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Cancers
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Metabolic Reprogramming and Vulnerabilities in Cancer
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Metabolic Reprogramming and Vulnerabilities in Cancer

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

Deadline for manuscript submissions: closed (1 August 2019) | Viewed by 192074

Special Issue Editors

Dr. Deepak Nagrath

E-Mail Website
Guest Editor
Department of Biomedical Engineering, Department of Chemical Engineering, University of Michigan, NCRC, Bldg 28, Room 3048W, 2800 Plymouth Rd, Ann Arbor, MI 48109, USA
Interests: cancer metabolism; tumor microenvironment; metabolic profiling; systems biology; metabolomics
Dr. Costas Lyssiotis

E-Mail Website
Guest Editor
Department of Molecular and Integrative Physiology; Division of Gastroenterology, Department of Internal Medicine, Comprehensive Cancer Center, University of Michigan Room 6308, 1150 East Medical Center Drive, Ann Arbor, MI 48109, USA
Interests: : tumor metabolism; pancreatic cancer; metabolomics; stromal metabolism; immunometabolism

Special Issue Information

The dysregulated metabolic traits of cancer are not confined to malignant cells; solid tumors systemically reprogram their metabolism to create a unique metabolic microenvironment to sustain tumorigenic properties. Alterations in extrinsic and intrinsic signals in tumors dictate how metabolic rewiring occurs. Rewired metabolism not only provides a selective advantage to malignant cells in nutrient-stressed and hypoxic environments, but also facilitates invasion, metastasis, immune suppression, drug resistance, and tumor-promoting epigenetic modifications. However, recent studies have highlighted an inherent complexity of dissecting metabolic mechanisms driving tumorigenesis. One aspect of this complexity is due to the impact of metabolic alterations on epigenetic modifications and DNA damage repair. Metabolic pathways responsible for regulating methyl and acetyl levels create a reciprocal feedback loop between metabolism and genetic reprogramming in tumors. We expect new studies elucidating how tumors rewire to provide substrates for chromatin regulation. Further, with the increasing interest in mitochondrial metabolism and its role as a signaling organelle, we expect studies focused on the effect of ROS on DNA damage, and regulation of NAD metabolism for sirtuin-mediated DNA damage repair.

The other aspect of complexity in metabolic reprogramming is due to intratumoral heterogeneity. Reactive stroma are important players in the metabolic interactions within the tumor microenvironment (TME). Cancer cells reprogram stromal cells to help meet there high bioenergetic demands via secreted metabolites, exosomes, proteins, and lipids. Rewired cancer metabolism can also create an immunosuppressive microenvironment that actively inhibits the antitumor response of T-cells and natural killer cells. Therefore, there is a growing interest in reversing the tumor-supporting properties of reactive stroma for therapeutic benefits. New studies are expected to focus on modulating stromal metabolism to improve immunotherapy response or inhibit pathways supporting cancer metabolism. The unique composition of the TME has also come under scientific scrutiny leading to the discovery of cancer cells utilizing exosomes, extracellular proteins and apoptotic bodies as fuel sources. We expect novel studies on non-canonical nutrient sources that can be selectively targeted in cancer cells. Thus, strategies targeting TME metabolism have the potential to elicit a systemic anti-tumor response in contrast to cancer-specific targets of antineoplastic drugs.

Contemporary research has demonstrated that the influence of cancer metabolism on the portfolio of cancer hallmarks is prevalent and has proven that it can be used to our advantage. Discovering and dissecting tumor-specific metabolic mechanisms will open new avenues of targeting metabolic vulnerabilities in cancers. In summary, this issue will highlight emerging aspects of metabolic reprogramming on tumor phenotype with a focus on exploiting these idiosyncratic metabolic mechanisms for therapeutic benefit.

Dr. Deepak Nagrath
Dr. Costas Lyssiotis
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.

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Editorial

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5 pages, 776 KiB  
Editorial
Metabolic Reprogramming and Vulnerabilities in Cancer
by Costas A. Lyssiotis and Deepak Nagrath
Cancers 2020, 12(1), 90; https://doi.org/10.3390/cancers12010090 - 30 Dec 2019
Cited by 7 | Viewed by 2836
Abstract
Metabolic programs are rewired in tumors to support growth, progression, and immune evasion. A wealth of work in the past decade has delineated how these metabolic rearrangements are facilitated by signaling pathways downstream of oncogene activation and tumor suppressor loss. More recently, this [...] Read more.
Metabolic programs are rewired in tumors to support growth, progression, and immune evasion. A wealth of work in the past decade has delineated how these metabolic rearrangements are facilitated by signaling pathways downstream of oncogene activation and tumor suppressor loss. More recently, this field has expanded to include metabolic interactions among the diverse cell types that exist within a tumor and how this impacts the immune system. In this special issue, 17 review articles discuss these phenomena, and, alongside four original research manuscripts, the vulnerabilities associated with deregulated metabolic programming are highlighted and examined. Full article
(This article belongs to the Special Issue Metabolic Reprogramming and Vulnerabilities in Cancer)
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Research

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25 pages, 7712 KiB  
Article
Decoupling of Nrf2 Expression Promotes Mesenchymal State Maintenance in Non-Small Cell Lung Cancer
by John A. Haley, Christian F. Ruiz, Emily D. Montal, Daifeng Wang, John D. Haley and Geoffrey D. Girnun
Cancers 2019, 11(10), 1488; https://doi.org/10.3390/cancers11101488 - 02 Oct 2019
Cited by 7 | Viewed by 3755
Abstract
Epithelial mesenchymal transition is a common mechanism leading to metastatic dissemination and cancer progression. In an effort to better understand this process we found an intersection of Nrf2/NLE2F2 (Nrf2), epithelial mesenchymal transition (EMT), and metabolic alterations using multiple in vitro and in vivo [...] Read more.
Epithelial mesenchymal transition is a common mechanism leading to metastatic dissemination and cancer progression. In an effort to better understand this process we found an intersection of Nrf2/NLE2F2 (Nrf2), epithelial mesenchymal transition (EMT), and metabolic alterations using multiple in vitro and in vivo approaches. Nrf2 is a key transcription factor controlling the expression of redox regulators to establish cellular redox homeostasis. Nrf2 has been shown to exert both cancer inhibitory and stimulatory activities. Using multiple isogenic non-small cell lung cancer (NSCLC) cell lines, we observed a reduction of Nrf2 protein and activity in a prometastatic mesenchymal cell state and increased reactive oxygen species. Knockdown of Nrf2 promoted a mesenchymal phenotype and reduced glycolytic, TCA cycle and lipogenic output from both glucose and glutamine in the isogenic cell models; while overexpression of Nrf2 promoted a more epithelial phenotype and metabolic reactivation. In both Nrf2 knockout mice and in NSCLC patient samples, Nrf2low was co-correlated with markedly decreased expression of glycolytic, lipogenic, and mesenchymal RNAs. Conversely, Nrf2high was associated with partial mesenchymal epithelial transition and increased expression of metabolic RNAs. The impact of Nrf2 on epithelial and mesenchymal cancer cell states and metabolic output provide an additional context to Nrf2 function in cancer initiation and progression, with implications for therapeutic inhibition of Nrf2 in cancer treatment. Full article
(This article belongs to the Special Issue Metabolic Reprogramming and Vulnerabilities in Cancer)
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18 pages, 5645 KiB  
Article
GLUT1 and TUBB4 in Glioblastoma Could be Efficacious Targets
by Maheedhara R. Guda, Collin M. Labak, Sara Ibrahim Omar, Swapna Asuthkar, Subra Airala, Jack Tuszynski, Andrew J. Tsung and Kiran K. Velpula
Cancers 2019, 11(9), 1308; https://doi.org/10.3390/cancers11091308 - 05 Sep 2019
Cited by 27 | Viewed by 4727
Abstract
Glioblastoma multiforme (GBM) is the most aggressive and deadly brain tumor, portending a median 13-month survival even following gross total resection with adjuvant chemotherapy and radiotherapy. This prognosis necessitates improved therapies for the disease. A target of interest for novel chemotherapies is the [...] Read more.
Glioblastoma multiforme (GBM) is the most aggressive and deadly brain tumor, portending a median 13-month survival even following gross total resection with adjuvant chemotherapy and radiotherapy. This prognosis necessitates improved therapies for the disease. A target of interest for novel chemotherapies is the Warburg Effect, which describes the tumor’s shift away from oxidative phosphorylation towards glycolysis. Here, we elucidate GLUT1 (Glucose transporter 1) and one of its associated binding partners, TUBB4 (Tubulin 4), as potentially druggable targets in GBM. Using data mining approach, we demonstrate that GLUT1 is overexpressed as a function of tumor grade in astrocytoma’s and that its overexpression is associated with poorer prognosis. Using both mass spectrometry performed on hGBM (human glioblastoma patient specimen) and in silico modeling, we show that GLUT1 interacts with TUBB4, and more accurately demonstrates GLUT1’s binding with fasentin. Proximity ligation assay (PLA) and immunoprecipitation studies confirm GLUT1 interaction with TUBB4. Treatment of GSC33 and GSC28 cells with TUBB4 inhibitor, CR-42-24, reduces the expression of GLUT1 however, TUBB4 expression is unaltered upon fasentin treatment. Using human pluripotent stem cell antibody array, we demonstrate reduced levels of Oct3/4, Nanog, Sox2, Sox17, Snail and VEGFR2 (Vascular endothelial growth factor receptor 2) upon CR-42-24 treatment. Overall, our data confirm that silencing TUBB4 or GLUT1 reduce GSC tumorsphere formation, self-renewal and proliferation in vitro. These findings suggest GLUT1 and its binding partner TUBB4 as druggable targets that warrant further investigation in GBM. Full article
(This article belongs to the Special Issue Metabolic Reprogramming and Vulnerabilities in Cancer)
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21 pages, 3522 KiB  
Article
Deciphering the Elevated Lipid via CD36 in Mantle Cell Lymphoma with Bortezomib Resistance Using Synchrotron-Based Fourier Transform Infrared Spectroscopy of Single Cells
by Sudjit Luanpitpong, Montira Janan, Kanjana Thumanu, Jirarat Poohadsuan, Napachai Rodboon, Phatchanat Klaihmon and Surapol Issaragrisil
Cancers 2019, 11(4), 576; https://doi.org/10.3390/cancers11040576 - 24 Apr 2019
Cited by 27 | Viewed by 4010
Abstract
Despite overall progress in improving cancer treatments, the complete response of mantle cell lymphoma (MCL) is still limited due to the inevitable development of drug resistance. More than half of patients did not attain response to bortezomib (BTZ), the approved treatment for relapsed [...] Read more.
Despite overall progress in improving cancer treatments, the complete response of mantle cell lymphoma (MCL) is still limited due to the inevitable development of drug resistance. More than half of patients did not attain response to bortezomib (BTZ), the approved treatment for relapsed or refractory MCL. Understanding how MCL cells acquire BTZ resistance at the molecular level may be a key to the long-term management of MCL patients and new therapeutic strategies. We established a series of de novo BTZ-resistant human MCL-derived cells with approximately 15- to 60-fold less sensitivity than those of parental cells. Using gene expression profiling, we discovered that putative cancer-related genes involved in drug resistance and cell survival tested were mostly downregulated, likely due to global DNA hypermethylation. Significant information on dysregulated lipid metabolism was obtained from synchrotron-based Fourier transform infrared (FTIR) spectroscopy of single cells. We demonstrated for the first time an upregulation of CD36 in highly BTZ-resistant cells in accordance with an increase in their lipid accumulation. Ectopic expression of CD36 causes an increase in lipid droplets and renders BTZ resistance to various human MCL cells. By contrast, inhibition of CD36 by neutralizing antibody strongly enhances BTZ sensitivity, particularly in CD36-overexpressing cells and de novo BTZ-resistant cells. Together, our findings highlight the potential application of CD36 inhibition for BTZ sensitization and suggest the use of FTIR spectroscopy as a promising technique in cancer research. Full article
(This article belongs to the Special Issue Metabolic Reprogramming and Vulnerabilities in Cancer)
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18 pages, 2940 KiB  
Article
Rac-Mediated Macropinocytosis of Extracellular Protein Promotes Glucose Independence in Non-Small Cell Lung Cancer
by Cindy Hodakoski, Benjamin D. Hopkins, Guoan Zhang, Taojunfeng Su, Zhe Cheng, Roxanne Morris, Kyu Y. Rhee, Marcus D. Goncalves and Lewis C. Cantley
Cancers 2019, 11(1), 37; https://doi.org/10.3390/cancers11010037 - 02 Jan 2019
Cited by 42 | Viewed by 6081
Abstract
Cancer cells can adapt to nutrient poor conditions by rewiring their metabolism and using alternate fuel sources. Identifying these adaptive metabolic pathways may provide novel targets for cancer therapy. Here, we identify a subset of non-small cell lung cancer (NSCLC) cell lines that [...] Read more.
Cancer cells can adapt to nutrient poor conditions by rewiring their metabolism and using alternate fuel sources. Identifying these adaptive metabolic pathways may provide novel targets for cancer therapy. Here, we identify a subset of non-small cell lung cancer (NSCLC) cell lines that survive in the absence of glucose by internalizing and metabolizing extracellular protein via macropinocytosis. Macropinocytosis is increased in these glucose independent cells, and is regulated by phosphoinositide 3-kinase (PI3K) activation of Rac-Pak signaling. Furthermore, inhibition of Rac-dependent macropinocytosis blocks glucose-independent proliferation. We find that degradation of internalized protein produces amino acids, including alanine, which generates TCA cycle and glycolytic intermediates in the absence of glucose. In this process, the conversion of alanine to pyruvate by alanine transaminase 2 (ALT2) is critical for survival during glucose starvation. Collectively, Rac driven macropinocytosis of extracellular protein is an adaptive metabolic pathway used by a subset of lung cancers to survive states of glucose deprivation, and may serve as a potential drug target for cancer therapy. Full article
(This article belongs to the Special Issue Metabolic Reprogramming and Vulnerabilities in Cancer)
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Review

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21 pages, 1490 KiB  
Review
Glutamine Metabolism in Brain Tumors
by Siva Kumar Natarajan and Sriram Venneti
Cancers 2019, 11(11), 1628; https://doi.org/10.3390/cancers11111628 - 24 Oct 2019
Cited by 51 | Viewed by 7281
Abstract
Altered metabolism is a hallmark of cancer cells. Tumor cells rewire their metabolism to support their uncontrolled proliferation by taking up nutrients from the microenvironment. The amino acid glutamine is a key nutrient that fuels biosynthetic processes including ATP generation, redox homeostasis, nucleotide, [...] Read more.
Altered metabolism is a hallmark of cancer cells. Tumor cells rewire their metabolism to support their uncontrolled proliferation by taking up nutrients from the microenvironment. The amino acid glutamine is a key nutrient that fuels biosynthetic processes including ATP generation, redox homeostasis, nucleotide, protein, and lipid synthesis. Glutamine as a precursor for the neurotransmitter glutamate, and plays a critical role in the normal functioning of the brain. Brain tumors that grow in this glutamine/glutamate rich microenvironment can make synaptic connections with glutamatergic neurons and reprogram glutamine metabolism to enable their growth. In this review, we examine the functions of glutamate/glutamine in the brain and how brain tumor cells reprogram glutamine metabolism. Altered glutamine metabolism can be leveraged to develop non-invasive imaging strategies and we review these imaging modalities. Finally, we examine if targeting glutamine metabolism could serve as a therapeutic strategy in brain tumors. Full article
(This article belongs to the Special Issue Metabolic Reprogramming and Vulnerabilities in Cancer)
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22 pages, 3183 KiB  
Review
The Many Facets of Tumor Heterogeneity: Is Metabolism Lagging Behind?
by Sara Loponte, Sara Lovisa, Angela K. Deem, Alessandro Carugo and Andrea Viale
Cancers 2019, 11(10), 1574; https://doi.org/10.3390/cancers11101574 - 16 Oct 2019
Cited by 30 | Viewed by 4628
Abstract
Tumor functional heterogeneity has been recognized for decades, and technological advancements are fueling renewed interest in uncovering the cell-intrinsic and extrinsic factors that influence tumor development and therapeutic response. Intratumoral heterogeneity is now arguably one of the most-studied topics in tumor biology, leading [...] Read more.
Tumor functional heterogeneity has been recognized for decades, and technological advancements are fueling renewed interest in uncovering the cell-intrinsic and extrinsic factors that influence tumor development and therapeutic response. Intratumoral heterogeneity is now arguably one of the most-studied topics in tumor biology, leading to the discovery of new paradigms and reinterpretation of old ones, as we aim to understand the profound implications that genomic, epigenomic, and functional heterogeneity hold with regard to clinical outcomes. In spite of our improved understanding of the biological complexity of cancer, characterization of tumor metabolic heterogeneity has lagged behind, lost in a century-old controversy debating whether glycolysis or mitochondrial respiration is more influential. But is tumor metabolism really so simple? Here, we review historical and current views of intratumoral heterogeneity, with an emphasis on summarizing the emerging data that begin to illuminate just how vast the spectrum of metabolic strategies a tumor can employ may be, and what this means for how we might interpret other tumor characteristics, such as mutational landscape, contribution of microenvironmental influences, and treatment resistance. Full article
(This article belongs to the Special Issue Metabolic Reprogramming and Vulnerabilities in Cancer)
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19 pages, 668 KiB  
Review
Glucose Metabolism in Pancreatic Cancer
by Liang Yan, Priyank Raj, Wantong Yao and Haoqiang Ying
Cancers 2019, 11(10), 1460; https://doi.org/10.3390/cancers11101460 - 29 Sep 2019
Cited by 75 | Viewed by 7942
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive and lethal cancers, with a five-year survival rate of around 5% to 8%. To date, very few available drugs have been successfully used to treat PDAC due to the poor understanding of the [...] Read more.
Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive and lethal cancers, with a five-year survival rate of around 5% to 8%. To date, very few available drugs have been successfully used to treat PDAC due to the poor understanding of the tumor-specific features. One of the hallmarks of pancreatic cancer cells is the deregulated cellular energetics characterized by the “Warburg effect”. It has been known for decades that cancer cells have a dramatically increased glycolytic flux even in the presence of oxygen and normal mitochondrial function. Glycolytic flux is the central carbon metabolism process in all cells, which not only produces adenosine triphosphate (ATP) but also provides biomass for anabolic processes that support cell proliferation. Expression levels of glucose transporters and rate-limiting enzymes regulate the rate of glycolytic flux. Intermediates that branch out from glycolysis are responsible for redox homeostasis, glycosylation, and biosynthesis. Beyond enhanced glycolytic flux, pancreatic cancer cells activate nutrient salvage pathways, which includes autophagy and micropinocytosis, from which the generated sugars, amino acids, and fatty acids are used to buffer the stresses induced by nutrient deprivation. Further, PDAC is characterized by extensive metabolic crosstalk between tumor cells and cells in the tumor microenvironment (TME). In this review, we will give an overview on recent progresses made in understanding glucose metabolism-related deregulations in PDAC. Full article
(This article belongs to the Special Issue Metabolic Reprogramming and Vulnerabilities in Cancer)
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23 pages, 1979 KiB  
Review
Hyperglycemia Associated Metabolic and Molecular Alterations in Cancer Risk, Progression, Treatment, and Mortality
by Pranay Ramteke, Ankita Deb, Varsha Shepal and Manoj Kumar Bhat
Cancers 2019, 11(9), 1402; https://doi.org/10.3390/cancers11091402 - 19 Sep 2019
Cited by 74 | Viewed by 12883
Abstract
Cancer and diabetes are amongst the leading causes of deaths worldwide. There is an alarming rise in cancer incidences and mortality, with approximately 18.1 million new cases and 9.6 million deaths in 2018. A major contributory but neglected factor for risk of neoplastic [...] Read more.
Cancer and diabetes are amongst the leading causes of deaths worldwide. There is an alarming rise in cancer incidences and mortality, with approximately 18.1 million new cases and 9.6 million deaths in 2018. A major contributory but neglected factor for risk of neoplastic transformation is hyperglycemia. Epidemiologically too, lifestyle patterns resulting in high blood glucose level, with or without the role of insulin, are more often correlated with cancer risk, progression, and mortality. The two conditions recurrently exist in comorbidity, and their interplay has rendered treatment regimens more challenging by restricting the choice of drugs, affecting surgical consequences, and having associated fatal complications. Limited comprehensive literature is available on their correlation, and a lack of clarity in understanding in such comorbid conditions contributes to higher mortality rates. Hence, a critical analysis of the elements responsible for enhanced mortality due to hyperglycemia-cancer concomitance is warranted. Given the lifestyle changes in the human population, increasing metabolic disorders, and glucose addiction of cancer cells, hyperglycemia related complications in cancer underline the necessity for further in-depth investigations. This review, therefore, attempts to shed light upon hyperglycemia associated factors in the risk, progression, mortality, and treatment of cancer to highlight important mechanisms and potential therapeutic targets. Full article
(This article belongs to the Special Issue Metabolic Reprogramming and Vulnerabilities in Cancer)
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30 pages, 5601 KiB  
Review
Anti-Tumor Potential of IMP Dehydrogenase Inhibitors: A Century-Long Story
by Rand Naffouje, Punita Grover, Hongyang Yu, Arun Sendilnathan, Kara Wolfe, Nazanin Majd, Eric P. Smith, Koh Takeuchi, Toshiya Senda, Satoshi Kofuji and Atsuo T. Sasaki
Cancers 2019, 11(9), 1346; https://doi.org/10.3390/cancers11091346 - 11 Sep 2019
Cited by 67 | Viewed by 10568
Abstract
The purine nucleotides ATP and GTP are essential precursors to DNA and RNA synthesis and fundamental for energy metabolism. Although de novo purine nucleotide biosynthesis is increased in highly proliferating cells, such as malignant tumors, it is not clear if this is merely [...] Read more.
The purine nucleotides ATP and GTP are essential precursors to DNA and RNA synthesis and fundamental for energy metabolism. Although de novo purine nucleotide biosynthesis is increased in highly proliferating cells, such as malignant tumors, it is not clear if this is merely a secondary manifestation of increased cell proliferation. Suggestive of a direct causative effect includes evidence that, in some cancer types, the rate-limiting enzyme in de novo GTP biosynthesis, inosine monophosphate dehydrogenase (IMPDH), is upregulated and that the IMPDH inhibitor, mycophenolic acid (MPA), possesses anti-tumor activity. However, historically, enthusiasm for employing IMPDH inhibitors in cancer treatment has been mitigated by their adverse effects at high treatment doses and variable response. Recent advances in our understanding of the mechanistic role of IMPDH in tumorigenesis and cancer progression, as well as the development of IMPDH inhibitors with selective actions on GTP synthesis, have prompted a reappraisal of targeting this enzyme for anti-cancer treatment. In this review, we summarize the history of IMPDH inhibitors, the development of new inhibitors as anti-cancer drugs, and future directions and strategies to overcome existing challenges. Full article
(This article belongs to the Special Issue Metabolic Reprogramming and Vulnerabilities in Cancer)
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26 pages, 1322 KiB  
Review
Metabolic Abnormalities in Glioblastoma and Metabolic Strategies to Overcome Treatment Resistance
by Weihua Zhou and Daniel R. Wahl
Cancers 2019, 11(9), 1231; https://doi.org/10.3390/cancers11091231 - 23 Aug 2019
Cited by 73 | Viewed by 7580
Abstract
Glioblastoma (GBM) is the most common and aggressive primary brain tumor and is nearly universally fatal. Targeted therapy and immunotherapy have had limited success in GBM, leaving surgery, alkylating chemotherapy and ionizing radiation as the standards of care. Like most cancers, GBMs rewire [...] Read more.
Glioblastoma (GBM) is the most common and aggressive primary brain tumor and is nearly universally fatal. Targeted therapy and immunotherapy have had limited success in GBM, leaving surgery, alkylating chemotherapy and ionizing radiation as the standards of care. Like most cancers, GBMs rewire metabolism to fuel survival, proliferation, and invasion. Emerging evidence suggests that this metabolic reprogramming also mediates resistance to the standard-of-care therapies used to treat GBM. In this review, we discuss the noteworthy metabolic features of GBM, the key pathways that reshape tumor metabolism, and how inhibiting abnormal metabolism may be able to overcome the inherent resistance of GBM to radiation and chemotherapy. Full article
(This article belongs to the Special Issue Metabolic Reprogramming and Vulnerabilities in Cancer)
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16 pages, 1048 KiB  
Review
Antioxidant Defenses: A Context-Specific Vulnerability of Cancer Cells
by Jordan A. Cockfield and Zachary T. Schafer
Cancers 2019, 11(8), 1208; https://doi.org/10.3390/cancers11081208 - 20 Aug 2019
Cited by 31 | Viewed by 6477
Abstract
Reactive oxygen species (ROS) are well known for their capacity to cause DNA damage, augment mutagenesis, and thereby promote oncogenic transformation. Similarly, agents that reduce ROS levels (antioxidants) are frequently thought to have anti-cancer properties given their propensity to minimize DNA damage and [...] Read more.
Reactive oxygen species (ROS) are well known for their capacity to cause DNA damage, augment mutagenesis, and thereby promote oncogenic transformation. Similarly, agents that reduce ROS levels (antioxidants) are frequently thought to have anti-cancer properties given their propensity to minimize DNA damage and mutagenesis. However, numerous clinical studies focused on antioxidants suggest that this is a facile premise and that antioxidant capacity can be important for cancer cells in a similar fashion to normal cells. As a consequence of this realization, numerous laboratories have been motivated to investigate the biological underpinnings explaining how and when antioxidant activity can potentially be beneficial to cancer cells. Relatedly, it has become clear that the reliance of cancer cells on antioxidant activity in certain contexts represents a potential vulnerability that could be exploited for therapeutic gain. Here, we review some of the recent, exciting findings documenting how cancer cells utilized antioxidant activity and under what circumstances this activity could represent an opportunity for selective elimination of cancer cells. Full article
(This article belongs to the Special Issue Metabolic Reprogramming and Vulnerabilities in Cancer)
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20 pages, 845 KiB  
Review
Reactive Oxygen Species in the Tumor Microenvironment: An Overview
by Frank Weinberg, Nithya Ramnath and Deepak Nagrath
Cancers 2019, 11(8), 1191; https://doi.org/10.3390/cancers11081191 - 16 Aug 2019
Cited by 275 | Viewed by 17073
Abstract
Reactive oxygen species (ROS) are important signaling molecules in cancer. The level of ROS will determine physiological effects. While high levels of ROS can cause damage to tissues and cell death, low levels of ROS can have a proliferative effect. ROS are produced [...] Read more.
Reactive oxygen species (ROS) are important signaling molecules in cancer. The level of ROS will determine physiological effects. While high levels of ROS can cause damage to tissues and cell death, low levels of ROS can have a proliferative effect. ROS are produced by tumor cells but also cellular components that make up the tumor microenvironment (TME). In this review, we discuss the mechanisms by which ROS can affect the TME with particular emphasis on tumor-infiltrating leukocytes. Greater insight into ROS biology in this setting may allow for therapeutic manipulation of ROS levels in order to remodel the tumor microenvironment and increase anti-tumor activity. Full article
(This article belongs to the Special Issue Metabolic Reprogramming and Vulnerabilities in Cancer)
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20 pages, 1349 KiB  
Review
Cancer Metabolism and the Evasion of Apoptotic Cell Death
by Aditi Sharma, Lawrence H. Boise and Mala Shanmugam
Cancers 2019, 11(8), 1144; https://doi.org/10.3390/cancers11081144 - 09 Aug 2019
Cited by 93 | Viewed by 8880
Abstract
Cellular growth and proliferation depend upon the acquisition and synthesis of specific metabolites. These metabolites fuel the bioenergy, biosynthesis, and redox potential required for duplication of cellular biomass. Multicellular organisms maintain tissue homeostasis by balancing signals promoting proliferation and removal of cells via [...] Read more.
Cellular growth and proliferation depend upon the acquisition and synthesis of specific metabolites. These metabolites fuel the bioenergy, biosynthesis, and redox potential required for duplication of cellular biomass. Multicellular organisms maintain tissue homeostasis by balancing signals promoting proliferation and removal of cells via apoptosis. While apoptosis is in itself an energy dependent process activated by intrinsic and extrinsic signals, whether specific nutrient acquisition (elevated or suppressed) and their metabolism regulates apoptosis is less well investigated. Normal cellular metabolism is regulated by lineage specific intrinsic features and microenvironment driven extrinsic features. In the context of cancer, genetic abnormalities, unconventional microenvironments and/or therapy engage constitutive pro-survival signaling to re-program and rewire metabolism to maintain survival, growth, and proliferation. It thus becomes particularly relevant to understand whether altered nutrient acquisition and metabolism in cancer can also contribute to the evasion of apoptosis and consequently therapy resistance. Our review attempts to dissect a causal relationship between two cancer hallmarks, i.e., deregulated cellular energetics and the evasion of programmed cell death with primary focus on the intrinsic pathway of apoptosis. Full article
(This article belongs to the Special Issue Metabolic Reprogramming and Vulnerabilities in Cancer)
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20 pages, 1370 KiB  
Review
Linking Cancer Metabolic Dysfunction and Genetic Instability through the Lens of Iron Metabolism
by Michael S. Petronek, Douglas R. Spitz, Garry R. Buettner and Bryan G. Allen
Cancers 2019, 11(8), 1077; https://doi.org/10.3390/cancers11081077 - 30 Jul 2019
Cited by 43 | Viewed by 7282
Abstract
Iron (Fe) is an essential element that plays a fundamental role in a wide range of cellular functions, including cellular proliferation, DNA synthesis, as well as DNA damage and repair. Because of these connections, iron has been strongly implicated in cancer development. Cancer [...] Read more.
Iron (Fe) is an essential element that plays a fundamental role in a wide range of cellular functions, including cellular proliferation, DNA synthesis, as well as DNA damage and repair. Because of these connections, iron has been strongly implicated in cancer development. Cancer cells frequently have changes in the expression of iron regulatory proteins. For example, cancer cells frequently upregulate transferrin (increasing uptake of iron) and down regulate ferroportin (decreasing efflux of intracellular iron). These changes increase the steady-state level of intracellular redox active iron, known as the labile iron pool (LIP). The LIP typically contains approximately 2% intracellular iron, which primarily exists as ferrous iron (Fe2+). The LIP can readily contribute to oxidative distress within the cell through Fe2+-dioxygen and Fenton chemistries, generating the highly reactive hydroxyl radical (HO•). Due to the reactive nature of the LIP, it can contribute to increased DNA damage. Mitochondrial dysfunction in cancer cells results in increased steady-state levels of hydrogen peroxide and superoxide along with other downstream reactive oxygen species. The increased presence of H2O2 and O2•− can increase the LIP, contributing to increased mitochondrial uptake of iron as well as genetic instability. Thus, iron metabolism and labile iron pools may play a central role connecting the genetic mutational theories of cancer to the metabolic theories of cancer. Full article
(This article belongs to the Special Issue Metabolic Reprogramming and Vulnerabilities in Cancer)
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24 pages, 2084 KiB  
Review
Metabolic Regulation of Redox Balance in Cancer
by Vinee Purohit, Diane M. Simeone and Costas A. Lyssiotis
Cancers 2019, 11(7), 955; https://doi.org/10.3390/cancers11070955 - 08 Jul 2019
Cited by 75 | Viewed by 8804
Abstract
Reactive oxygen species (ROS) are chemically active free radicals produced by partial reduction of oxygen that can activate discrete signaling pathways or disrupt redox homeostasis depending on their concentration. ROS interacts with biomolecules, including DNA, and can cause mutations that can transform normal [...] Read more.
Reactive oxygen species (ROS) are chemically active free radicals produced by partial reduction of oxygen that can activate discrete signaling pathways or disrupt redox homeostasis depending on their concentration. ROS interacts with biomolecules, including DNA, and can cause mutations that can transform normal cells into cancer cells. Furthermore, certain cancer-causing mutations trigger alterations in cellular metabolism that can increase ROS production, resulting in genomic instability, additional DNA mutations, and tumor evolution. To prevent excess ROS-mediated toxicity, cancer-causing mutations concurrently activate pathways that manage this oxidative burden. Hence, an understanding of the metabolic pathways that regulate ROS levels is imperative for devising therapies that target tumor cells. In this review, we summarize the dual role of metabolism as a generator and inhibitor of ROS in cancer and discuss current strategies to target the ROS axis. Full article
(This article belongs to the Special Issue Metabolic Reprogramming and Vulnerabilities in Cancer)
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15 pages, 898 KiB  
Review
Starve Cancer Cells of Glutamine: Break the Spell or Make a Hungry Monster?
by Jie Jiang, Sankalp Srivastava and Ji Zhang
Cancers 2019, 11(6), 804; https://doi.org/10.3390/cancers11060804 - 11 Jun 2019
Cited by 73 | Viewed by 8633
Abstract
Distinct from normal differentiated tissues, cancer cells reprogram nutrient uptake and utilization to accommodate their elevated demands for biosynthesis and energy production. A hallmark of these types of reprogramming is the increased utilization of, and dependency on glutamine, a nonessential amino acid, for [...] Read more.
Distinct from normal differentiated tissues, cancer cells reprogram nutrient uptake and utilization to accommodate their elevated demands for biosynthesis and energy production. A hallmark of these types of reprogramming is the increased utilization of, and dependency on glutamine, a nonessential amino acid, for cancer cell growth and survival. It is well-accepted that glutamine is a versatile biosynthetic substrate in cancer cells beyond its role as a proteinogenic amino acid. In addition, accumulating evidence suggests that glutamine metabolism is regulated by many factors, including tumor origin, oncogene/tumor suppressor status, epigenetic alternations and tumor microenvironment. However, despite the emerging understanding of why cancer cells depend on glutamine for growth and survival, the contribution of glutamine metabolism to tumor progression under physiological conditions is still under investigation, partially because the level of glutamine in the tumor environment is often found low. Since targeting glutamine acquisition and utilization has been proposed to be a new therapeutic strategy in cancer, it is central to understand how tumor cells respond and adapt to glutamine starvation for optimized therapeutic intervention. In this review, we first summarize the diverse usage of glutamine to support cancer cell growth and survival, and then focus our discussion on the influence of other nutrients on cancer cell adaptation to glutamine starvation as well as its implication in cancer therapy. Full article
(This article belongs to the Special Issue Metabolic Reprogramming and Vulnerabilities in Cancer)
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16 pages, 732 KiB  
Review
The Pleiotropic Effects of Glutamine Metabolism in Cancer
by Alex J. Bott, Sara Maimouni and Wei-Xing Zong
Cancers 2019, 11(6), 770; https://doi.org/10.3390/cancers11060770 - 04 Jun 2019
Cited by 88 | Viewed by 8651
Abstract
Metabolic programs are known to be altered in cancers arising from various tissues. Malignant transformation can alter signaling pathways related to metabolism and increase the demand for both energy and biomass for the proliferating cancerous cells. This scenario is further complexed by the [...] Read more.
Metabolic programs are known to be altered in cancers arising from various tissues. Malignant transformation can alter signaling pathways related to metabolism and increase the demand for both energy and biomass for the proliferating cancerous cells. This scenario is further complexed by the crosstalk between transformed cells and the microenvironment. One of the most common metabolic alterations, which occurs in many tissues and in the context of multiple oncogenic drivers, is the increased demand for the amino acid glutamine. Many studies have attributed this increased demand for glutamine to the carbon backbone and its role in the tricarboxylic acid (TCA) cycle anaplerosis. However, an increasing number of studies are now emphasizing the importance of glutamine functioning as a proteogenic building block, a nitrogen donor and carrier, an exchanger for import of other amino acids, and a signaling molecule. Herein, we highlight the recent literature on glutamine’s versatile role in cancer, with a focus on nitrogen metabolism, and therapeutic implications of glutamine metabolism in cancer. Full article
(This article belongs to the Special Issue Metabolic Reprogramming and Vulnerabilities in Cancer)
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20 pages, 1521 KiB  
Review
Cancer Cells Tune the Signaling Pathways to Empower de Novo Synthesis of Nucleotides
by Elodie Villa, Eunus S. Ali, Umakant Sahu and Issam Ben-Sahra
Cancers 2019, 11(5), 688; https://doi.org/10.3390/cancers11050688 - 17 May 2019
Cited by 164 | Viewed by 20163
Abstract
Cancer cells exhibit a dynamic metabolic landscape and require a sufficient supply of nucleotides and other macromolecules to grow and proliferate. To meet the metabolic requirements for cell growth, cancer cells must stimulate de novo nucleotide synthesis to obtain adequate nucleotide pools to [...] Read more.
Cancer cells exhibit a dynamic metabolic landscape and require a sufficient supply of nucleotides and other macromolecules to grow and proliferate. To meet the metabolic requirements for cell growth, cancer cells must stimulate de novo nucleotide synthesis to obtain adequate nucleotide pools to support nucleic acid and protein synthesis along with energy preservation, signaling activity, glycosylation mechanisms, and cytoskeletal function. Both oncogenes and tumor suppressors have recently been identified as key molecular determinants for de novo nucleotide synthesis that contribute to the maintenance of homeostasis and the proliferation of cancer cells. Inactivation of tumor suppressors such as TP53 and LKB1 and hyperactivation of the mTOR pathway and of oncogenes such as MYC, RAS, and AKT have been shown to fuel nucleotide synthesis in tumor cells. The molecular mechanisms by which these signaling hubs influence metabolism, especially the metabolic pathways for nucleotide synthesis, continue to emerge. Here, we focus on the current understanding of the molecular mechanisms by which oncogenes and tumor suppressors modulate nucleotide synthesis in cancer cells and, based on these insights, discuss potential strategies to target cancer cell proliferation. Full article
(This article belongs to the Special Issue Metabolic Reprogramming and Vulnerabilities in Cancer)
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19 pages, 1091 KiB  
Review
The Non-Essential Amino Acid Cysteine Becomes Essential for Tumor Proliferation and Survival
by Joseph A. Combs and Gina M. DeNicola
Cancers 2019, 11(5), 678; https://doi.org/10.3390/cancers11050678 - 16 May 2019
Cited by 154 | Viewed by 10784
Abstract
The non-essential amino acid cysteine is used within cells for multiple processes that rely on the chemistry of its thiol group. Under physiological conditions, many non-transformed tissues rely on glutathione, circulating cysteine, and the de novo cysteine synthesis (transsulfuration) pathway as sources of [...] Read more.
The non-essential amino acid cysteine is used within cells for multiple processes that rely on the chemistry of its thiol group. Under physiological conditions, many non-transformed tissues rely on glutathione, circulating cysteine, and the de novo cysteine synthesis (transsulfuration) pathway as sources of intracellular cysteine to support cellular processes. In contrast, many cancers require exogeneous cystine for proliferation and viability. Herein, we review how the cystine transporter, xCT, and exogenous cystine fuel cancer cell proliferation and the mechanisms that regulate xCT expression and activity. Further, we discuss the potential contribution of additional sources of cysteine to the cysteine pool and what is known about the essentiality of these processes in cancer cells. Finally, we discuss whether cyst(e)ine dependency and associated metabolic alterations represent therapeutically targetable metabolic vulnerabilities. Full article
(This article belongs to the Special Issue Metabolic Reprogramming and Vulnerabilities in Cancer)
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17 pages, 1108 KiB  
Review
The Diverse Functions of Non-Essential Amino Acids in Cancer
by Bo-Hyun Choi and Jonathan L. Coloff
Cancers 2019, 11(5), 675; https://doi.org/10.3390/cancers11050675 - 15 May 2019
Cited by 122 | Viewed by 15206
Abstract
Far beyond simply being 11 of the 20 amino acids needed for protein synthesis, non-essential amino acids play numerous important roles in tumor metabolism. These diverse functions include providing precursors for the biosynthesis of macromolecules, controlling redox status and antioxidant systems, and serving [...] Read more.
Far beyond simply being 11 of the 20 amino acids needed for protein synthesis, non-essential amino acids play numerous important roles in tumor metabolism. These diverse functions include providing precursors for the biosynthesis of macromolecules, controlling redox status and antioxidant systems, and serving as substrates for post-translational and epigenetic modifications. This functional diversity has sparked great interest in targeting non-essential amino acid metabolism for cancer therapy and has motivated the development of several therapies that are either already used in the clinic or are currently in clinical trials. In this review, we will discuss the important roles that each of the 11 non-essential amino acids play in cancer, how their metabolic pathways are linked, and how researchers are working to overcome the unique challenges of targeting non-essential amino acid metabolism for cancer therapy. Full article
(This article belongs to the Special Issue Metabolic Reprogramming and Vulnerabilities in Cancer)
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15 pages, 1001 KiB  
Review
Fibroblasts as Modulators of Local and Systemic Cancer Metabolism
by Hannah Sanford-Crane, Jaime Abrego and Mara H. Sherman
Cancers 2019, 11(5), 619; https://doi.org/10.3390/cancers11050619 - 03 May 2019
Cited by 52 | Viewed by 6264
Abstract
Fibroblast activation is an accompanying feature of solid tumor progression, resembling a conserved host response to tissue damage. Cancer-associated fibroblasts (CAFs) comprise a heterogeneous and plastic population with increasingly appreciated roles in tumor growth, metastatic capacity, and response to therapy. Classical features of [...] Read more.
Fibroblast activation is an accompanying feature of solid tumor progression, resembling a conserved host response to tissue damage. Cancer-associated fibroblasts (CAFs) comprise a heterogeneous and plastic population with increasingly appreciated roles in tumor growth, metastatic capacity, and response to therapy. Classical features of fibroblasts in a wound-healing response, including profound extracellular matrix production and cytokine release, are recapitulated in cancer. Emerging evidence suggests that fibroblastic cells in the microenvironments of solid tumors also critically modulate cellular metabolism in the neoplastic compartment through mechanisms including paracrine transfer of metabolites or non-cell-autonomous regulation of metabolic signaling pathways. These metabolic functions may represent common mechanisms by which fibroblasts stimulate growth of the regenerating epithelium during a wound-healing reaction, or may reflect unique co-evolution of cancer cells and surrounding stroma within the tumor microenvironment. Here we review the recent literature supporting an important role for CAFs in regulation of cancer cell metabolism, and relevant pathways that may serve as targets for therapeutic intervention. Full article
(This article belongs to the Special Issue Metabolic Reprogramming and Vulnerabilities in Cancer)
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