Metabolic reprogramming of the tumor (original) (raw)

Fundamentals of cancer metabolism

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 tumor-igenesis and metastasis. Understanding these concepts will progressively support the development of new strategies to treat human cancer.

Tumor cell metabolism: An integral view

Cancer Biology & Therapy, 2011

Cancer is a genetic disease that is caused by mutations in oncogenes, tumor suppressor genes and stability genes. The fact that the metabolism of tumor cells is altered has been known for many years. However, the mechanisms and consequences of metabolic reprogramming have just begun to be understood. In this review, an integral view of tumor cell metabolism is presented, showing how metabolic pathways are reprogrammed to satisfy tumor cell proliferation and survival requirements. In tumor cells, glycolysis is strongly enhanced to fulfill the high ATP demands of these cells; glucose carbons are the main building blocks in fatty acid and nucleotide biosynthesis. Glutaminolysis is also increased to satisfy NADPH regeneration, whereas glutamine carbons replenish the Krebs cycle, which produces metabolites that are constantly used for macromolecular biosynthesis. A characteristic feature of the tumor microenvironment is acidosis, which results from the local increase in lactic acid production by tumor cells. This phenomenon is attributed to the carbons from glutamine and glucose, which are also used for lactic acid production. Lactic acidosis also directs the metabolic reprogramming of tumor cells and serves as an additional selective pressure. Finally, we also discuss the role of mitochondria in supporting tumor cell metabolism.

Cancer metabolism: a therapeutic perspective

Nature reviews. Clinical oncology, 2016

Awareness that the metabolic phenotype of cells within tumours is heterogeneous - and distinct from that of their normal counterparts - is growing. In general, tumour cells metabolize glucose, lactate, pyruvate, hydroxybutyrate, acetate, glutamine, and fatty acids at much higher rates than their nontumour equivalents; however, the metabolic ecology of tumours is complex because they contain multiple metabolic compartments, which are linked by the transfer of these catabolites. This metabolic variability and flexibility enables tumour cells to generate ATP as an energy source, while maintaining the reduction-oxidation (redox) balance and committing resources to biosynthesis - processes that are essential for cell survival, growth, and proliferation. Importantly, experimental evidence indicates that metabolic coupling between cell populations with different, complementary metabolic profiles can induce cancer progression. Thus, targeting the metabolic differences between tumour and nor...

Editorial: Reviews in cancer metabolism

Frontiers in Oncology, 2023

The Research Topic Reviews in Cancer Metabolism aimed to compile publications about the current state of the art on tumor cell metabolism, the implications on the aberrant functioning, tumor microenvironment, genomic features, and its impact on developing therapeutic targets. The issue is enriched by seven articles from diverse research groups with remarkable contributions to the metabolism field in cancer, leaving open queries for discussion and future follow-up. The review suggests fresh ideas worth to be taken as cancer treatment targets. According to the World Health Organization (1), cancer is the second leading cause of death from noncommunicable diseases worldwide, accounting for 9.3 million annually (1 https://www.who.int/data/gho/data/themes/topics/topic-details/GHO/ncd-mortality). Regardless of the daily work of the scientific community in tight collaboration with clinicians, deaths have not ceased (2). Understanding its origin, evolution, signaling pathways, and dysregulated metabolism are keys to preventing, controlling, or curing this atypic cell metabolism state, finding new therapeutic targets, and proposing new medications.

Alteration of cellular metabolism in cancer cells and its therapeutic prospects

Journal of oral and maxillofacial pathology : JOMFP

Transformation of a normal cell into a cancerous phenotype is essentially backed by genetic mutations that trigger several oncogenic signaling pathways. These signaling pathways rewire the cellular metabolism to meet the bioenergetic and biomass requirement of proliferating cell, which is different from a quiescent cell. Although the change of metabolism in a cancer cell was observed and studied in the mid-20 century, it was not adequate to explain oncogenesis. Now, equipped with a revolution of oncogenes, we have a genetic basis to explain the transformation. Through several studies, it is clear now that such metabolic alterations not only promote cancer progression but also contribute to the chemoresistance of cancer. Targeting specific enzymes and combinations of enzymes can improve the efficacy of cancer therapy and help to overcome the therapeutic resistance.

The Metabolic Alterations of Cancer Cells

Methods in Enzymology, 2014

Cancer cells exhibit profound metabolic alterations, allowing them to fulfill the metabolic needs that come with increased proliferation and additional facets of malignancy. Such a metabolic transformation is orchestrated by the genetic changes that drive tumorigenesis, that is, the activation of oncogenes and/or the loss of oncosuppressor genes, and further shaped by environmental cues, such as oxygen concentration and nutrient availability. Understanding this metabolic rewiring is essential to elucidate the fundamental mechanisms of tumorigenesis as well as to find novel, therapeutically exploitable liabilities of malignant cells. Here, we describe key features of the metabolic transformation of cancer cells, which frequently include the switch to aerobic glycolysis, a profound mitochondrial reprogramming, and the deregulation of lipid metabolism, highlighting the notion that these pathways are not independent but rather cooperate to sustain proliferation. Finally, we hypothesize that only those Methods in Enzymology, Volume 542 # 2014 Elsevier Inc.

Cancer metabolism: New insights into classic characteristics

The Japanese dental science review, 2018

Initial studies of cancer metabolism in the early 1920s found that cancer cells were phenotypically characterized by aerobic glycolysis, in that these cells favor glucose uptake and lactate production, even in the presence of oxygen. This property, called the Warburg effect, is considered a hallmark of cancer. The mechanism by which these cells acquire aerobic glycolysis has been uncovered. Acidic extracellular fluid, secreted by cancer cells, induces a malignant phenotype, including invasion and metastasis. Cancer cells survival depends on a critical balance of redox status, which is regulated by amino acid metabolism. Glutamine is extremely important for oxidative phosphorylation and redox regulation. Cells highly dependent on glutamine and that cannot survive with glutamine are called glutamine-addicted cells. Metabolic reprogramming has been observed in cancer stem cells, which have the property of self-renewal and are resistant to chemotherapy and radiotherapy. These findings s...

Metabolism – A cornerstone of cancer initiation, progression, immune evasion and treatment response

Current Opinion in Systems Biology, 2018

Highlights • Crosstalk between metabolism and epigenetics can be a driver of cancer • Nucleotide metabolism is a common metabolic vulnerability of proliferating tumors • Metastasis formation depends on energy and antioxidant metabolism • Cancer cells impair the anti-tumor immune response • Metabolic rewiring and microbiota metabolism can define therapy response Abstract Cancer is not a single disease, but a spectrum of diseases with common hallmarks. One of these hallmarks is deregulated metabolism. Changes in the metabolism of cancers are not a mere downstream event of an oncogenic transformation; rather, metabolism is an essential cornerstone enabling various aspects of cancer. In this review, we highlight the role of metabolism in cancer initiation, proliferation, metastasis formation, immune evasion, and therapy response. We further provide metabolic concepts by which metabolic pathways support these different aspects of cancer. oncogenic transformation, but essential changes that support and/or drive cancer initiation, progression and treatment response. In this review, we present the current knowledge on the role of metabolism in different aspects of cancer. Crosstalk between metabolism and epigenetics can be a driver of cancer Only few changes in metabolism can be considered drivers of tumor initiation. A common feature of all such metabolic changes is the induction of epigenetic remodeling. In particular, metabolite concentrations alter the activity of enzymes that modify DNA and/or histones (3, 4). Consequently, a change in the global transcriptional program occurs, which can result in tumor initiation (Figure 1a). Examples are mutations or loss of the TCA cycle enzymes isocitrate dehydrogenase (IDH), succinate dehydrogenase (SDH), and fumarate hydratase (FH) (5-7). Each of these tumor-driving alterantion results in the accumulation of a particular metabolite (2-hydroxyglutarate with IDH mutation, succinate with SDH mutation, and fumarate with FH mutation) that inhibits ten-eleven translocation methylcytosine dioxygenase (TET) enzyme activity by preventing the conversion of the substrate α-ketoglutarate to succinate and consequently the demethylation of DNA (8-12). However, epigenetic remodeling may only be a part of the mechanism that enables metabolism-driven tumor initiation. While hereditary SDH mutations disrupt epigenetic homeostasis in each organ, only particular cell types and tissues, such as paraganglia, are prone to tumor initiation (13). Additionally, mutations in SDH are found in each subunit of the enzyme and always result in succinate accumulation, but aggressive tumors predominantly arise from SDH mutations in subunit B (13). Interestingly, SDH mutations are not only associated with tumor initiation, but can also lead to neurodegeneration (14), which constitutes the opposite of a proliferation-defined disease. These findings indicate that further cellular changes, beyond epigenetic remodeling, are necessary to enable metabolism to initiate tumors (15, 16). One reason for the inability of metabolite concentration-induced epigenetic remodeling to drive tumor initiation in any cell might be the basal metabolism of the tumororiginating cell (17). In conclusion, crosstalk with epigenetics is required, but likely not sufficient, to explain the ability of metabolic changes to initiate tumors. Nucleotide metabolism is a converging metabolic vulnerability of proliferating tumors A hallmark of tumors is uncontrolled proliferation (18, 19). Any biosynthetic pathway supporting proliferation may therefore be considered a drug target in cancer treatment. Yet, cancer therapy drug screens conducted in the 1950s mainly identified compounds that target nucleotide biosynthesis, and some are still used as chemotherapeutics today (2, 20, 21). Accordingly, recent research has identified changes in nucleotide metabolism as a converging metabolic vulnerability of tumors (22-27) (Figure 1b). While targeting the enzymes of nucleotide biosynthesis in tumors also impairs proliferating non-transformed cells, this limitation could be overcome by targeting metabolic pathways that fuel nucleotide biosynthesis. There is evidence suggesting that such metabolic pathways depend predominantly on the tumor microenvironment (28-30) (Figure 1b). This observation provides an opportunity for cancer treatment: tumors within the same organ could be treated

Defining the Molecular Basis of Tumor Metabolism: a Continuing Challenge Since Warburg’s Discovery

Cancer cells are the product of genetic disorders that alter crucial intracellular signaling pathways associated with the regulation of cell survival, proliferation, differentiation and death mechanisms. The role of oncogene activation and tumor suppressor inhibition in the onset of cancer is well established. Traditional antitumor therapies target specific molecules, the action/expression of which is altered in cancer cells. However, since the physiology of normal cells involves the same signaling pathways that are disturbed in cancer cells, targeted therapies have to deal with side effects and multidrug resistance, the main causes of therapy failure. Since the pioneering work of Otto Warburg, over 80 years ago, the subversion of normal metabolism displayed by cancer cells has been highlighted by many studies. Recently, the study of tumor metabolism has received much attention because metabolic transformation is a crucial cancer hallmark and a direct consequence of disturbances in the activities of oncogenes and tumor suppressors. In this review we discuss tumor metabolism from the molecular perspective of oncogenes, tumor suppressors and protein signaling pathways relevant to metabolic transformation and tumorigenesis. We also identify the principal unanswered questions surrounding this issue and the attempts to relate these to their potential for future cancer treatment. As will be made clear, tumor metabolism is still only partly understood and the metabolic aspects of transformation constitute a major challenge for science. Nevertheless, cancer metabolism can be exploited to devise novel avenues for the rational treatment of this disease.

Cancer as a Metabolic Disease: Implications for Novel Therapeutics

Carcinogenesis

Emerging evidence indicates that cancer is primarily a metabolic disease involving disturbances in energy production through respiration and fermentation. The genomic instability observed in tumor cells and all other recognized hallmarks of cancer are considered downstream epiphenomena of the initial disturbance of cellular energy metabolism. The disturbances in tumor cell energy metabolism can be linked to abnormalities in the structure and function of the mitochondria. When viewed as a mitochondrial metabolic disease, the evolutionary theory of Lamarck can better explain cancer progression than can the evolutionary theory of Darwin. Cancer growth and progression can be managed following a whole-body transition from fermentable metabolites, primarily glucose and glutamine, to respiratory metabolites, primarily ketone bodies. As each individual is a unique metabolic entity, personalization of metabolic therapy as a broad-based cancer treatment strategy will require fine-tuning to match the therapy to an individual's unique physiology.