Defining the Molecular Basis of Tumor Metabolism: a Continuing Challenge Since Warburg’s Discovery (original) (raw)
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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.
Journal of Cancer Science & Therapy, 2012
Cancer cells compared to their normal counterparts reveal different metabolic needs and this differential requirement of metabolic intermediates and their subsequent consequences require an elaborate understanding of cancer cell metabolism and increased energy production in these cells. Nevertheless these metabolic differences have provided opportunities for developing novel therapeutic approaches for the cancer diagnosis and treatment. In addition enhanced proliferative capacities of tumor cells associated with aberrations of many signal transduction pathways resulting from genetic or epigenetic alterations has made it possible to develop countless targeted therapeutics for several types of malignancies. However at present most of our understanding about the dysregulated cancer cell metabolism is at physiological stages. With advancement in technology development, we may eventually be able to differentiate the metabolic differences between normal cells and cancerous at the single-tumor level that may influence the development of personalized cancer medicine. In this review, the focal point will be the recent developments in understanding the crucial role of metabolic enzymes, oncogenes and tumor suppressor genes in progression of cancer and their targeting to establish the most appropriate therapeutic strategies for better clinical outcome.
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.
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.
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.
On the metabolic origin of cancer: substances that target tumor metabolism
Biomedical Research, 2011
Work from our group and others clearly suggest the key role of altered metabolism in cancer. The goal of this review is to summarize current knowledge on cancer metabolism, draw hypothesis explaining metabolic alterations and associated gene changes. Most importantly, we indicate a list of possible pharmacological targets. In short, tumor metabolism displays mixed glycolysis and neoglucogenesis features; most glycolitic enzymes are activate, but the pyruvate kinase and the pyruvate deshydrogenase are inhibited. This would result from an activation of their specific kinases, or from the inactivation of phosphatases, such as PP2A, regulated by methylation. In parallel, the phosphatase failure would enhance "tyrosine kinase receptor" signals, as occurs with oncogenes. Such signaling pathways are similar to those activated by insuline, or IGF-Growth hormone; they control mitosis, cell survival, carbohydrate metabolism. If for some reason, their regulation fails (oncogenes, PP2A methylation deficit, enhanced kinases…) a typical tumor metabolism starts the carcinogenic process. We also describe changes in the citric acid-urea cycles, polyamines, and show how body stores feed tumor metabolic pathways above and below "bottlenecks" resulting from wrongly switched enzymes. Studying the available literature, we list a number of medications that target enzymes that are essential for tumor cells. Hoping to prevent, reverse or eradicate the process. Experimental data published elsewhere by our group, seem to confirm some of these assumptions.
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.
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...
Searching for the Metabolic Signature of Cancer: A Review from Warburg’s Time to Now
Biomolecules
This review focuses on the evolving understanding that we have of tumor cell metabolism, particularly glycolytic and oxidative metabolism, and traces back its evolution through time. This understanding has developed since the pioneering work of Otto Warburg, but the understanding of tumor cell metabolism continues to be hampered by misinterpretation of his work. This has contributed to the use of the new concepts of metabolic switch and metabolic reprogramming， that are out of step with reality. The Warburg effect is often considered to be a hallmark of cancer, but is it really? More generally, is there a metabolic signature of cancer? We draw the conclusion that the signature of cancer cannot be reduced to a single factor, but is expressed at the tissue level in terms of the capacity of cells to dynamically explore a vast metabolic landscape in the context of significant environmental heterogeneities.