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Is Cancer a Metabolic Disease? The Answer of Metabolomics
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Is Cancer a Metabolic Disease? The Answer of Metabolomics

A special issue of Metabolites (ISSN 2218-1989). This special issue belongs to the section "Advances in Metabolomics".

Deadline for manuscript submissions: closed (15 December 2021) | Viewed by 48789

Special Issue Editor

Dr. Daniel Oscar Cicero

E-Mail Website
Guest Editor
Department of Chemical Science and Technology, Università degli Studi di Roma Tor Vergata, 1, 00133 Rome, Italy
Interests: nuclear magnetic resonance; metabolomics; bladder cancer; cardiovascular diseases; metabolism and exercise
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Cancer is almost unanimously considered to be the result of genetic alterations at the nuclear level of oncogenes and tumor suppressor genes. This theory is considered almost a dogma, to the point that the National Cancer Institute states that “Cancer is a genetic disease—that is, it is caused by changes to genes that control the way our cells function, especially how they grow and divide”. In this context, the metabolic changes observed in cells, tissues, and organisms are the consequence of these genetic signatures. However, several inconsistencies of this theory have been observed, giving rise to an alternative explanation of cancer as a disease that begins with a mitochondrial metabolic dysfunction, in some sense returning to Otto Warburg’s original observation. Recent data indicate, however, that mitochondrial metabolism can be down- or upregulated, giving rise to two types of tumors: oxidative and nonoxidative. From this perspective, metabolic alterations are the cause of the genetic alterations that influence the development of cancer. What causes metabolic alteration is a matter of discussion, but potential candidates are increased inflammation, increased ROS formation, and overstimulation of PARPs. Although we do not yet have enough evidence to fully embrace the metabolic theory, or to accurately weight the relative importance that both factors, genetic mutations and metabolic alterations, play in the origin of the disease, metabolomics can make a significant contribution. The fact that metabolism can have a crucial role places it on the same level as genomics and transcriptomics for the diagnosis and prognosis of cancer and assigns it a unique place for the discovery of new specific therapeutic targets. In this exciting field, we still have almost everything to discover and much to gain in the understanding of a disease that has become one of the most demanding challenges of modern medicine.

Prof. Dr. Daniel Oscar Cicero
Guest Editor

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Keywords

  • Cancer metabolism
  • Metabolomics
  • Carcinogenesis
  • Cancer biomarkers

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Published Papers (4 papers)

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Research

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16 pages, 3792 KiB  
Article
AMPK-Mediated Metabolic Switching Is High Effective for Phytochemical Levo-Tetrahydropalmatine (l-THP) to Reduce Hepatocellular Carcinoma Tumor Growth
by Xunzhe Yin, Wenbo Li, Jiaxin Zhang, Wenjing Zhao, Huaxing Cai, Chi Zhang, Zuojia Liu, Yan Guo and Jin Wang
Metabolites 2021, 11(12), 811; https://doi.org/10.3390/metabo11120811 - 29 Nov 2021
Cited by 11 | Viewed by 2744
Abstract
Targeting cancer cell metabolism has been an attractive approach for cancer treatment. However, the role of metabolic alternation in cancer is still unknown whether it functions as a tumor promoter or suppressor. Applying the cancer gene-metabolism integrative network model, we predict adenosine monophosphate-activated [...] Read more.
Targeting cancer cell metabolism has been an attractive approach for cancer treatment. However, the role of metabolic alternation in cancer is still unknown whether it functions as a tumor promoter or suppressor. Applying the cancer gene-metabolism integrative network model, we predict adenosine monophosphate-activated protein kinase (AMPK) to function as a central hub of metabolic landscape switching in specific liver cancer subtypes. For the first time, we demonstrate that the phytochemical levo-tetrahydropalmatine (l-THP), a Corydalis yanhusuo-derived clinical drug, as an AMPK activator via autophagy-mediated metabolic switching could kill the hepatocellular carcinoma HepG2 cells. Mechanistically, l-THP promotes the autophagic response by activating the AMPK-mTOR-ULK1 and the ROS-JNK-ATG cascades and impairing the ERK/AKT signaling. All these processes ultimately synergize to induce the decreased mitochondrial oxidative phosphorylation (OXPHOS) and mitochondrial damage. Notably, silencing AMPK significantly inhibits the autophagic flux and recovers the decreased OXPHOS metabolism, which results in HepG2 resistance to l-THP treatment. More importantly, l-THP potently reduces the growth of xenograft HepG2 tumor in nude mice without affecting other organs. From this perspective, our findings support the conclusion that metabolic change is an alternative approach to influence the development of HCC. Full article
(This article belongs to the Special Issue Is Cancer a Metabolic Disease? The Answer of Metabolomics)
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Review

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29 pages, 5237 KiB  
Review
Metabolomics and the Multi-Omics View of Cancer
by David Wishart
Metabolites 2022, 12(2), 154; https://doi.org/10.3390/metabo12020154 - 7 Feb 2022
Cited by 23 | Viewed by 16606
Abstract
Cancer is widely regarded to be a genetic disease. Indeed, over the past five decades, the genomic perspective on cancer has come to almost completely dominate the field. However, this genome-only view is incomplete and tends to portray cancer as a disease that [...] Read more.
Cancer is widely regarded to be a genetic disease. Indeed, over the past five decades, the genomic perspective on cancer has come to almost completely dominate the field. However, this genome-only view is incomplete and tends to portray cancer as a disease that is highly heritable, driven by hundreds of complex genetic interactions and, consequently, difficult to prevent or treat. New evidence suggests that cancer is not as heritable or purely genetic as once thought and that it really is a multi-omics disease. As highlighted in this review, the genome, the exposome, and the metabolome all play roles in cancer’s development and manifestation. The data presented here show that >90% of cancers are initiated by environmental exposures (the exposome) which lead to cancer-inducing genetic changes. The resulting genetic changes are, then, propagated through the altered DNA of the proliferating cancer cells (the genome). Finally, the dividing cancer cells are nourished and sustained by genetically reprogrammed, cancer-specific metabolism (the metabolome). As shown in this review, all three “omes” play roles in initiating cancer. Likewise, all three “omes” interact closely, often providing feedback to each other to sustain or enhance tumor development. Thanks to metabolomics, these multi-omics feedback loops are now much more evident and their roles in explaining the hallmarks of cancer are much better understood. Importantly, this more holistic, multi-omics view portrays cancer as a disease that is much more preventable, easier to understand, and potentially, far more treatable. Full article
(This article belongs to the Special Issue Is Cancer a Metabolic Disease? The Answer of Metabolomics)
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23 pages, 1192 KiB  
Review
Urinary Metabolic Markers of Bladder Cancer: A Reflection of the Tumor or the Response of the Body?
by Greta Petrella, Giorgia Ciufolini, Riccardo Vago and Daniel Oscar Cicero
Metabolites 2021, 11(11), 756; https://doi.org/10.3390/metabo11110756 - 31 Oct 2021
Cited by 12 | Viewed by 4782
Abstract
This work will review the metabolic information that various studies have obtained in recent years on bladder cancer, with particular attention to discovering biomarkers in urine for the diagnosis and prognosis of this disease. In principle, they would be capable of complementing cystoscopy, [...] Read more.
This work will review the metabolic information that various studies have obtained in recent years on bladder cancer, with particular attention to discovering biomarkers in urine for the diagnosis and prognosis of this disease. In principle, they would be capable of complementing cystoscopy, an invasive but nowadays irreplaceable technique or, in the best case, of replacing it. We will evaluate the degree of reproducibility that the different experiments have shown in the indication of biomarkers, and a synthesis will be attempted to obtain a consensus list that is more likely to become a guideline for clinical practice. In further analysis, we will inquire into the origin of these dysregulated metabolites in patients with bladder cancer. For this purpose, it will be helpful to compare the imbalances measured in urine with those known inside tumor cells or tissues. Although the urine analysis is sometimes considered a liquid biopsy because of its direct contact with the tumor in the bladder wall, it contains metabolites from all organs and tissues of the body, and the tumor is separated from urine by the most impermeable barrier found in mammals. The distinction between the specific and systemic responses can help understand the disease and its consequences in more depth. Full article
(This article belongs to the Special Issue Is Cancer a Metabolic Disease? The Answer of Metabolomics)
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Other

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21 pages, 2112 KiB  
Concept Paper
Can the Mitochondrial Metabolic Theory Explain Better the Origin and Management of Cancer than Can the Somatic Mutation Theory?
by Thomas N. Seyfried and Christos Chinopoulos
Metabolites 2021, 11(9), 572; https://doi.org/10.3390/metabo11090572 - 25 Aug 2021
Cited by 24 | Viewed by 22895
Abstract
A theory that can best explain the facts of a phenomenon is more likely to advance knowledge than a theory that is less able to explain the facts. Cancer is generally considered a genetic disease based on the somatic mutation theory (SMT) where [...] Read more.
A theory that can best explain the facts of a phenomenon is more likely to advance knowledge than a theory that is less able to explain the facts. Cancer is generally considered a genetic disease based on the somatic mutation theory (SMT) where mutations in proto-oncogenes and tumor suppressor genes cause dysregulated cell growth. Evidence is reviewed showing that the mitochondrial metabolic theory (MMT) can better account for the hallmarks of cancer than can the SMT. Proliferating cancer cells cannot survive or grow without carbons and nitrogen for the synthesis of metabolites and ATP (Adenosine Triphosphate). Glucose carbons are essential for metabolite synthesis through the glycolysis and pentose phosphate pathways while glutamine nitrogen and carbons are essential for the synthesis of nitrogen-containing metabolites and ATP through the glutaminolysis pathway. Glutamine-dependent mitochondrial substrate level phosphorylation becomes essential for ATP synthesis in cancer cells that over-express the glycolytic pyruvate kinase M2 isoform (PKM2), that have deficient OxPhos, and that can grow in either hypoxia (0.1% oxygen) or in cyanide. The simultaneous targeting of glucose and glutamine, while elevating levels of non-fermentable ketone bodies, offers a simple and parsimonious therapeutic strategy for managing most cancers. Full article
(This article belongs to the Special Issue Is Cancer a Metabolic Disease? The Answer of Metabolomics)
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