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Tumor and Metabolism

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A special issue of Cancers (ISSN 2072-6694).

Deadline for manuscript submissions: closed (20 June 2022) | Viewed by 45220

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Special Issue Editors

Dr. Ángel Luis García-Otín

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Guest Editor

Instituto Aragonés de Ciencias de la Salud (IACS), 50009 Zaragoza, Spain
Interests: endothelium; angiogenesis; tumor angiogenesis; antiangiogenic drugs; endothelial progenitor cells; exosomes

Dr. Patricia Sancho

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Guest Editor

Instituto de Investigación Sanitaria Aragón (IIS Aragón)
Interests: pancreatic cancer; cancer stem cells; lipid metabolism; mitochondria; OXPHOS; redox metabolism; oxidative stress; EMT; metastasis

Special Issue Information

Dear Colleagues,

Historically, the study of the mechanisms related to tumorigenicity and the possible therapies to manage it have focused on processes of regulation of cell growth and ways to control it. However, it is becoming increasingly clear that the appearance of tumor cells and their proliferation is due to a number of factors that interact to generate the conditions for tumor development.

Among these conditions are aspects of cellular metabolism that show distinctive characteristics relative to healthy cells and tissues that contribute to the adaptive survival of tumor cells.

Metabolism is defined as the set of chemical reactions that occur in an organism with the functions of providing energy, creating building blocks for the maintenance of cells and tissues, and eliminating potentially harmful waste. Its regulation constitutes an important part of homeostasis both at the cellular and systemic levels, which are intertwined.

The field of tumor metabolism has exponentially grown during the last decade, and it is currently recognized as one of the main cancer hallmarks. While initial reports focused on the increased glycolytic activity of cancer cells (Warburg effect), it is now well known that tumor cells undergo global metabolic reprogramming and display numerous metabolic adaptations also involving lipids, amino acids, and other biomolecules. Interestingly, recent pioneering works have unveiled the crucial contribution of stromal cells to malignant cell metabolism and vice versa, establishing a complex crosstalk among the different components of the tumor microenvironment. Additionally, oxygen and nutrient availability dictated by the tumor conditions (stromal content, vessel density) and dietary intake are essential contributors to tumor growth and progression.

For this Special Issue of Cancers, we invite authors to submit contributions that provide novel findings in the field of tumor metabolism. Insights in the areas of metabolic reprogramming and heterogeneity, metabolic crosstalk with the microenvironment, angiogenesis, dietary interventions, and therapeutic approaches targeting cancer metabolism at the cellular or organismal levels are of particular interest, although other relevant topics will also be considered. We welcome results from the basic research, preclinical, or clinical fields. Reviews that highlight new findings in the areas mentioned above are also welcome.

Dr. Ángel Luis García-Otín
Dr. Patricia Sancho
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

cellular metabolism
redox regulation
hypoxia
angiogenesis
microenvironment
stroma
nutrients
diet
therapeutics

Published Papers (11 papers)

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Research

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18 pages, 3035 KiB

Open AccessArticle

Genetic Disruption of the γ-Glutamylcysteine Ligase in PDAC Cells Induces Ferroptosis-Independent Cell Death In Vitro without Affecting In Vivo Tumor Growth

by Boutaina Daher, Willian Meira, Jerome Durivault, Celia Gotorbe, Jacques Pouyssegur and Milica Vucetic

Cancers 2022, 14(13), 3154; https://doi.org/10.3390/cancers14133154 - 28 Jun 2022

Cited by 3 | Viewed by 2562

Abstract

The conceptualization of a novel type of cell death, called ferroptosis, opens new avenues for the development of more efficient anti-cancer therapeutics. In this context, a full understanding of the ferroptotic pathways, the players involved, their precise role, and dispensability is prerequisite. Here, we focused on the importance of glutathione (GSH) for ferroptosis prevention in pancreatic ductal adenocarcinoma (PDAC) cells. We genetically deleted a unique, rate-limiting enzyme for GSH biosynthesis, γ-glutamylcysteine ligase (GCL), which plays a key role in tumor cell proliferation and survival. Surprisingly, although glutathione peroxidase 4 (GPx4) has been described as a guardian of ferroptosis, depletion of its substrate (GSH) led preferentially to apoptotic cell death, while classical ferroptotic markers (lipid hydroperoxides) have not been observed. Furthermore, the sensitivity of PDAC cells to the pharmacological/genetic inhibition of GPx4 revealed GSH dispensability in this context. To the best of our knowledge, this is the first time that the complete dissection of the xCT-GSH-GPx4 axis in PDAC cells has been investigated in great detail. Collectively, our results revealed the necessary role of GSH in the overall redox homeostasis of PDAC cells, as well as the dispensability of this redox-active molecule for a specific, antioxidant branch dedicated to ferroptosis prevention. Full article

(This article belongs to the Special Issue Tumor and Metabolism)

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17 pages, 3863 KiB

Open AccessEditor’s ChoiceArticle

Estrogens and Progestins Cooperatively Shift Breast Cancer Cell Metabolism

by Ashley V. Ward, Shawna B. Matthews, Lynsey M. Fettig, Duncan Riley, Jessica Finlay-Schultz, Kiran V. Paul, Matthew Jackman, Peter Kabos, Paul S. MacLean and Carol A. Sartorius

Cancers 2022, 14(7), 1776; https://doi.org/10.3390/cancers14071776 - 31 Mar 2022

Cited by 6 | Viewed by 2699

Abstract

Metabolic reprogramming remains largely understudied in relation to hormones in estrogen receptor (ER) and progesterone receptor (PR) positive breast cancer. In this study, we investigated how estrogens, progestins, or the combination, impact metabolism in three ER and PR positive breast cancer cell lines. We measured metabolites in the treated cells using ultra-performance liquid chromatography coupled with mass spectrometry (UPLC-MS). Top metabolic processes upregulated with each treatment involved glucose metabolism, including Warburg effect/glycolysis, gluconeogenesis, and the pentose phosphate pathway. RNA-sequencing and pathway analysis on two of the cell lines treated with the same hormones, found estrogens target oncogenes, such as MYC and PI3K/AKT/mTOR that control tumor metabolism, while progestins increased genes associated with fatty acid metabolism, and the estrogen/progestin combination additionally increased glycolysis. Phenotypic analysis of cell energy metabolism found that glycolysis was the primary hormonal target, particularly for the progestin and estrogen-progestin combination. Transmission electron microscopy found that, compared to vehicle, estrogens elongated mitochondria, which was reversed by co-treatment with progestins. Progestins promoted lipid storage both alone and in combination with estrogen. These findings highlight the shift in breast cancer cell metabolism to a more glycolytic and lipogenic phenotype in response to combination hormone treatment, which may contribute to a more metabolically adaptive state for cell survival. Full article

(This article belongs to the Special Issue Tumor and Metabolism)

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16 pages, 5122 KiB

Open AccessArticle

Tumor Metabolism Is Affected by Obesity in Preclinical Models of Triple-Negative Breast Cancer

by Caner Yelek, Lionel Mignion, Adrien Paquot, Caroline Bouzin, Cyril Corbet, Giulio G. Muccioli, Patrice D. Cani and Bénédicte F. Jordan

Cancers 2022, 14(3), 562; https://doi.org/10.3390/cancers14030562 - 23 Jan 2022

Cited by 6 | Viewed by 3578

Abstract

Obesity is characterized by an excessive fat mass accumulation associated with multiple disorders, including impaired glucose homeostasis, altered adipokine levels, and hyperlipidemia. Despite clear associations between tumor progression and obesity, the effects of these disorders on tumor metabolism remain largely unknown. Thus, we studied the metabolic differences between tumors of obese and lean mice in murine models of triple-negative breast cancer (E0771 and PY8819). For this purpose, a real-time hyperpolarized 1-¹³C-pyruvate-to-lactate conversion was studied before and after glucose administration in fasting mice. This work was completed by U-¹³C glucose tracing experiments using nuclear magnetic resonance (NMR) spectroscopy, as well as mass spectrometry (MS). Ex vivo analyses included immunostainings of major lipid, glucose, and monocarboxylic acids transporters. On the one hand, we discovered that tumors of obese mice yield higher lactate/pyruvate ratios after glucose administration. On the other hand, we found that the same tumors produce higher levels of lactate and alanine from glucose than tumors from lean mice, while no differences on the expression of key transporters associated with glycolysis (i.e., GLUT1, MCT1, MCT4) have been observed. In conclusion, our data suggests that breast tumor metabolism is regulated by the host’s physiological status, such as obesity and diabetes. Full article

(This article belongs to the Special Issue Tumor and Metabolism)

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17 pages, 2454 KiB

Open AccessArticle

Tissue-Specific Warburg Effect in Breast Cancer and Cancer-Associated Adipose Tissue—Relationship between AMPK and Glycolysis

by Andjelika Kalezic, Mirjana Udicki, Biljana Srdic Galic, Marija Aleksic, Aleksandra Korac, Aleksandra Jankovic and Bato Korac

Cancers 2021, 13(11), 2731; https://doi.org/10.3390/cancers13112731 - 31 May 2021

Cited by 19 | Viewed by 4160

Abstract

Typical features of the breast malignant phenotype rely on metabolic reprogramming of cancer cells and their interaction with surrounding adipocytes. Obesity is strongly associated with breast cancer mortality, yet the effects of obesity on metabolic reprogramming of cancer and cancer-associated adipose tissue remain largely unknown. Paired biopsies of breast tumor tissue and adipose tissue from premenopausal women were divided according to pathohistological analyses and body mass index on normal-weight and overweight/obese with benign or malignant tumors. We investigated the protein expression of key regulatory enzymes of glycolysis, pentose phosphate pathway (PPP), and glycogen synthesis. Breast cancer tissue showed a simultaneous increase in 5′-AMP-activated protein kinase (AMPK) protein expression with typical features of the Warburg effect, including hexokinase 2 (HK 2) overexpression and its association with mitochondrial voltage-dependent anion-selective channel protein 1, associated with an overexpression of rate-limiting enzymes of glycolysis (phosphofructokinase 1—PFK-1) and pentose phosphate pathway (glucose-6-phosphate dehydrogenase—G6PDH). In parallel, cancer-associated adipose tissue showed increased AMPK protein expression with overexpression of HK 2 and G6PDH in line with increased PPP activity. Moreover, important obesity-associated differences in glucose metabolism were observed in breast cancer tissue showing prominent glycogen deposition and higher glycogen synthase kinase-3 protein expression in normal-weight women and higher PFK-1 and glyceraldehyde 3-phosphate dehydrogenase (GAPDH) protein expression in overweight/obese women. In conclusion, metabolic reprogramming of glycolysis contributes to tissue-specific Warburg effect in breast cancer and cancer-associated adipose tissue. Full article

(This article belongs to the Special Issue Tumor and Metabolism)

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21 pages, 2016 KiB

Open AccessArticle

Inhibition of Mitochondrial Dynamics Preferentially Targets Pancreatic Cancer Cells with Enhanced Tumorigenic and Invasive Potential

by Sarah Courtois, Beatriz de Luxán-Delgado, Laure Penin-Peyta, Alba Royo-García, Beatriz Parejo-Alonso, Petra Jagust, Sonia Alcalá, Juan A. Rubiolo, Laura Sánchez, Bruno Sainz, Jr., Christopher Heeschen and Patricia Sancho

Cancers 2021, 13(4), 698; https://doi.org/10.3390/cancers13040698 - 9 Feb 2021

Cited by 27 | Viewed by 4596

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest tumors, partly due to its intrinsic aggressiveness, metastatic potential, and chemoresistance of the contained cancer stem cells (CSCs). Pancreatic CSCs strongly rely on mitochondrial metabolism to maintain their stemness, therefore representing a putative target for their elimination. Since mitochondrial homeostasis depends on the tightly controlled balance between fusion and fission processes, namely mitochondrial dynamics, we aim to study this mechanism in the context of stemness. In human PDAC tissues, the mitochondrial fission gene DNM1L (DRP1) was overexpressed and positively correlated with the stemness signature. Moreover, we observe that primary human CSCs display smaller mitochondria and a higher DRP1/MFN2 expression ratio, indicating the activation of the mitochondrial fission. Interestingly, treatment with the DRP1 inhibitor mDivi-1 induced dose-dependent apoptosis, especially in CD133⁺ CSCs, due to the accumulation of dysfunctional mitochondria and the subsequent energy crisis in this subpopulation. Mechanistically, mDivi-1 inhibited stemness-related features, such as self-renewal, tumorigenicity, and invasiveness and chemosensitized the cells to the cytotoxic effects of Gemcitabine. In summary, mitochondrial fission is an essential process for pancreatic CSCs and represents an attractive target for designing novel multimodal treatments that will more efficiently eliminate cells with high tumorigenic potential. Full article

(This article belongs to the Special Issue Tumor and Metabolism)

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Review

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29 pages, 4295 KiB

Open AccessReview

Metabolic Pathways, Enzymes, and Metabolites: Opportunities in Cancer Therapy

by Rishabh Kumar, Anurag Mishra, Priyanka Gautam, Zainab Feroz, Sivakumar Vijayaraghavalu, Eviania M. Likos, Girish C. Shukla and Munish Kumar

Cancers 2022, 14(21), 5268; https://doi.org/10.3390/cancers14215268 - 27 Oct 2022

Cited by 7 | Viewed by 4664

Abstract

Metabolic reprogramming enables cancer cells to proliferate and produce tumor biomass under a nutrient-deficient microenvironment and the stress of metabolic waste. A cancer cell adeptly undergoes a variety of adaptations in metabolic pathways and differential expression of metabolic enzyme genes. Metabolic adaptation is mainly determined by the physiological demands of the cancer cell of origin and the host tissue. Numerous metabolic regulators that assist cancer cell proliferation include uncontrolled anabolism/catabolism of glucose metabolism, fatty acids, amino acids metabolism, nucleotide metabolism, tumor suppressor genes, microRNAs, and many regulatory enzymes and genes. Using this paradigm, we review the current understanding of metabolic reprogramming in tumors and discuss the new strategies of cancer metabolomics that can be tapped into for cancer therapeutics. Full article

(This article belongs to the Special Issue Tumor and Metabolism)

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23 pages, 1901 KiB

Open AccessReview

Mutant p53, the Mevalonate Pathway and the Tumor Microenvironment Regulate Tumor Response to Statin Therapy

by Madison Pereira, Kathy Matuszewska, Alice Glogova and Jim Petrik

Cancers 2022, 14(14), 3500; https://doi.org/10.3390/cancers14143500 - 19 Jul 2022

Cited by 6 | Viewed by 4129

Abstract

Tumor cells have the ability to co-opt multiple metabolic pathways, enhance glucose uptake and utilize aerobic glycolysis to promote tumorigenesis, which are characteristics constituting an emerging hallmark of cancer. Mutated tumor suppressor and proto-oncogenes are frequently responsible for enhanced metabolic pathway signaling. The link between mutant p53 and the mevalonate (MVA) pathway has been implicated in the advancement of various malignancies, with tumor cells relying heavily on increased MVA signaling to fuel their rapid growth, metastatic spread and development of therapy resistance. Statin drugs inhibit HMG-CoA reductase, the pathway’s rate-limiting enzyme, and as such, have long been studied as a potential anti-cancer therapy. However, whether statins provide additional anti-cancer properties is worthy of debate. Here, we examine retrospective, prospective and pre-clinical studies involving the use of statins in various cancer types, as well as potential issues with statins’ lack of efficacy observed in clinical trials and future considerations for upcoming clinical trials. Full article

(This article belongs to the Special Issue Tumor and Metabolism)

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14 pages, 16003 KiB

Open AccessReview

The Interplay between Cell-Extracellular Matrix Interaction and Mitochondria Dynamics in Cancer

by Bian Yanes and Elena Rainero

Cancers 2022, 14(6), 1433; https://doi.org/10.3390/cancers14061433 - 10 Mar 2022

Cited by 11 | Viewed by 4308

Abstract

The tumor microenvironment, in particular the extracellular matrix (ECM), plays a pivotal role in controlling tumor initiation and progression. In particular, the interaction between cancer cells and the ECM promotes cancer cell growth and invasion, leading to the formation of distant metastasis. Alterations in cancer cell metabolism is a key hallmark of cancer, which is often associated with alterations in mitochondrial dynamics. Recent research highlighted that, changes in mitochondrial dynamics are associated with cancer migration and metastasis—these has been extensively reviewed elsewhere. However, less is known about the interplay between the extracellular matrix and mitochondria functions. In this review, we will highlight how ECM remodeling associated with tumorigenesis contribute to the regulation of mitochondrial function, ultimately promoting cancer cell metabolic plasticity, able to fuel cancer invasion and metastasis. Full article

(This article belongs to the Special Issue Tumor and Metabolism)

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30 pages, 11715 KiB

Open AccessReview

Metabolic Features of Tumor Dormancy: Possible Therapeutic Strategies

by Erica Pranzini, Giovanni Raugei and Maria Letizia Taddei

Cancers 2022, 14(3), 547; https://doi.org/10.3390/cancers14030547 - 21 Jan 2022

Cited by 19 | Viewed by 4677

Abstract

Tumor relapse represents one of the main obstacles to cancer treatment. Many patients experience cancer relapse even decades from the primary tumor eradication, developing more aggressive and metastatic disease. This phenomenon is associated with the emergence of dormant cancer cells, characterized by cell cycle arrest and largely insensitive to conventional anti-cancer therapies. These rare and elusive cells may regain proliferative abilities upon the induction of cell-intrinsic and extrinsic factors, thus fueling tumor re-growth and metastasis formation. The molecular mechanisms underlying the maintenance of resistant dormant cells and their awakening are intriguing but, currently, still largely unknown. However, increasing evidence recently underlined a strong dependency of cell cycle progression to metabolic adaptations of cancer cells. Even if dormant cells are frequently characterized by a general metabolic slowdown and an increased ability to cope with oxidative stress, different factors, such as extracellular matrix composition, stromal cells influence, and nutrient availability, may dictate specific changes in dormant cells, finally resulting in tumor relapse. The main topic of this review is deciphering the role of the metabolic pathways involved in tumor cells dormancy to provide new strategies for selectively targeting these cells to prevent fatal recurrence and maximize therapeutic benefit. Full article

(This article belongs to the Special Issue Tumor and Metabolism)

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20 pages, 1823 KiB

Open AccessReview

Metabolic Anti-Cancer Effects of Melatonin: Clinically Relevant Prospects

by Marek Samec, Alena Liskova, Lenka Koklesova, Kevin Zhai, Elizabeth Varghese, Samson Mathews Samuel, Miroslava Šudomová, Vincent Lucansky, Monika Kassayova, Martin Pec, Kamil Biringer, Aranka Brockmueller, Karol Kajo, Sherif T. S. Hassan, Mehdi Shakibaei, Olga Golubnitschaja, Dietrich Büsselberg and Peter Kubatka

Cancers 2021, 13(12), 3018; https://doi.org/10.3390/cancers13123018 - 16 Jun 2021

Cited by 15 | Viewed by 4746

Abstract

Metabolic reprogramming characterized by alterations in nutrient uptake and critical molecular pathways associated with cancer cell metabolism represents a fundamental process of malignant transformation. Melatonin (N-acetyl-5-methoxytryptamine) is a hormone secreted by the pineal gland. Melatonin primarily regulates circadian rhythms but also exerts anti-inflammatory, anti-depressant, antioxidant and anti-tumor activities. Concerning cancer metabolism, melatonin displays significant anticancer effects via the regulation of key components of aerobic glycolysis, gluconeogenesis, the pentose phosphate pathway (PPP) and lipid metabolism. Melatonin treatment affects glucose transporter (GLUT) expression, glucose-6-phosphate dehydrogenase (G6PDH) activity, lactate production and other metabolic contributors. Moreover, melatonin modulates critical players in cancer development, such as HIF-1 and p53. Taken together, melatonin has notable anti-cancer effects at malignancy initiation, progression and metastasing. Further investigations of melatonin impacts relevant for cancer metabolism are expected to create innovative approaches supportive for the effective prevention and targeted therapy of cancers. Full article

(This article belongs to the Special Issue Tumor and Metabolism)

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Other

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13 pages, 1146 KiB

Open AccessPerspective

How Phosphofructokinase-1 Promotes PI3K and YAP/TAZ in Cancer: Therapeutic Perspectives

by Luca Simula, Marco Alifano and Philippe Icard

Cancers 2022, 14(10), 2478; https://doi.org/10.3390/cancers14102478 - 18 May 2022

Cited by 9 | Viewed by 3317

Abstract

PI3K/AKT is one of the most frequently altered signaling pathways in human cancers, supporting the activation of many proteins sustaining cell metabolism, proliferation, and aggressiveness. Another important pathway frequently altered in cancer cells is the one regulating the YAP/TAZ transcriptional coactivators, which promote the expression of genes sustaining aerobic glycolysis (such as WNT, MYC, HIF-1), EMT, and drug resistance. Of note, the PI3K/AKT pathway can also regulate the YAP/TAZ one. Unfortunately, although PI3K and YAP inhibitors are currently tested in highly resistant cancers (both solid and hematologic ones), several resistance mechanisms may arise. Resistance mechanisms to PI3K inhibitors may involve the stimulation of alternative pathways (such as RAS, HER, IGFR/AKT), the inactivation of PTEN (the physiologic inhibitor of PI3K), and the expression of anti-apoptotic Bcl-xL and MCL1 proteins. Therefore, it is important to improve current therapeutic strategies to overcome these limitations. Here, we want to highlight how the glycolytic enzyme PFK1 (and its product F-1,6-BP) promotes the activation of both PI3K/AKT and YAP/TAZ pathways by several direct and indirect mechanisms. In turn, PI3K/AKT and YAP/TAZ can promote PFK1 activity and F-1,6-BP production in a positive feedback loop, thus sustaining the Warburg effect and drug resistance. Thus, we propose that the inhibition of PFK1 (and of its key activator PFK2/PFKFB3) could potentiate the sensitivity to PI3K and YAP inhibitors currently tested. Awaiting the development of non-toxic inhibitors of these enzymes, we propose to test the administration of citrate at a high dosage, because citrate is a physiologic inhibitor of both PFK1 and PFK2/PFKFB3. Consistently, in various cultured cancer cells (including melanoma, sarcoma, hematologic, and epithelial cancer cells), this “citrate strategy” efficiently inhibits the IGFR1/AKT pathway, promotes PTEN activity, reduces Bcl-xL and MCL1 expression, and increases sensitivity to standard chemotherapy. It also inhibits the development of sarcoma, pancreatic, mammary HER⁺ and lung RAS-driven tumors in mice without apparent toxicities. Full article

(This article belongs to the Special Issue Tumor and Metabolism)

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