Oncometabolism

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Oncometabolism is the field of study that focuses on the metabolic changes that occur in cells that make up the tumor microenvironment (TME) and accompany oncogenesis and tumor progression toward a neoplastic state. [1]

Contents

Cells with increased growth and survivability differ from non-tumorigenic cells in terms of metabolism. [2] The Warburg Effect, which describes how cancer cells change their metabolism to become more oncogenic in order to proliferate and eventually invade other tissues in a process known as metastasis. [1]

The chemical reactions associated with oncometabolism are triggered by the alteration of oncogenes, which are genes that have the potential to cause cancer. [3] These genes can be functional and active during physiological conditions, producing normal amounts of metabolites. Their upregulation as a result of DNA damage can result in an overabundance of these metabolites, and lead to tumorigenesis. These metabolites are known as oncometabolites, and can act as biomarkers. [4]

Otto Heinrich Warburg, considered the "Father of Oncometabolism" for his early discoveries in the field Otto Warburg.jpg
Otto Heinrich Warburg, considered the "Father of Oncometabolism" for his early discoveries in the field

History

In the 1920s, Otto Heinrich Warburg discovered an intriguing bioenergetic phenotype shared by most tumor cells: a higher-than-normal reliance on lactic acid fermentation for energy generation. He is known as the "Father of Oncometabolism". [1] [2] Although the roots of this research field trace back to the 1920s, it was only recently recognized [1] Over the last decade, research on cancer progression has focused on the role of shifting metabolic pathways for both the cancer and immune cells, leading to an increase interest in characterizing the metabolic alterations that cells undergo in the TME. [5]

Warburg Effect

In the absence of hypoxic conditions (i.e. physiological levels of oxygen), cancer cells preferentially convert glucose to lactate, according to Otto H. Warburg, who believed that aerobic glycolysis was the key metabolic change in cancer cell malignancy. The "Warburg effect" was later coined to describe this metabolic shift. [6] Warburg thought this change in metabolism was due to mitochondrial "respiration injury", but this interpretation was questioned by other researchers in 1956 showing that intact and functional cytochromes detected in most tumor cells clearly speak against a general mitochondrial dysfunction. [7] Furthermore, Potter et al. and several other authors provided significant evidence that oxidative phosphorylation and a normal Krebs cycle persist in the vast majority malignant tumors, adding to the growing body of evidence that most cancers exhibit the Warburg effect while maintaining a proper mitochondrial respiration. [6] [8] Dang et al. [9] in 2008 provided evidence that the tumor tissue sections used in Warburg's experiments should have been thinner for the oxygen diffusion constants employed, implying that the tissue slices studied were partially hypoxic and the calculated critical diffusion distance was of 470 micrometers. [6] As a result, endless debates and discussions about Warburg's discovery took place and have piqued the interest of scientists all over the world, which has helped bring attention to cell metabolism in cancer and immune cells and the use of modern technology to discover what these pathways are and how they are modified as well as potential therapeutic targets.

Metabolic reprogramming

Simplified view of the aerobic glycolysis (Warburg's effect). Warburg's effect.png
Simplified view of the aerobic glycolysis (Warburg's effect).

Carcinogenic cells undergo a metabolic rewiring during oncogenesis, and oncometabolites play an important role. In cancer, there are several reprogrammed metabolic pathways that help cells survive when nutrients are scarce: Aerobic glycolysis, an increase in glycolytic flux, also known as the Warburg effect, allows glycolytic intermediates to supply subsidiary pathways to meet the metabolic demands of proliferating tumorigenic cells. [10] Another studied reprogrammed pathway is gain of function of the oncogene MYC. This gene encodes a transcription factor that boosts the expression of a number of genes involved in anabolic growth via mitochondrial metabolism. [11] Oncometabolite production is another example of metabolic deregulation. [12]

Oncometabolites

Oncometabolites are metabolites whose abundance increases markedly in cancer cells through loss-of-function or gain-of-function mutations in specific enzymes involved in their production, the accumulation of these endogenous metabolites initiates or sustains tumor growth and metastasis. [13] Cancer cells rely on aerobic glycolysis, which is reached through defects in enzymes involved in normal cell metabolism, this allows the cancer cells to meet their energy needs and divert acetyl-CoA from the TCA cycle to build essential biomolecules such as amino acids and lipids. [14] These defects cause an overabundance of endogenous metabolites, which are frequently involved in critical epigenetic changes and signaling pathways that have a direct impact on cancer cell metabolism. [15]

OncometaboliteRole Oncogenes Enzyme affectedAssociated malignanciesReferences
D-2-hydroxyglutarate Inhibits ATP synthase and mTOR signallingIDH1

IDH2

 Isocitrate dehydrogenase Brain cancer, Leukemia [15] [16] [17] [13]
Succinate Inhibits 2-oxoglutarate-dependent oxygenaseSDHA,SDHB,SDHC,SDHD,SDHAF1,SDHAF2 succinate dehydrogenase Renal and Thyroid tumors [15] [13]
Fumarate Inhibits 2-oxoglutarate-dependent oxygenaseFH Fumarate hydratase Leiomyomata, Renal cysts [15] [16] [13]
Glutamine**(Primary carbon-source for the biosynthesis of the oncometabolite 2-hydroxyglutarate) [18] [19]
Sarcosine Activates mTOR signalling pathwayGNMT Glycine-N-methyltransferase Pancreatic cancer, Hepatocellular carcinoma [18] [20] [21] [13] [22] [23]
Asparagine Anti-apoptotic agentASNS Asparagine synthetase Acute Lymphoblastic Leukemia [18] [13] [24]
Choline Methyl donor for DNA methylation which disrupts DNA repairPCYT1Aphosphate cytidylyltransferase 1 choline-αBreast, Brain and Prostate cancer [18] [13] [24]
LactateInduces local immunosuppressionLDHA Lactate dehydrogenase A Various types of cancer [25] [13] [26]

Epigenetics

Oncometabolite dysregulation and cancer progression are linked to epigenetic changes in cancer cells. Several mechanisms have been linked to D-2-hydroxyglutarate, succinate, and fumarate with the inhibition of α-KG–dependent dioxygenases, this causes epigenetic changes that affect the expression of genes involved in cell differentiation and the development of malignant characteristics. [27] The group of Timothy A. Chan [28] described a mechanism by which abnormal accumulation of the oncometabolite D-2-hydroxyglutarate in brain tumor samples increased DNA methylation, a process that has been shown to play a key role in oncogenesis. [29] On the other hand, in paraganglioma cells, succinate and fumarate were found to methylate histones, effectively silencing the genes PNMT and KRT19, which are involved in neuroendocrine differentiation and epithelial-mesenchymal transition, respectively. [30]

Biomarkers for cancer detection

The discovery of oncometabolites has ushered in a new era in cancer biology, one that has the potential to improve patient care. The discovery of new therapeutic and reliable markers that exploit vulnerabilities of cancer cells, are being used to targeting either upstream or downstream effectors of these pathways. [15] Oncometabolites can be used as diagnostic biomarkers and may be able to assist oncologists in making more precise decisions in early stages of tumorigenesis, particularly in predicting more aggressive tumor behavior. [4]

Isocitrate dehydrogenase

Crystallographic structure of protein isocitrate dehydrogenase. Isocitrate dehydrogenase.png
Crystallographic structure of protein isocitrate dehydrogenase.

The detection of D-2-hydroxyglutarate in glioma patients using proton magnetic resonance spectroscopy (MRS) has been shown to be a noninvasive procedure. The presence of IDH1 or IDH2 mutations was linked to the detection of this oncometabolite 100 percent of the time. [31] [27] IDH2/R140Q is a specific mutation that has shown promising results after its inhibition by the small molecule AGI-6780. [32] Therefore, limiting the supply of D-2-hydroxyglutarate by inhibiting the detected mutant IDH enzymes could be a good therapeutical approach to IDH-mutant cancers. [33]

Succinate dehydrogenase

IHC staining has been shown to be a useful diagnostic tool for prioritizing patients for SDH mutation testing in early stages of cancer. The absence of SDHB in IHC staining would be linked to the presence of SDH oncogene mutations. [34] The already commercialized drug decitabine (Dacogen®) could be an effective therapy to repress the migration capacities of SDHB-mutant cells, [30]

Fumarate hydratase

IHC staining for FH is used to detect lack of this protein in patients with papillary renal cell carcinoma type 2. [35] The lack of FH in renal carcinoma cells induces pro-survival metabolic adaptations where several cascades are affected. [36]

Glycine-N-methyltransferase

Downregulation of glycine-N-methyltransferase has been linked to hepatocellular carcinoma and pancreatic cancer. Serving this as a reliable marker for oncogenesis. [22] When compared to patients with deletions in GNMT, patients with no deletions early-stage pancreatic cancer had twice the median months overall survival. [23]

Applications

Oncometabolomics

Metabolomics can be applied to oncometabolism, since the changes in cancer's genomic, transcriptomic, and proteomic profiles can result in changes in downstream metabolic pathways. With this information we can elucidate the responsible pathways and oncometabolites for various diseases. Actually, through the use of this technique, the dysregulation of the pyruvate kinase enzyme in glucose metabolism was discovered in cancer cells. Another common used technique is glucose or glutamine labeled with 13C to show that the TCA cycle is used to generate large amounts of fatty acids (phospholipids) and to replenish the TCA cycle intermediates. [37] But oncometabolomics does not necessarily need to be used on cancer cells, but on cells immediately surrounding them in the TME. [38]

Metabolomics applied to cancer has the potential to significantly improve current oncological treatments and has a great diagnostic value, since metabolic changes are the prequel of phenotypic changes in cells (thus tissues and organs) making it suitable for early detection of difficult-to-detect cancers. [14] This also leads to a more personalized medicine and customize an individual's cancer treatment according to their specific oncometabolite profiles, which would allow for better cancer therapy customization or informed adjustments. [13] [39]

Software and libraries

Ingenuity Pathway Analysis (IPA)

Ingenuity Pathway Analysis (IPA) is a metabolic pathway analysis software package that helps researchers model, analyze, and comprehend complex biological systems by associating specific metabolites with potential metabolic pathways for data analysis. [40] This software has been used by researchers to elucidate regulatory networks on oncometabolites like hydroxyglutarate. [41]

Metabolights

Metabolights is an open-access database for metabolomics research that collects all experimental data from leading journals' metabolic experiments. [42] Since its initial release in 2012, the MetaboLights repository has seen consistent year-on-year growth. It is a resource that surged in response to the needs of the scientific community to easy access to metabolite data. [43] [44]

Research

Transmission electron microscopy of purified exosomes. Exosomas vesiculas Cardiomiocito.png
Transmission electron microscopy of purified exosomes.

Cancer research has been ongoing for centuries, trying to elucidate the origin of its cause. As cancer research evolves with time, the scientific community tends to pay more attention to cell metabolism and how to target these metabolic needs and changes that cells undergo during carcinogenesis. [45] There is growing evidence that metabolic dependencies in cancer are influenced by tissue environment, being this important to consider the TME for different in vitro and in vivo models to study oncometabolism in different cancer scenarios. [46]

There is extensive research on the modulation of BET proteins in cancer models of breast. These proteins appear to be involved in oncometabolism and targeting and uncoupling BRD4 actions in carcinogenic cells, as well as stopping pro-migratory signals and changing cytokine metabolism, particularly IL-6. [47] The same group has reported on the importance of exosomes in the TME and how these vesicles, shed by adipocytes, can carry a specific molecular cargo that causes metabolic changes in the cell, leading to pro-metastatic changes in the recipient breast cancer cells. [48]

Related Research Articles

<span class="mw-page-title-main">Citric acid cycle</span> Interconnected biochemical reactions releasing energy

The citric acid cycle—also known as the Krebs cycle, Szent–Györgyi–Krebs cycle, or TCA cycle —is a series of biochemical reactions to release the energy stored in nutrients through the oxidation of acetyl-CoA derived from carbohydrates, fats, proteins, and alcohol. The chemical energy released is available in the form of ATP. The Krebs cycle is used by organisms that respire to generate energy, either by anaerobic respiration or aerobic respiration. In addition, the cycle provides precursors of certain amino acids, as well as the reducing agent NADH, that are used in numerous other reactions. Its central importance to many biochemical pathways suggests that it was one of the earliest components of metabolism. Even though it is branded as a "cycle", it is not necessary for metabolites to follow only one specific route; at least three alternative segments of the citric acid cycle have been recognized.

<span class="mw-page-title-main">Metabolic pathway</span> Linked series of chemical reactions occurring within a cell

In biochemistry, a metabolic pathway is a linked series of chemical reactions occurring within a cell. The reactants, products, and intermediates of an enzymatic reaction are known as metabolites, which are modified by a sequence of chemical reactions catalyzed by enzymes. In most cases of a metabolic pathway, the product of one enzyme acts as the substrate for the next. However, side products are considered waste and removed from the cell.

<span class="mw-page-title-main">Succinic acid</span> Dicarboxylic acid

Succinic acid is a dicarboxylic acid with the chemical formula (CH2)2(CO2H)2. In living organisms, succinic acid takes the form of an anion, succinate, which has multiple biological roles as a metabolic intermediate being converted into fumarate by the enzyme succinate dehydrogenase in complex 2 of the electron transport chain which is involved in making ATP, and as a signaling molecule reflecting the cellular metabolic state.

<span class="mw-page-title-main">Metabolomics</span> Scientific study of chemical processes involving metabolites

Metabolomics is the scientific study of chemical processes involving metabolites, the small molecule substrates, intermediates, and products of cell metabolism. Specifically, metabolomics is the "systematic study of the unique chemical fingerprints that specific cellular processes leave behind", the study of their small-molecule metabolite profiles. The metabolome represents the complete set of metabolites in a biological cell, tissue, organ, or organism, which are the end products of cellular processes. Messenger RNA (mRNA), gene expression data, and proteomic analyses reveal the set of gene products being produced in the cell, data that represents one aspect of cellular function. Conversely, metabolic profiling can give an instantaneous snapshot of the physiology of that cell, and thus, metabolomics provides a direct "functional readout of the physiological state" of an organism. There are indeed quantifiable correlations between the metabolome and the other cellular ensembles, which can be used to predict metabolite abundances in biological samples from, for example mRNA abundances. One of the ultimate challenges of systems biology is to integrate metabolomics with all other -omics information to provide a better understanding of cellular biology.

<span class="mw-page-title-main">Metabolome</span> Complete set of small molecules in a biological sample

The metabolome refers to the complete set of small-molecule chemicals found within a biological sample. The biological sample can be a cell, a cellular organelle, an organ, a tissue, a tissue extract, a biofluid or an entire organism. The small molecule chemicals found in a given metabolome may include both endogenous metabolites that are naturally produced by an organism as well as exogenous chemicals that are not naturally produced by an organism.

<span class="mw-page-title-main">Isocitrate dehydrogenase</span> Class of enzymes

Isocitrate dehydrogenase (IDH) (EC 1.1.1.42) and (EC 1.1.1.41) is an enzyme that catalyzes the oxidative decarboxylation of isocitrate, producing alpha-ketoglutarate (α-ketoglutarate) and CO2. This is a two-step process, which involves oxidation of isocitrate (a secondary alcohol) to oxalosuccinate (a ketone), followed by the decarboxylation of the carboxyl group beta to the ketone, forming alpha-ketoglutarate. In humans, IDH exists in three isoforms: IDH3 catalyzes the third step of the citric acid cycle while converting NAD+ to NADH in the mitochondria. The isoforms IDH1 and IDH2 catalyze the same reaction outside the context of the citric acid cycle and use NADP+ as a cofactor instead of NAD+. They localize to the cytosol as well as the mitochondrion and peroxisome.

<span class="mw-page-title-main">Birt–Hogg–Dubé syndrome</span> Rare autosomal dominant cancer syndrome

Birt–Hogg–Dubé syndrome (BHD), also Hornstein–Birt–Hogg–Dubé syndrome, Hornstein–Knickenberg syndrome, and fibrofolliculomas with trichodiscomas and acrochordons is a human, adult onset, autosomal dominant genetic disorder caused by a mutation in the folliculin (FLCN) gene. It can cause susceptibility to kidney cancer, renal and pulmonary cysts, and noncancerous tumors of the hair follicles, called fibrofolliculomas. The symptoms seen in each family are unique, and can include any combination of the three symptoms. Fibrofolliculomas are the most common manifestation, found on the face and upper trunk in over 80% of people with BHD over the age of 40. Pulmonary cysts are equally common (84%) and 24% of people with BHD eventually experience a collapsed lung. Kidney tumors, both cancerous and benign, occur in 14–34% of people with BHD; the associated kidney cancers are often rare hybrid tumors.

In oncology, the Warburg effect is the observation that most cancer use anaerobic glycolysis for energy generation rather than the mechanisms used by non-cancerous cells. This observation was first published by Otto Heinrich Warburg, who was awarded the 1931 Nobel Prize in Physiology for his "discovery of the nature and mode of action of the respiratory enzyme". The existence of the Warburg effect has fuelled popular misconceptions that cancer can be treated by dietary reductions in sugar and carbohydrate, according to an article in the Lancet.

<span class="mw-page-title-main">Tumor metabolome</span>

The study of the tumor metabolism, also known as tumor metabolome describes the different characteristic metabolic changes in tumor cells. The characteristic attributes of the tumor metabolome are high glycolytic enzyme activities, the expression of the pyruvate kinase isoenzyme type M2, increased channeling of glucose carbons into synthetic processes, such as nucleic acid, amino acid and phospholipid synthesis, a high rate of pyrimidine and purine de novo synthesis, a low ratio of Adenosine triphosphate and Guanosine triphosphate to Cytidine triphosphate and Uridine triphosphate, low Adenosine monophosphate levels, high glutaminolytic capacities, release of immunosuppressive substances and dependency on methionine.

<span class="mw-page-title-main">Warburg hypothesis</span> Hypothesis explaining cancer

The Warburg hypothesis, sometimes known as the Warburg theory of cancer, postulates that the driver of carcinogenesis is insufficient cellular respiration caused by insult (damage) to mitochondria. The Warburg effect, on the other hand, describes the observation that cancer cells, and many cells grown in vitro, exhibit glucose fermentation even when enough oxygen is present to properly respire. In other words, instead of fully respiring in the presence of adequate oxygen, cancer cells ferment. The Warburg hypothesis is that the Warburg effect is the root cause of cancer.

<span class="mw-page-title-main">KRAS</span> Protein-coding gene in humans

KRAS is a gene that provides instructions for making a protein called K-Ras, a part of the RAS/MAPK pathway. The protein relays signals from outside the cell to the cell's nucleus. These signals instruct the cell to grow and divide (proliferate) or to mature and take on specialized functions (differentiate). It is called KRAS because it was first identified as a viral oncogene in the KirstenRAt Sarcoma virus. The oncogene identified was derived from a cellular genome, so KRAS, when found in a cellular genome, is called a proto-oncogene.

<span class="mw-page-title-main">MTAP</span> Protein-coding gene in the species Homo sapiens

S-methyl-5'-thioadenosine phosphorylase (MTAP) is an enzyme responsible for polyamine metabolism. In humans, it is encoded by the methylthioadenosine phosphorylase (MTAP) gene on chromosome 9. Multiple alternatively spliced transcript variants have been described for this gene, but their full-length natures remain unknown.

<span class="mw-page-title-main">IDH2</span> Protein-coding gene in the species Homo sapiens

Isocitrate dehydrogenase [NADP], mitochondrial is an enzyme that in humans is encoded by the IDH2 gene.

<span class="mw-page-title-main">PKM2</span> Protein-coding gene in the species Homo sapiens

Pyruvate kinase isozymes M1/M2 (PKM1/M2), also known as pyruvate kinase muscle isozyme (PKM), pyruvate kinase type K, cytosolic thyroid hormone-binding protein (CTHBP), thyroid hormone-binding protein 1 (THBP1), or opa-interacting protein 3 (OIP3), is an enzyme that in humans is encoded by the PKM2 gene.

α-Hydroxyglutaric acid Chemical compound

α-Hydroxyglutaric acid is an alpha hydroxy acid form of glutaric acid.

Edelfosine is a synthetic alkyl-lysophospholipid (ALP). It has antineoplastic (anti-cancer) effects.

<span class="mw-page-title-main">The Hallmarks of Cancer</span> 2000 paper by Hanahan and Weinberg

The hallmarks of cancer were originally six biological capabilities acquired during the multistep development of human tumors and have since been increased to eight capabilities and two enabling capabilities. The idea was coined by Douglas Hanahan and Robert Weinberg in their paper "The Hallmarks of Cancer" published January 2000 in Cell.

<span class="mw-page-title-main">IDH1</span> Protein-coding gene in the species Homo sapiens

Isocitrate dehydrogenase 1 (NADP+), soluble is an enzyme that in humans is encoded by the IDH1 gene on chromosome 2. Isocitrate dehydrogenases catalyze the oxidative decarboxylation of isocitrate to 2-oxoglutarate. These enzymes belong to two distinct subclasses, one of which uses NAD+ as the electron acceptor and the other NADP+. Five isocitrate dehydrogenases have been reported: three NAD+-dependent isocitrate dehydrogenases, which localize to the mitochondrial matrix, and two NADP+-dependent isocitrate dehydrogenases, one of which is mitochondrial and the other predominantly cytosolic. Each NADP+-dependent isozyme is a homodimer. The protein encoded by this gene is the NADP+-dependent isocitrate dehydrogenase found in the cytoplasm and peroxisomes. It contains the PTS-1 peroxisomal targeting signal sequence. The presence of this enzyme in peroxisomes suggests roles in the regeneration of NADPH for intraperoxisomal reductions, such as the conversion of 2,4-dienoyl-CoAs to 3-enoyl-CoAs, as well as in peroxisomal reactions that consume 2-oxoglutarate, namely the alpha-hydroxylation of phytanic acid. The cytoplasmic enzyme serves a significant role in cytoplasmic NADPH production. Alternatively spliced transcript variants encoding the same protein have been found for this gene. [provided by RefSeq, Sep 2013]

<span class="mw-page-title-main">Hereditary leiomyomatosis and renal cell cancer syndrome</span> Medical condition

Hereditary leiomyomatosis and renal cell carcinoma (HLRCC) or Reed's syndrome is rare autosomal dominant disorder associated with benign smooth muscle tumors and an increased risk of renal cell carcinoma. It is characterised by multiple cutaneous leiomyomas and, in women, uterine leiomyomas. It predisposes individuals to renal cell cancer, an association denominated hereditary leiomyomatosis and renal cell cancer. It is also associated with increased risk of uterine leiomyosarcoma. The syndrome is caused by a mutation in the fumarate hydratase gene, which leads to an accumulation of fumarate. The inheritance pattern is autosomal dominant and screening can typically begin in childhood.

<span class="mw-page-title-main">Tumor microenvironment</span> Surroundings of tumors including nearby cells and blood vessels

The tumor microenvironment is a complex ecosystem surrounding a tumor, composed of cancer cells, stromal tissue and the extracellular matrix. Mutual interaction between cancer cells and the different components of the tumor microenvironment support its growth and invasion in healthy tissues which correlates with tumor resistance to current treatments and poor prognosis. The tumor microenvironment is in constant change because of the tumor's ability to influence the microenvironment by releasing extracellular signals, promoting tumor angiogenesis and inducing peripheral immune tolerance, while the immune cells in the microenvironment can affect the growth and evolution of cancerous cells.

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