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Cancers
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Metabolic Dysfunction in Cancer
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Metabolic Dysfunction 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 January 2022) | Viewed by 20272

Special Issue Editors

Prof. Dr. Arif Hussain

E-Mail Website
Guest Editor
1. Department of Medicine, Department of Pathology and Department of Biochemistry & Molecular Biology, The Marlene & Stewart Greenebaum Comprehensive Cancer Center, University of Maryland School of Medicine, Baltimore, MD, USA
2. The Veteran's Health Administration Research & Development Service, 655 W Baltimore Street, Baltimore, MD 21201, USA
Interests: drug resistance; androgen signaling; genitourinary cancers; cell death pathways; metabolism in cancer
Prof. Dr. Antonino Passaniti

E-Mail Website
Guest Editor
Greenebaum National Cancer Institute Comprehensive Cancer Center, Department of Pathology, University of Maryland School of Medicine, 655 West Baltimore St., Bressler Research Bldg., Rm. 9-045, Baltimore, MD 21201, USA
Interests: breast cancer; transcriptional regulation; angiogenesis; drug development

Special Issue Information

Dear Colleagues,

Nutrient metabolism and energy utilization are essential processes in organ development, physiological function, and normal tissue homeostasis. However, major alterations in basic metabolism can occur with age, cancer initiation, and cancer progression. Some of these metabolic dysfunctions, described by Otto Warburg, involve reprogramming of  glycolysis (Warburg effect) and oxidative phosphorylation (mitochondrial glucose oxidation) by tumor cells. There is considerable heterogeneity associated with these alterations, which depend on the specific primary tumor, the cancer stem cell components of the tumor, proliferative invasive versus dormant circulating tumor cells, and changes in the tumor microenvironment. Additionally, the tumor epithelial and mesenchymal components are in constant flux that modulate metastatic potential and drug resistance, thus contributing to further metabolic heterogeneity.

Glucose, in particular, plays distinct roles in carcinogenesis depending on differences between catabolic (energy generation) and anabolic (biosynthetic) metabolism, which can also contribute to anti-oxidant defenses and cell survival. Other substrates for these metabolic pathways may include amino acids (such as glutamine metabolism controlled by c-Myc) and lipid synthesis and oxidation (through acetyl-CoA and citrate metabolism). The unique roles of metabolism in specific cancers can also generate oncogenic intermediates and metabolites (IDH1/2 regulation and 2-hydroxyglutarate) that may lend to more directed and improved cancer targeting.

Inhibiting metabolism to prevent or treat cancer progression focuses on targeting metabolic vulnerabilities. Some of these include the oncogenic transcription factors that regulate metabolism (Hif1a, c-Myc) or strategies to restore expression of tumor suppressors (p53, SIRT6) to help normalize metabolism. Additional primary targets include the metabolic enzymes that control the nodal or branch points (rate-limiting steps) in cancer metabolism (pyruvate kinase; lactate dehydrogenase) or the signaling components that regulate downstream effectors of metabolic regulation (MAPK, Akt). The focus of the research on metabolic regulation is to acquire a comprehensive understanding that can guide further clinical development of effective cancer therapies and minimize potential toxicities to normal tissues and organs. 

This Special Issue will highlight the current concepts of metabolic regulation in cancer biology and approaches directed at developing treatments for metabolic dysfunction to prevent or treat tumor growth, progression, drug resistance, and metastasis.

Prof. Dr. Arif Hussain
Prof. Dr. Antonino Passaniti
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 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

  • Tumor metabolism and dysfunction
  • Metabolic vulnerabilities
  • Targeted tumor metabolism
  • Microenvironment
  • Glucose catabolism and anabolism
  • Glucose transporters
  • Mitochondrial oxidative phosphorylation

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Published Papers (5 papers)

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Research

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18 pages, 30049 KiB  
Article
Reduced Expression of Annexin A6 Induces Metabolic Reprogramming That Favors Rapid Fatty Acid Oxidation in Triple-Negative Breast Cancer Cells
by Stephen D. Williams and Amos M. Sakwe
Cancers 2022, 14(5), 1108; https://doi.org/10.3390/cancers14051108 - 22 Feb 2022
Cited by 4 | Viewed by 2538
Abstract
The ability of cancer cells to alter their metabolism is one of the major mechanisms underlying rapid tumor progression and/or therapeutic resistance in solid tumors, including the hard-to-treat triple-negative breast cancer (TNBC) subtype. Here, we assessed the contribution of the tumor suppressor, Annexin [...] Read more.
The ability of cancer cells to alter their metabolism is one of the major mechanisms underlying rapid tumor progression and/or therapeutic resistance in solid tumors, including the hard-to-treat triple-negative breast cancer (TNBC) subtype. Here, we assessed the contribution of the tumor suppressor, Annexin A6 (AnxA6), in the metabolic adaptation of basal-like (AnxA6-low) versus mesenchymal-like (AnxA6-high), as well as in lapatinib-resistant TNBC cells. Using model basal-like and mesenchymal-like TNBC cell lines, we show that TNBC cells also exhibit metabolic heterogeneity. The downregulation of AnxA6 in TNBC cells generally attenuated mitochondrial respiration, glycolytic flux, and cellular ATP production capacity resulting in a quiescent metabolic phenotype. We also show that AnxA6 depletion in mesenchymal-like TNBC cells was associated with a rapid uptake and mitochondrial fatty acid oxidation and diminished lipid droplet accumulation and altered the lipogenic metabolic phenotype of these cells to a lypolytic metabolic phenotype. The overexpression or chronic lapatinib-induced upregulation of AnxA6 in AnxA6-low TNBC cells reversed the quiescent/lypolytic phenotype to a more lipogenic/glycolytic phenotype with gluconeogenic precursors as additional metabolites. Collectively, these data suggest that the expression status of AnxA6 in TNBC cells underlies distinct metabolic adaptations of basal-like and mesenchymal-like TNBC subsets in response to cellular stress and/or therapeutic intervention and suggest AnxA6 as a biomarker for metabolic subtyping of TNBC subsets. Full article
(This article belongs to the Special Issue Metabolic Dysfunction in Cancer)
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15 pages, 5038 KiB  
Article
Myeloid-Specific Acly Deletion Alters Macrophage Phenotype In Vitro and In Vivo without Affecting Tumor Growth
by Kyra E. de Goede, Sanne G. S. Verberk, Jeroen Baardman, Karl J. Harber, Yvette van Kooyk, Menno P. J. de Winther, Sjoerd T. T. Schetters and Jan Van den Bossche
Cancers 2021, 13(12), 3054; https://doi.org/10.3390/cancers13123054 - 19 Jun 2021
Cited by 5 | Viewed by 4102
Abstract
Cancer cells rely on ATP-citrate lyase (Acly)-derived acetyl-CoA for lipid biogenesis and proliferation, marking Acly as a promising therapeutic target. However, inhibitors may have side effects on tumor-associated macrophages (TAMs). TAMs are innate immune cells abundant in the tumor microenvironment (TME) and play [...] Read more.
Cancer cells rely on ATP-citrate lyase (Acly)-derived acetyl-CoA for lipid biogenesis and proliferation, marking Acly as a promising therapeutic target. However, inhibitors may have side effects on tumor-associated macrophages (TAMs). TAMs are innate immune cells abundant in the tumor microenvironment (TME) and play central roles in tumorigenesis, progression and therapy response. Since macrophage Acly deletion was previously shown to elicit macrophages with increased pro- and decreased anti-inflammatory responses in vitro, we hypothesized that Acly targeting may elicit anti-tumor responses in macrophages, whilst inhibiting cancer cell proliferation. Here, we used a myeloid-specific knockout model to validate that absence of Acly decreases IL-4-induced macrophage activation. Using two distinct tumor models, we demonstrate that Acly deletion slightly alters tumor immune composition and TAM phenotype in a tumor type-dependent manner without affecting tumor growth. Together, our results indicate that targeting Acly in macrophages does not have detrimental effects on myeloid cells. Full article
(This article belongs to the Special Issue Metabolic Dysfunction in Cancer)
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23 pages, 12113 KiB  
Article
Integrated Metabolomics and Transcriptomics Analysis of Monolayer and Neurospheres from Established Glioblastoma Cell Lines
by Joana Peixoto, Sudha Janaki-Raman, Lisa Schlicker, Werner Schmitz, Susanne Walz, Alina M. Winkelkotte, Christel Herold-Mende, Paula Soares, Almut Schulze and Jorge Lima
Cancers 2021, 13(6), 1327; https://doi.org/10.3390/cancers13061327 - 16 Mar 2021
Cited by 7 | Viewed by 3322
Abstract
Altered metabolic processes contribute to carcinogenesis by modulating proliferation, survival and differentiation. Tumours are composed of different cell populations, with cancer stem-like cells being one of the most prominent examples. This specific pool of cells is thought to be responsible for cancer growth [...] Read more.
Altered metabolic processes contribute to carcinogenesis by modulating proliferation, survival and differentiation. Tumours are composed of different cell populations, with cancer stem-like cells being one of the most prominent examples. This specific pool of cells is thought to be responsible for cancer growth and recurrence and plays a particularly relevant role in glioblastoma (GBM), the most lethal form of primary brain tumours. Here, we have analysed the transcriptome and metabolome of an established GBM cell line (U87) and a patient-derived GBM stem-like cell line (NCH644) exposed to neurosphere or monolayer culture conditions. By integrating transcriptome and metabolome data, we identified key metabolic pathways and gene signatures that are associated with stem-like and differentiated states in GBM cells, and demonstrated that neurospheres and monolayer cells differ substantially in their metabolism and gene regulation. Furthermore, arginine biosynthesis was identified as the most significantly regulated pathway in neurospheres, although individual nodes of this pathway were distinctly regulated in the two cellular systems. Neurosphere conditions, as opposed to monolayer conditions, cause a transcriptomic and metabolic rewiring that may be crucial for the regulation of stem-like features, where arginine biosynthesis may be a key metabolic pathway. Additionally, TCGA data from GBM patients showed significant regulation of specific components of the arginine biosynthesis pathway, providing further evidence for the importance of this metabolic pathway in GBM. Full article
(This article belongs to the Special Issue Metabolic Dysfunction in Cancer)
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Review

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29 pages, 1500 KiB  
Review
Sphingolipids and Lymphomas: A Double-Edged Sword
by Alfredo Pherez-Farah, Rosa del Carmen López-Sánchez, Luis Mario Villela-Martínez, Rocío Ortiz-López, Brady E. Beltrán and José Ascención Hernández-Hernández
Cancers 2022, 14(9), 2051; https://doi.org/10.3390/cancers14092051 - 19 Apr 2022
Cited by 5 | Viewed by 3800
Abstract
Lymphomas are a highly heterogeneous group of hematological neoplasms. Given their ethiopathogenic complexity, their classification and management can become difficult tasks; therefore, new approaches are continuously being sought. Metabolic reprogramming at the lipid level is a hot topic in cancer research, and sphingolipidomics [...] Read more.
Lymphomas are a highly heterogeneous group of hematological neoplasms. Given their ethiopathogenic complexity, their classification and management can become difficult tasks; therefore, new approaches are continuously being sought. Metabolic reprogramming at the lipid level is a hot topic in cancer research, and sphingolipidomics has gained particular focus in this area due to the bioactive nature of molecules such as sphingoid bases, sphingosine-1-phosphate, ceramides, sphingomyelin, cerebrosides, globosides, and gangliosides. Sphingolipid metabolism has become especially exciting because they are involved in virtually every cellular process through an extremely intricate metabolic web; in fact, no two sphingolipids share the same fate. Unsurprisingly, a disruption at this level is a recurrent mechanism in lymphomagenesis, dissemination, and chemoresistance, which means potential biomarkers and therapeutical targets might be hiding within these pathways. Many comprehensive reviews describing their role in cancer exist, but because most research has been conducted in solid malignancies, evidence in lymphomagenesis is somewhat limited. In this review, we summarize key aspects of sphingolipid biochemistry and discuss their known impact in cancer biology, with a particular focus on lymphomas and possible therapeutical strategies against them. Full article
(This article belongs to the Special Issue Metabolic Dysfunction in Cancer)
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22 pages, 1431 KiB  
Review
Prostate Cancer—Focus on Cholesterol
by Lucija Škara, Ana Huđek Turković, Ivan Pezelj, Alen Vrtarić, Nino Sinčić, Božo Krušlin and Monika Ulamec
Cancers 2021, 13(18), 4696; https://doi.org/10.3390/cancers13184696 - 19 Sep 2021
Cited by 24 | Viewed by 5547
Abstract
Prostate cancer (PC) is the most common malignancy in men. Common characteristic involved in PC pathogenesis are disturbed lipid metabolism and abnormal cholesterol accumulation. Cholesterol can be further utilized for membrane or hormone synthesis while cholesterol biosynthesis intermediates are important for oncogene membrane [...] Read more.
Prostate cancer (PC) is the most common malignancy in men. Common characteristic involved in PC pathogenesis are disturbed lipid metabolism and abnormal cholesterol accumulation. Cholesterol can be further utilized for membrane or hormone synthesis while cholesterol biosynthesis intermediates are important for oncogene membrane anchoring, nucleotide synthesis and mitochondrial electron transport. Since cholesterol and its biosynthesis intermediates influence numerous cellular processes, in this review we have described cholesterol homeostasis in a normal cell. Additionally, we have illustrated how commonly deregulated signaling pathways in PC (PI3K/AKT/MTOR, MAPK, AR and p53) are linked with cholesterol homeostasis regulation. Full article
(This article belongs to the Special Issue Metabolic Dysfunction in Cancer)
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