The bioenergetic strategy of living things how catabolic and anabolic pathways fit togetherTumors reprogram pathways of nutrient acquisition and metabolism to meet the bioenergetic, biosynthetic, and redox demands of malignant cells. These reprogrammed activities are now recognized as hallmarks of cancer, and recent work has uncovered remarkable flexibility in the specific pathways activated by tumor cells to support these key functions. In this perspective, we provide a conceptual framework to understand how and why metabolic reprogramming occurs in tumor cells, and the mechanisms linking altered metabolism to tumorigenesis and metastasis. Understanding steroidsftw real or fake concepts will progressively support the development of new strategies to treat human cancer. Cancer metabolism is one of the oldest areas of research in cancer biology, predating the discovery of oncogenes and tumor suppressors by some 50 years.
Overview of metabolism (article) | Khan Academy
Tumors reprogram pathways of nutrient acquisition and metabolism to meet the bioenergetic, biosynthetic, and redox demands of malignant cells. These reprogrammed activities are now recognized as hallmarks of cancer, and recent work has uncovered remarkable flexibility in the specific pathways activated by tumor cells to support these key functions. In this perspective, we provide a conceptual framework to understand how and why metabolic reprogramming occurs in tumor cells, and the mechanisms linking altered metabolism to tumorigenesis and metastasis.
Understanding these concepts will progressively support the development of new strategies to treat human cancer. Cancer metabolism is one of the oldest areas of research in cancer biology, predating the discovery of oncogenes and tumor suppressors by some 50 years.
The field is based on the principle that metabolic activities are altered in cancer cells relative to normal cells, and that these alterations support the acquisition and maintenance of malignant properties. Because some altered metabolic features are observed quite generally across many types of cancer cells, reprogrammed metabolism is considered a hallmark of cancer 1 , 2. Precisely how metabolism becomes reprogrammed in cancer cells, whose functions or malignant properties are enabled by these activities, and how to exploit metabolic changes for therapeutic benefit are among the key questions driving research in the field.
This review covers several fundamental principles in cancer metabolism, with the goal of introducing non-experts to the concepts motivating ongoing research. With the explosion of research in cancer metabolism over the past decade, no single review can possibly cover it all.
The sections below highlight some of the essential, recent papers supporting these core principles. An overarching theme in cancer metabolism is that reprogrammed activities improve cellular fitness to provide a selective advantage during tumorigenesis. Most of the classical examples of reprogrammed activities either support cell survival under stressful conditions or allow cells to grow and proliferate at pathologically elevated levels.
Three of these—altered bioenergetics, enhanced biosynthesis, and redox balance—are discussed at length below. It logically flows that if these activities provide benefit to the malignant cell, then some of them might be suitable therapeutic targets.
This rendering of cancer metabolism is supported by many examples in which inhibition of an enhanced metabolic activity results in impaired growth of experimental tumors 3 , 4. In some cases, the particular metabolic liabilities of cancer cells have been translated into effective therapies in human cancer. Asparaginase, an enzyme that converts the amino acid asparagine to aspartic acid and ammonia, is an essential component of treatment for acute lymphoblastic leukemia ALL 5.
Because of their high rates of protein synthesis and poor ability to synthesize asparagine de novo, ALL cells require a constant supply of asparagine from the plasma. This supply is essentially eliminated by systemic administration of asparaginase. Ultimately, effective metabolic therapy will require defining the stage of tumor progression in which each pathway provides its benefit to the cancer cell.
Some activities first become essential very early in tumorigenesis as the nascent tumor begins to experience nutrient limitations 6. In other cases, altered pathways may be dispensable in primary tumors but essential for metastasis 7 , 8.
Because new therapeutic targets are nominated from simple experimental models like cultured cells, it will be essential to define their context-specific roles in biologically accurate models of tumor initiation and progression.
Altered metabolic activity supports anabolic growth during nutrient-replete conditions, catabolism to support cell survival during nutrient limitation, and fortification of redox homeostatic systems to counteract the metabolic effects of oncogene activation, tumor suppressor loss, and other stresses 9. Discovery and characterization of reprogrammed activities may provide opportunities to image tumor tissue noninvasively, predict tumor behavior, and prevent tumor progression by blocking essential pathways.
Oncometabolite is a relatively new term that refers to metabolites whose abundance increases markedly in tumors. We suggest that this term be reserved for metabolites for which i there is a clear mechanism connecting a specific mutation in the tumor to accumulation of the metabolite, and ii there is compelling evidence for involvement of the metabolite in the development of malignancy.
The classical example of a reprogrammed metabolic pathway in cancer is the Warburg effect or aerobic glycolysis Glycolysis is a physiological response to hypoxia in normal tissues, but Otto Warburg in the s observed that tumor slices and ascites cancer cells constitutively take up glucose and produce lactate regardless of oxygen availability, an observation that has been seen in many types of cancer cells and tumors The increase in glycolytic flux allows glycolytic intermediates to supply subsidiary pathways to fulfill the metabolic demands of proliferating cells Like glycolytic intermediates, tricarboxylic acid TCA cycle intermediates are also used as precursors for macromolecule synthesis Oxidation of the branched-chain amino acids BCAAs isoleucine and valine also provides an anaplerotic flux in some tissues.
Despite the incredible genetic and histological heterogeneity of tumors, malignancy seems to involve the common induction of a finite set of pathways to support core functions like anabolism, catabolism, and redox balance The general induction of these pathways may reflect their regulation by signaling pathways that are commonly perturbed in cancer cells Fig.
Normal cells, upon stimulation by growth factors, activate phosphatidylinositol 3-kinase PI3K and its downstream pathways AKT and mammalian target of rapamycin mTOR , thereby promoting a robust anabolic program involving increased glycolytic flux and fatty acid synthesis through activation of hypoxia-inducible factor—1 HIF-1 and sterol regulatory element—binding protein SREBP , respectively Tumor cells very frequently contain mutations that allow the PI3K-AKT-mTOR network to achieve high levels of signaling with minimal dependence on extrinsic stimulation by growth factors Many of the best-characterized oncogenes and tumor suppressors reside in the PI3K-AKT-mTOR network, and aberrant activation of this pathway is among the most frequent alterations seen in a diverse set of cancers.
Tumor cells have aberrant activation of mTORC1 that induces an anabolic growth program resulting in nucleotide, protein, and lipid synthesis. Loss of tumor suppressors like p53 or activation of oncogenes like MYC further promotes anabolism through transcriptional regulation of metabolic genes. Metabolism controls signaling through regulating reactive oxygen species ROS , acetylation, and methylation.
Another commonly deregulated pathway in cancer is gain of function of MYC by chromosomal translocations, gene amplification, and single-nucleotide polymorphisms. MYC increases the expression of many genes that support anabolic growth, including transporters and enzymes involved in glycolysis, fatty acid synthesis, glutaminolysis, serine metabolism, and mitochondrial metabolism Oncogenes like Kras, which is frequently mutated in lung, colon, and pancreatic cancers, co-opt the physiological functions of PI3K and MYC pathways to promote tumorigenicity.
Aside from oncogenes, tumor suppressors such as the p53 transcription factor can also regulate metabolism The tumor-suppressive functions of p53 have been ascribed to execution of DNA repair, cell cycle arrest, senescence, and apoptosis. However, recent studies indicate that p53 tumor-suppressive actions might be independent of these canonical p53 activities but rather dependent on the regulation of metabolism and oxidative stress 20 , Loss of p53 increases glycolytic flux to promote anabolism and redox balance, two key processes that promote tumorigenesis The metabolic adaptation to hypoxia is coordinated by HIF-1, which induces metabolic genes involved in increasing glycolytic flux Some tumors display constitutive activation of HIF-1 under normoxic conditions through a variety of mechanisms, including i hyperactivation of mTORC1, ii loss of von Hippel—Lindau, iii accumulation of ROS, and iv accumulation of the TCA cycle metabolites succinate or fumarate due to cancer-specific mutations in succinate dehydrogenase SDH or fumarate hydratase FH , respectively The robust coordinated induction of metabolic pathways that support tumorigenesis by combination of deregulation of PI3K-AKT-mTOR signaling pathways, loss of tumor suppressors, and activation of oncogenes alleviates the necessity of having mutations or amplifications in metabolic enzymes per se.
Thus, examples of metabolic enzyme deregulation through genetic mutation are rare. One example is the elevated expression of phosphoglycerate dehydrogenase PHGDH due to amplification in a fraction of breast cancer and melanoma 25 , PHGDH catalyzes the conversion of the glycolytic intermediate 3-phosphoglycerate to 3-phosphohydroxypyruvate in the first step of the serine biosynthesis pathway.
Serine metabolism supplies methyl groups to the one-carbon and folate pools contributing to nucleotide synthesis, methylation reactions, and NADPH reduced nicotinamide adenine dinucleotide phosphate production Inhibiting serine biosynthesis by silencing PHGDH in cells with high levels of this enzyme results in growth suppression, and the enzyme displays oncogenic properties in gain of function assays 25 , The other examples of mutational deregulation of metabolic enzymes are those that generate oncometabolites.
The current list of true oncometabolites is short These mutations occur commonly in gliomas, acute myelogenous leukemias AMLs , and other types of cancer 29 — These include prolyl hydroxylases, cytosine hydroxylases, and histone demethylases, whose inhibition influences gene expression in part via an altered epigenetic state characterized by a failure to express differentiation programs 35 — Thus, although D2HG arises from an alteration of the metabolic network, its role in cancer seems to depend on nonmetabolic effects.
Affected children have seizures, mental retardation, white matter abnormalities of the brain, and systemically elevated levels of L2HG. L2HG and D2HG exhibit different effects on dioxygenase function 38 , suggesting that the sensitivity of a particular tissue to the presence of either metabolite may depend on which dioxygenases are expressed. Recent work has demonstrated modest accumulation of L2HG in cells experiencing hypoxia or electron transport chain ETC dysfunction 42 , 47 and in human renal cell carcinomas, which frequently display epigenetic silencing of L2HGDH It is unknown whether reducing L2HG levels in these settings will promote cellular differentiation or suppress tumor progression.
The principle that oncometabolites exert their effects outside of the conventional metabolic network also applies to the other two molecules that can reasonably be called oncometabolites: Although these mutations markedly reprogram metabolism by impairing TCA cycle flux, the extent to which fumarate and succinate participate in cancer development likely involves their nonmetabolic functions Like D2HG, evidence indicates that succinate and fumarate interfere with dioxygenase activity, supporting the notion that a general property of oncometabolites is the ability to regulate epigenetics 52 , Some metabolites, notably fumarate, covalently bind to sulfhydryl groups in glutathione, proteins, and peptides, altering their function and perhaps accounting for another mechanism by which oncometabolites promote or perpetuate malignant phenotypes 55 — Today, it is clear that cancer cells exhibit aerobic glycolysis due to activation of oncogenes, loss of tumor suppressors, and up-regulation of the PI3K pathway, and that one advantage of high glycolytic rates is the availability of precursors for anabolic pathways 2 , Nevertheless, many studies have demonstrated that the great majority of tumor cells have the capacity to produce energy through glucose oxidation that is, the process by which glucose-derived carbons enter the TCA cycle and are oxidized to CO 2 , producing ATP through oxidative phosphorylation.
Furthermore, limiting glycolytic ATP production by inhibiting the activity of pyruvate kinase fails to prevent tumorigenesis, suggesting that the major role of glycolysis is not to supply ATP Moreover, mitochondrial metabolism is necessary for cancer cell proliferation and tumorigenesis 63 — Thus, despite their high glycolytic rates, most cancer cells generate the majority of ATP through mitochondrial function, with the likely exception of tumors bearing mutations in enzymes involved in mitochondrial respiration for example, SDH and FH Nevertheless, cells harboring mutations in FH or SDH still rely on mitochondrial metabolism by metabolically rewiring themselves to provide the necessary TCA cycle intermediates and ROS for cell proliferation 55 , 67 — In addition to pyruvate derived from glycolysis, fatty acids and amino acids can supply substrates to the TCA cycle to sustain mitochondrial ATP production in cancer cells Fig.
Furthermore, the BCAAs isoleucine, valine, and leucine, which are elevated in plasma of patients with pancreatic cancers, can be converted into acetyl-CoA and other organic molecules that also enter the TCA cycle The metabolic flexibility afforded by multiple inputs into the TCA cycle allows cancer cells to adequately respond to the fuels available in the changing microenvironment during the evolution of the tumor 9.
A combination of the local tumor microenvironment and oncogenic lesions is likely to dictate the fuel used by mitochondria to sustain tumor growth. Accessibility to nutrients within solid tumors is regulated by proximity to the vasculature. Cells located adjacent to the vasculature use nutrients and oxygen to fuel anabolic pathways that support proliferation. However, cells distant from the vasculature have diminished accessibility to nutrients and oxygen and may engage in alternative forms of metabolism including oxidation of fatty acids and BCAAs as well as macromolecular degradation through autophagy and macropinocytosis to support cell viability.
Solid tumors contain significant heterogeneity of perfusion, such that many tumor cells reside in nutrient- and oxygen-poor environments. Cancer cells have therefore adapted multiple mechanisms to sustain mitochondrial function for survival.
For example, the mitochondrial ETC can function optimally at oxygen levels as low as 0. Kras-driven pancreatic cancer cells in nutrient-depleted conditions use proteins scavenged from the extracellular space to produce glutamine and other amino acids to fuel the TCA cycle for cell survival and growth Fig. Furthermore, if pyruvate oxidation to acetyl-CoA is compromised by hypoxia or ETC impairment, glutamine can provide acetyl-CoA as a biosynthetic precursor to sustain tumor growth 69 , 78 , When tumor cells become nutrient-deprived, they adapt to the microenvironment by decreasing their demand for ATP.
The anabolic kinase mTOR, discussed in greater detail below, drives the energetically demanding growth of tumor cells. This kinase is inhibited when amino acids and oxygen levels are diminished Furthermore, decreased mTOR activity increases autophagic flux. In oncogenic Kras- or Braf-driven non—small-cell lung cancer NSCLC cells, autophagy provides an intracellular glutamine supply to sustain mitochondrial function 81 , In conditions of metabolic stress, certain Ras-driven cancer cells scavenge lipids to support ATP production Ovarian cancer cells use fatty acids from neighboring adipocytes to fuel mitochondrial ATP production Biosynthetic or anabolic pathways are an essential aspect of cancer metabolism because they enable cells to produce the macromolecules required for replicative cell division and tumor growth.
As a general theme, these pathways involve the acquisition of simple nutrients sugars, essential amino acids, etc. Evidence indicates that biosynthesis of all three classes is under the control of the same signaling pathways that govern cell growth and are activated in cancer via tumorigenic mutations, particularly PI3K-mTOR signaling.
Glucose metabolism generates glycolytic intermediates that can supply subsidiary pathways including the hexosamine pathway, PPP, and one-carbon metabolism, all of which support cell growth.
Mitochondrial TCA cycle intermediates such as oxaloacetate OAA and citrate are used to generate cytosolic aspartate and acetyl-CoA for nucleotide and lipid synthesis, respectively.