Editorial: Reviews in cancer metabolism (original) (raw)

Cancer cell metabolism as new targets for novel designed therapies

Future Medicinal Chemistry, 2014

Metabolic processes are altered in cancer cells, which obtain advantages from this metabolic reprogramming in terms of energy production and synthesis of biomolecules that sustain their uncontrolled proliferation. Due to the conceptual progresses in the last decade, metabolic reprogramming was recently included as one of the new hallmarks of cancer. The advent of high-throughput technologies to amass an abundance of omic data, together with the development of new computational methods that allow the integration and analysis of omic data by using genome-scale reconstructions of human metabolism, have increased and accelerated the discovery and development of anticancer drugs and tumor-specific metabolic biomarkers. Here we review and discuss the latest advances in the context of metabolic reprogramming and the future in cancer research.

Cancer Metabolism as a New Real Target in Tumor Therapy

Cells, 2021

Cancer cells exhibit common hallmarks consisting of specific competencies acquired during the tumorigenesis process, including stimulation of cancer cell proliferation, insensitivity to growth signal inhibition, apoptosis evasion, enhancement of replicative potential, induction of angiogenesis, and tissue invasion and metastasis [...].

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...

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.

More Than Meets the Eye Regarding Cancer Metabolism

International Journal of Molecular Sciences, 2021

In spite of the continuous improvement in our knowledge of the nature of cancer, the causes of its formation and the development of new treatment methods, our knowledge is still incomplete. A key issue is the difference in metabolism between normal and cancer cells. The features that distinguish cancer cells from normal cells are the increased proliferation and abnormal differentiation and maturation of these cells, which are due to regulatory changes in the emerging tumour. Normal cells use oxidative phosphorylation (OXPHOS) in the mitochondrion as a major source of energy during division. During OXPHOS, there are 36 ATP molecules produced from one molecule of glucose, in contrast to glycolysis which provides an ATP supply of only two molecules. Although aerobic glucose metabolism is more efficient, metabolism based on intensive glycolysis provides intermediate metabolites necessary for the synthesis of nucleic acids, proteins and lipids, which are in constant high demand due to th...

Cancer metabolism: new validated targets for drug discovery

Oncotarget, 2013

Recent studies in cancer metabolism directly implicate catabolic fibroblasts as a new rich source of i) energy and ii) biomass, for the growth and survival of anabolic cancer cells. Conversely, anabolic cancer cells upregulate oxidative mitochondrial metabolism, to take advantage of the abundant fibroblast fuel supply. This simple model of "metabolic-symbiosis" has now been independently validated in several different types of human cancers, including breast, ovarian, and prostate tumors. Biomarkers of metabolic-symbiosis are excellent predictors of tumor recurrence, metastasis, and drug resistance, as well as poor patient survival. New pre-clinical models of metabolic-symbiosis have been generated and they genetically validate that catabolic fibroblasts promote tumor growth and metastasis. Over 30 different stable lines of catabolic fibroblasts and >10 different lines of anabolic cancer cells have been created and are well-characterized. For example, catabolic fibrobla...

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.

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

From cancer metabolism to new biomarkers and drug targets

Biotechnology Advances, 2012

Great interest is presently given to the analysis of metabolic changes that take place specifically in cancer cells. In this review we summarize the alterations in glycolysis, glutamine utilization, fatty acid synthesis and mitochondrial function that have been reported to occur in cancer cells and in human tumors. We then propose considering cancer as a system-level disease and argue how two hallmarks of cancer, enhanced cell proliferation and evasion from apoptosis, may be evaluated as system-level properties, and how this perspective is going to modify drug discovery. Given the relevance of the analysis of metabolism both for studies on the molecular basis of cancer cell phenotype and for clinical applications, the more relevant technologies for this purpose, from metabolome and metabolic flux analysis in cells by Nuclear Magnetic Resonance and Mass Spectrometry technologies to positron emission tomography on patients, are analyzed. The perspectives offered by specific changes in metabolism for a new drug discovery strategy for cancer are discussed and a survey of the industrial activity already going on in the field is reported.