...] Read more.
Hyperpolarized magnetic resonance spectroscopy (MRS) is a technology for characterizing tumors in vivo based on their metabolic activities. The conversion rates (kpl) of hyperpolarized [1-13C]pyruvate to [1-13C]lactate depend on monocarboxylate transporters (MCT) and lactate dehydrogenase (LDH); these are also indicators of tumor malignancy. An unresolved issue is how glucose and glutamine availability in the tumor microenvironment affects metabolic characteristics of the cancer and how this relates to kpl-values. Two breast cancer cells of different malignancy (MCF-7, MDA-MB-231) were cultured in media containing defined combinations of low glucose (1 mM; 2.5 mM) and glutamine (0.1 mM; 1 mM) and analyzed for pyruvate uptake, intracellular metabolite levels, LDH and pyruvate kinase activities, and 13C6-glucose-derived metabolomics. The results show variability of kpl with the different glucose/glutamine conditions, congruent with glycolytic activity, but not with LDH activity or the Warburg effect; this suggests metabolic compartmentation. Remarkably, kpl-values were almost two-fold higher in MCF-7 than in the more malignant MDA-MB-231 cells, the latter showing a higher flux of 13C-glucose-derived pyruvate to the TCA-cycle metabolites 13C2-citrate and 13C3-malate, i.e., pyruvate decarboxylation and carboxylation, respectively. Thus, MRS with hyperpolarized [1-13C-pyruvate] is sensitive to both the metabolic program and the nutritional state of cancer cells. Full article
(This article belongs to the Special Issue Metabolic Networks in Cancer)
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30 pages, 5494 KiB  
Article
Dual Effect of Combined Metformin and 2-Deoxy-D-Glucose Treatment on Mitochondrial Biogenesis and PD-L1 Expression in Triple-Negative Breast Cancer Cells
by Jernej Repas, Mateja Zupin, Maja Vodlan, Peter Veranič, Boris Gole, Uroš Potočnik and Mojca Pavlin
Cancers 2022, 14(5), 1343; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers14051343 - 05 Mar 2022
Cited by 8 | Viewed by 5196
Abstract
Metformin and 2-deoxy-D-glucose (2DG) exhibit multiple metabolic and immunomodulatory anti-cancer effects, such as suppressed proliferation or PD-L1 expression. Their combination or 2DG alone induce triple-negative breast cancer (TNBC) cell detachment, but their effects on mitochondria, crucial for anchorage-independent growth and metastasis formation, have [...] Read more.
Metformin and 2-deoxy-D-glucose (2DG) exhibit multiple metabolic and immunomodulatory anti-cancer effects, such as suppressed proliferation or PD-L1 expression. Their combination or 2DG alone induce triple-negative breast cancer (TNBC) cell detachment, but their effects on mitochondria, crucial for anchorage-independent growth and metastasis formation, have not yet been evaluated. In the present study, we explored the effects of metformin, 2DG and their combination (metformin + 2DG) on TNBC cell mitochondria in vitro. Metformin + 2DG increased mitochondrial mass in TNBC cells. This was associated with an increased size but not number of morphologically normal mitochondria and driven by the induction of mitochondrial biogenesis rather than suppressed mitophagy. 2DG and metformin + 2DG strongly induced the unfolded protein response by inhibiting protein N-glycosylation. Together with adequate energy stress, this was one of the possible triggers of mitochondrial enlargement. Suppressed N-glycosylation by 2DG or metformin + 2DG also caused PD-L1 deglycosylation and reduced surface expression in MDA-MB-231 cells. PD-L1 was increased in low glucose and normalized by both drugs. 2DG and metformin + 2DG reduced PD-1 expression in Jurkat cells beyond the effects on activation, while cytokine secretion was mostly preserved. Despite increasing mitochondrial mass in TNBC cells, metformin and 2DG could therefore potentially be used as an adjunct therapy to improve anti-tumor immunity in TNBC. Full article
(This article belongs to the Special Issue Metabolic Networks in Cancer)
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15 pages, 2439 KiB  
Article
MCT1 Is a New Prognostic Biomarker and Its Therapeutic Inhibition Boosts Response to Temozolomide in Human Glioblastoma
by Vera Miranda-Gonçalves, Céline S. Gonçalves, Sara Granja, Joana Vieira de Castro, Rui M. Reis, Bruno M. Costa and Fátima Baltazar
Cancers 2021, 13(14), 3468; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers13143468 - 11 Jul 2021
Cited by 13 | Viewed by 3319
Abstract
Background: Glioblastomas (GBMs) present remarkable metabolism reprograming, in which many cells display the “Warburg effect”, with the production of high levels of lactate that are extruded to the tumour microenvironment by monocarboxylate transporters (MCTs). We described previously that MCT1 is up-regulated in human [...] Read more.
Background: Glioblastomas (GBMs) present remarkable metabolism reprograming, in which many cells display the “Warburg effect”, with the production of high levels of lactate that are extruded to the tumour microenvironment by monocarboxylate transporters (MCTs). We described previously that MCT1 is up-regulated in human GBM samples, and MCT1 inhibition decreases glioma cell viability and aggressiveness. In the present study, we aimed to unveil the role of MCT1 in GBM prognosis and to explore it as a target for GBM therapy in vivo. Methods: MCT1 activity and protein expression were inhibited by AR-C155858 and CHC compounds or stable knockdown with shRNA, respectively, to assess in vitro and in vivo the effects of MCT1 inhibition and on response of GBM to temozolomide. Survival analyses on GBM patient cohorts were performed using Cox regression and Log-rank tests. Results: High levels of MCT1 expression were revealed to be a predictor of poor prognosis in multiple cohorts of GBM patients. Functionally, in U251 GBM cells, MCT1 stable knockdown decreased glucose consumption and lactate efflux, compromising the response to the MCT1 inhibitors CHC and AR-C155858. MCT1 knockdown significantly increased the survival of orthotopic GBM intracranial mice models when compared to their control counterparts. Furthermore, MCT1 downregulation increased the sensitivity to temozolomide in vitro and in vivo, resulting in significantly longer mice survival. Conclusions: This work provides first evidence for MCT1 as a new prognostic biomarker of GBM survival and further supports MCT1 targeting, alone or in combination with classical chemotherapy, for the treatment of GBM. Full article
(This article belongs to the Special Issue Metabolic Networks in Cancer)
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Review

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24 pages, 1440 KiB  
Review
Metabolic Regulation of Epigenetic Modifications and Cell Differentiation in Cancer
by Pasquale Saggese, Assunta Sellitto, Cesar A. Martinez, Giorgio Giurato, Giovanni Nassa, Francesca Rizzo, Roberta Tarallo and Claudio Scafoglio
Cancers 2020, 12(12), 3788; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers12123788 - 16 Dec 2020
Cited by 20 | Viewed by 3586
Abstract
Metabolic reprogramming is a hallmark of cancer, with consistent rewiring of glucose, glutamine, and mitochondrial metabolism. While these metabolic alterations are adequate to meet the metabolic needs of cell growth and proliferation, the changes in critical metabolites have also consequences for the regulation [...] Read more.
Metabolic reprogramming is a hallmark of cancer, with consistent rewiring of glucose, glutamine, and mitochondrial metabolism. While these metabolic alterations are adequate to meet the metabolic needs of cell growth and proliferation, the changes in critical metabolites have also consequences for the regulation of the cell differentiation state. Cancer evolution is characterized by progression towards a poorly differentiated, stem-like phenotype, and epigenetic modulation of the chromatin structure is an important prerequisite for the maintenance of an undifferentiated state by repression of lineage-specific genes. Epigenetic modifiers depend on intermediates of cellular metabolism both as substrates and as co-factors. Therefore, the metabolic reprogramming that occurs in cancer likely plays an important role in the process of the de-differentiation characteristic of the neoplastic process. Here, we review the epigenetic consequences of metabolic reprogramming in cancer, with particular focus on the role of mitochondrial intermediates and hypoxia in the regulation of cellular de-differentiation. We also discuss therapeutic implications. Full article
(This article belongs to the Special Issue Metabolic Networks in Cancer)
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