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Proliferating cells must adapt their metabolism to fulfill the increased requirements for energy demands and biosynthetic intermediates. This adaptation is particularly relevant in cancer, where sustained rapid proliferation combined with the harsh conditions of the tumor microenvironment represent a major metabolic challenge. Noteworthy, metabolic reprogramming is now considered one of the hallmarks of cancer. However, the one size fits all rarely applies to the metabolic rewiring occurring in cancer cells, which ultimately depends on the combination of several factors such as the tumor’s origin, the specific genetic alterations and the surrounding microenvironment. In the present Research Topic, we compile a series of articles that discuss different metabolic adaptations that proliferating cells undergo to sustain growth and division, as well as the potential therapeutic window to treat certain pathologies, with a special focus on cancer.

cancer metabolism --- proliferation --- mitochondria --- lipogenesis --- metabolic adaptation --- obesity --- Warburg effect

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Proliferating cells must adapt their metabolism to fulfill the increased requirements for energy demands and biosynthetic intermediates. This adaptation is particularly relevant in cancer, where sustained rapid proliferation combined with the harsh conditions of the tumor microenvironment represent a major metabolic challenge. Noteworthy, metabolic reprogramming is now considered one of the hallmarks of cancer. However, the one size fits all rarely applies to the metabolic rewiring occurring in cancer cells, which ultimately depends on the combination of several factors such as the tumor’s origin, the specific genetic alterations and the surrounding microenvironment. In the present Research Topic, we compile a series of articles that discuss different metabolic adaptations that proliferating cells undergo to sustain growth and division, as well as the potential therapeutic window to treat certain pathologies, with a special focus on cancer.

cancer metabolism --- proliferation --- mitochondria --- lipogenesis --- metabolic adaptation --- obesity --- Warburg effect --- cancer metabolism --- proliferation --- mitochondria --- lipogenesis --- metabolic adaptation --- obesity --- Warburg effect

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Development of an effective anticancer therapeutic necessitates the selection of cancer-related or cancer-specific pathways or molecules that are sensitive to intervention. Several such critical yet sensitive molecular targets have been recognized, and their specific antagonists or inhibitors validated as potential therapeutics in preclinical models. Yet, majority of anticancer principles or therapeutics show limited success in the clinical translation. Thus, the need for the development of an effective therapeutic strategy persists. “Altered energy metabolism” in cancer is one of the earliest known biochemical phenotypes which dates back to the early 20th century. The German scientist, Otto Warburg and his team (Warburg, Wind, Negelein 1926; Warburg, Wind, Negelein 1927) provided the first evidence that the glucose metabolism of cancer cells diverge from normal cells. This phenomenal discovery on deregulated glucose metabolism or cellular bioenergetics is frequently witnessed in majority of solid malignancies. Currently, the altered glucose metabolism is used in the clinical diagnosis of cancer through positron emission tomography (PET) imaging. Thus, the “deregulated bioenergetics” is a clinically relevant metabolic signature of cancer cells, hence recognized as one of the hallmarks of cancer (Hanahan and Weinberg 2011). Accumulating data unequivocally demonstrate that, besides cellular bioenergetics, cancer metabolism facilitates several cancer-related processes including metastasis, therapeutic resistance and so on. Recent reports also demonstrate the oncogenic regulation of glucose metabolism (e.g. glycolysis) indicating a functional link between neoplastic growth and cancer metabolism. Thus, cancer metabolism, which is already exploited in cancer diagnosis, remains an attractive target for therapeutic intervention as well. The Frontiers in Oncology Research Topic “Cancer Metabolism: Molecular Targeting and Implications for Therapy” emphases on recent advances in our understanding of metabolic reprogramming in cancer, and the recognition of key molecules for therapeutic targeting. Besides, the topic also deliberates the implications of metabolic targeting beyond the energy metabolism of cancer. The research topic integrates a series of reviews, mini-reviews and original research articles to share current perspectives on cancer metabolism, and to stimulate an open forum to discuss potential challenges and future directions of research necessary to develop effective anticancer strategies.

Tumor microenvironment --- metastasis --- Cancer Metabolism --- glycolysis --- immunotherapy --- epigenetic regulation --- metabolic reprogramming --- Warburg effect --- Tumor microenvironment --- metastasis --- Cancer Metabolism --- glycolysis --- immunotherapy --- epigenetic regulation --- metabolic reprogramming --- Warburg effect

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Development of an effective anticancer therapeutic necessitates the selection of cancer-related or cancer-specific pathways or molecules that are sensitive to intervention. Several such critical yet sensitive molecular targets have been recognized, and their specific antagonists or inhibitors validated as potential therapeutics in preclinical models. Yet, majority of anticancer principles or therapeutics show limited success in the clinical translation. Thus, the need for the development of an effective therapeutic strategy persists. “Altered energy metabolism” in cancer is one of the earliest known biochemical phenotypes which dates back to the early 20th century. The German scientist, Otto Warburg and his team (Warburg, Wind, Negelein 1926; Warburg, Wind, Negelein 1927) provided the first evidence that the glucose metabolism of cancer cells diverge from normal cells. This phenomenal discovery on deregulated glucose metabolism or cellular bioenergetics is frequently witnessed in majority of solid malignancies. Currently, the altered glucose metabolism is used in the clinical diagnosis of cancer through positron emission tomography (PET) imaging. Thus, the “deregulated bioenergetics” is a clinically relevant metabolic signature of cancer cells, hence recognized as one of the hallmarks of cancer (Hanahan and Weinberg 2011). Accumulating data unequivocally demonstrate that, besides cellular bioenergetics, cancer metabolism facilitates several cancer-related processes including metastasis, therapeutic resistance and so on. Recent reports also demonstrate the oncogenic regulation of glucose metabolism (e.g. glycolysis) indicating a functional link between neoplastic growth and cancer metabolism. Thus, cancer metabolism, which is already exploited in cancer diagnosis, remains an attractive target for therapeutic intervention as well. The Frontiers in Oncology Research Topic “Cancer Metabolism: Molecular Targeting and Implications for Therapy” emphases on recent advances in our understanding of metabolic reprogramming in cancer, and the recognition of key molecules for therapeutic targeting. Besides, the topic also deliberates the implications of metabolic targeting beyond the energy metabolism of cancer. The research topic integrates a series of reviews, mini-reviews and original research articles to share current perspectives on cancer metabolism, and to stimulate an open forum to discuss potential challenges and future directions of research necessary to develop effective anticancer strategies.

Tumor microenvironment --- metastasis --- Cancer Metabolism --- glycolysis --- immunotherapy --- epigenetic regulation --- metabolic reprogramming --- Warburg effect

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Living cells require a constant supply of energy for the orchestration of a variety of biological processes in fluctuating environmental conditions. In heterotrophic organisms, energy mainly derives from the oxidation of carbohydrates and lipids, whose chemical bonds breakdown allows electrons to generate ATP and to provide reducing equivalents needed to restore the antioxidant systems and prevent from damage induced by reactive oxygen and nitric oxide (NO)-derived species (ROS and RNS). Studies of the last two decades have highlighted that cancer cells reprogram the metabolic circuitries in order to sustain their high growth rate, invade other tissues, and escape death. Therefore, this broad metabolic reorganization is mandatory for neoplastic growth, allowing the generation of adequate amounts of ATP and metabolites, as well as the optimization of redox homeostasis in the changeable environmental conditions of the tumor mass. Among these, ROS, as well as NO and RNS, which are produced at high extent in the tumor microenvironment or intracellularly, have been demonstrated acting as positive modulators of cell growth and frequently associated with malignant phenotype. Metabolic changes are also emerging as primary drivers of neoplastic onset and growth, and alterations of mitochondrial metabolism and homeostasis are emerging as pivotal in driving tumorigenesis. Targeting the metabolic rewiring, as well as affecting the balance between production and scavenging of ROS and NO-derived species, which underpin cancer growth, opens the possibility of finding selective and effective anti-neoplastic approaches, and new compounds affecting metabolic and/or redox adaptation of cancer cells are emerging as promising chemotherapeutic tools. In this Research Topic we have elaborated on all these aspects and provided our contribution to this increasingly growing field of research with new results, opinions and general overviews about the extraordinary plasticity of cancer cells to change metabolism and redox homeostasis in order to overcome the adverse conditions and sustain their “individualistic” behavior under a teleonomic viewpoint.

hypoxia --- Mitochondria --- Bioenergetics --- Cancer Metabolism --- ROS --- S-nitrosylation --- Autophagy --- redox --- Warburg effect