Disrupting proton dynamics and energy metabolism for cancer therapy
TL;DR: This Review presents the key pH-regulating systems and synthesizes recent advances in strategies that combine the disruption of pH control with bioenergetic mechanisms and discusses the possibility of exploiting, in rapidly growing tumours, acute cell death by 'metabolic catastrophe'.
Abstract: Intense interest in the 'Warburg effect' has been revived by the discovery that hypoxia-inducible factor 1 (HIF1) reprogrammes pyruvate oxidation to lactic acid conversion; lactic acid is the end product of fermentative glycolysis. The most aggressive and invasive cancers, which are often hypoxic, rely on exacerbated glycolysis to meet the increased demand for ATP and biosynthetic precursors and also rely on robust pH-regulating systems to combat the excessive generation of lactic and carbonic acids. In this Review, we present the key pH-regulating systems and synthesize recent advances in strategies that combine the disruption of pH control with bioenergetic mechanisms. We discuss the possibility of exploiting, in rapidly growing tumours, acute cell death by 'metabolic catastrophe'.
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TL;DR: It is shown that LDHA-associated lactic acid accumulation in melanomas inhibits tumor surveillance by T and NK cells, and is a potent inhibitor of function and survival of T andNK cells leading to tumor immune escape.
948 citations
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...MCT1 inhibition could not block acidification, as other MCTs or transporter-independent diffu- sion may be involved (Parks et al., 2013)....
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...MCT1 inhibition could not block acidification, as other MCTs or transporter-independent diffusion may be involved (Parks et al., 2013)....
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TL;DR: P pH-responsive biomaterials bring forth conformational changes in these nanocarriers through various mechanisms such as protonation, charge reversal or cleavage of a chemical bond, facilitating tumour specific cell uptake or drug release, helping to design more efficient drug delivery systems.
698 citations
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...carbonic anhydrase IX) are transcriptional targets of HIF-1 and thus are upregulated under hypoxia [32, 33]....
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TL;DR: The current understanding of how H+-generating metabolic processes segregate within tumours according to the distance from blood vessels is summarized and how ambient acidosis influences tumour metabolism, reducing glycolysis while promoting mitochondrial activity is summarized.
Abstract: This Review by Corbet and Feron summarizes recent data showing that tumour acidosis influences cancer metabolism and contributes to cancer progression; it also highlights advances in therapeutic modalities aimed at either inhibiting or exploiting tumour acidification. The high metabolic demand of cancer cells leads to an accumulation of H+ ions in the tumour microenvironment. The disorganized tumour vasculature prevents an efficient wash-out of H+ ions released into the extracellular medium but also favours the development of tumour hypoxic regions associated with a shift towards glycolytic metabolism. Under hypoxia, the final balance of glycolysis, including breakdown of generated ATP, is the production of lactate and a stoichiometric amount of H+ ions. Another major source of H+ ions results from hydration of CO2 produced in the more oxidative tumour areas. All of these events occur at high rates in tumours to fulfil bioenergetic and biosynthetic needs. This Review summarizes the current understanding of how H+-generating metabolic processes segregate within tumours according to the distance from blood vessels and inversely how ambient acidosis influences tumour metabolism, reducing glycolysis while promoting mitochondrial activity. The Review also presents novel insights supporting the participation of acidosis in cancer progression via stimulation of autophagy and immunosuppression. Finally, recent advances in the different therapeutic modalities aiming to either block pH-regulatory systems or exploit acidosis will be discussed.
573 citations
TL;DR: How the tumor and its microenvironment influences T cell trafficking and function with a focus on melanoma, and pancreatic and ovarian cancer, is discussed, and how scientific advances may help overcome these hurdles are discussed.
453 citations
TL;DR: This review discusses the cellular, chemical and physical factors contributing to zonation and cellular crosstalk within tumor masses and describes 3D cell culture technologies for growth of MCTS as advanced tools for exploring molecular tumor growth determinants and facilitating drug discovery efforts.
394 citations
Cites background from "Disrupting proton dynamics and ener..."
...1B) [66]....
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...Besides theMCT4-mediated active lactate export out of hypoxic cells to counter-balance acidification of the intracellularmilieu, carbonic anhydrases also contribute to maintain a balanced pH [66]....
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References
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TL;DR: It is proposed that the metabolism of cancer cells, and indeed all proliferating cells, is adapted to facilitate the uptake and incorporation of nutrients into the biomass needed to produce a new cell.
Abstract: In contrast to normal differentiated cells, which rely primarily on mitochondrial oxidative phosphorylation to generate the energy needed for cellular processes, most cancer cells instead rely on aerobic glycolysis, a phenomenon termed “the Warburg effect.” Aerobic glycolysis is an inefficient way to generate adenosine 5′-triphosphate (ATP), however, and the advantage it confers to cancer cells has been unclear. Here we propose that the metabolism of cancer cells, and indeed all proliferating cells, is adapted to facilitate the uptake and incorporation of nutrients into the biomass (e.g., nucleotides, amino acids, and lipids) needed to produce a new cell. Supporting this idea are recent studies showing that (i) several signaling pathways implicated in cell proliferation also regulate metabolic pathways that incorporate nutrients into biomass; and that (ii) certain cancer-associated mutations enable cancer cells to acquire and metabolize nutrients in a manner conducive to proliferation rather than efficient ATP production. A better understanding of the mechanistic links between cellular metabolism and growth control may ultimately lead to better treatments for human cancer.
12,380 citations
TL;DR: Hypoxia-inducible factor 1 (HIF-1) is found in mammalian cells cultured under reduced O2 tension and is necessary for transcriptional activation mediated by the erythropoietin gene enhancer in hypoxic cells.
Abstract: Hypoxia-inducible factor 1 (HIF-1) is found in mammalian cells cultured under reduced O2 tension and is necessary for transcriptional activation mediated by the erythropoietin gene enhancer in hypoxic cells. We show that both HIF-1 subunits are basic-helix-loop-helix proteins containing a PAS domain, defined by its presence in the Drosophila Per and Sim proteins and in the mammalian ARNT and AHR proteins. HIF-1 alpha is most closely related to Sim. HIF-1 beta is a series of ARNT gene products, which can thus heterodimerize with either HIF-1 alpha or AHR. HIF-1 alpha and HIF-1 beta (ARNT) RNA and protein levels were induced in cells exposed to 1% O2 and decayed rapidly upon return of the cells to 20% O2, consistent with the role of HIF-1 as a mediator of transcriptional responses to hypoxia.
5,729 citations
TL;DR: In this article, the authors propose that persistent metabolism of glucose to lactate even in aerobic conditions is an adaptation to intermittent hypoxia in pre-malignant lesions, which leads to microenvironmental acidosis requiring evolution to phenotypes resistant to acid-induced cell toxicity.
Abstract: If carcinogenesis occurs by somatic evolution, then common components of the cancer phenotype result from active selection and must, therefore, confer a significant growth advantage. A near-universal property of primary and metastatic cancers is upregulation of glycolysis, resulting in increased glucose consumption, which can be observed with clinical tumour imaging. We propose that persistent metabolism of glucose to lactate even in aerobic conditions is an adaptation to intermittent hypoxia in pre-malignant lesions. However, upregulation of glycolysis leads to microenvironmental acidosis requiring evolution to phenotypes resistant to acid-induced cell toxicity. Subsequent cell populations with upregulated glycolysis and acid resistance have a powerful growth advantage, which promotes unconstrained proliferation and invasion.
4,361 citations
Journal Article•
TL;DR: Current knowledge of blood flow and perfusion-related parameters, which usually go hand in hand and in turn define the cellular metabolic microenvironment of human malignancies, are summarized for predicting the acute and/or long-term response of tumors to therapy.
Abstract: The objective of this review article is to summarize current knowledge of blood flow and perfusion-related parameters, which usually go hand in hand and in turn define the cellular metabolic microenvironment of human malignancies. A compilation of available data from the literature on blood flow, oxygen and nutrient supply, and tissue oxygen and pH distribution in human tumors is presented. Whenever possible, data obtained for human tumors are compared with the respective parameters in normal tissues, isotransplanted or spontaneous rodent tumors, and xenografted human tumors. Although data on human tumors in situ are scarce and there may be significant errors associated with the techniques used for measurements, experimental evidence is provided for the existence of a compromised and anisotropic blood supply to many tumors. As a result, O2-depleted areas develop in human malignancies which coincide with nutrient and energy deprivation and with a hostile metabolic microenvironment (e.g., existence of severe tissue acidosis). Significant variations in these relevant parameters must be expected between different locations within the same tumor, at the same location at different times, and between individual tumors of the same grading and staging. Furthermore, this synopsis will attempt to identify relevant pathophysiological parameters and other related areas future research of which might be most beneficial for designing individually tailored treatment protocols with the goal of predicting the acute and/or long-term response of tumors to therapy.
3,379 citations
TL;DR: The question of whether tumor cells in living animals can be killed off through lack of energy, and the related question of how the tumors are supplied with oxygen and glucose in the body are discussed.
Abstract: In this contribution we discuss the question of whether tumor cells in living animals can be killed off through lack of energy, and the related question of how the tumors are supplied with oxygen and glucose in the body. We assume it is understood that tumor cells obtain the energy required for their existence in two ways: by respiration and by fermentation. In respiration they burn organic materials to carbon dioxide and water; in fermentation they split glucose to lactic acid. All tumors so far tested behave fundamentally alike. There is no essential difference between the cancer cells of transplanted rat tumors and spontaneous tumors, sarcoma and carcinoma cells, and the tar carcinoma, and Rous sarcoma produced by filtrate. The fermentation of tumors was first found with cut pieces of tumor in vitro. I C. and G. Cori 2 demonstrated it in living animals as well. They determined the glucose and lactic acid in the axillary veins of hens having in one wing a Rous sarcoma, and found in 100 cc. of blood 23 mg. less glucose and 16 rag. more lactic acid on the tumor side than on the normal side. A corresponding experiment with a human fore-arm tumor showed in 100 cc. of blood 12 rag. less glucose and 9 rag. more lactic acid on the tumor side. In experiments on the nourishment of tumors through the blood stream, we, like Cori, determined the glucose and lactic acid in tumor veins. Our procedure differed from Cori's in that we compared tumor veins and arteries, not tumor veins and corresponding normal veins. Our differences were greater than Cori's because we went closer to
3,306 citations