Deregulation Of Energy Metabolism Research Articles

ETIOLOGY AND PATHOGENESIS OF HYPOPHARYNX CANCER: GENETIC AND IMMUNOLOGICAL FACTORS OF DEVELOPMENT. Review

Relevance. In the modern oncology hypopharynx malignant tumors are one of the urgent and significant problems. Hypopharynx is one of the most frequent localizations in the head and neck. An important factor causing the high occurrence in the population is the asymptomatic course of the disease, resulting in patients presenting for treatment with аn already widespread tumour process.
 Objective: to summarize and systematize data on the etiology and pathogenesis of hypopharynx cancer.
 Materials and methods. Analysis of scientific publications in the international electronic scientometric databases Scopus, PubMed by keywords. Search depth – 20 years (2001-2020).
 Results. In recent years, the view on the mechanisms of the development of carcinogenesis has changed dramatically, the tumour is no longer considered as a mass of malignant cells, but rather as a self-sufficient biological structure with a complex microenvironment in which other subpopulations of cells damaged by cancer are involved. The stromal component of the tumour microenvironment consists of various types of cells such as cancer-associated fibroblasts, neutrophils, macrophages, regulatory T-cells, myeloid suppressor cells, NK-cells etc. These subpopulations of cells interact with each other as well as with cancer cells. In addition to amplification, deletion, loss of heterozygosity, as well as polymorphism of some genes that are directly involved in the cell cycle or act as regulators of posttranscriptional modifiers of their products at the early stages of carcinogenesis may be one of the promising directions in creating a panel of markers for the risk of developing hypopharynx cancer.
 Conclusions. The microenvironment of the tumor consists of many different cell populations. These parts of the surrounding stroma can function as both positive and negative regulators of all signs of cancer, including evasion of apoptosis, induction of angiogenesis, deregulation of energy metabolism, resistance to detection and destruction by the immune system, and activation of invasion and metastasis. Exploring differences in the composition of the tumour microenvironment and their influence on the development and progression of hypopharynx cancer can help better understand mechanisms underlying different responses to therapy, and help to identify possible targets for clinical intervention.

Lactate as a Regulator of Cancer Inflammation and Immunity

Abstract Resistance to anti-cancer therapies is a consequence of adaptation of cancer cells but also of maladaptation of tumor-infiltrating immune cells. The opposing roles acquired by the immune system have to be faced in order to fight tumor growth and therapy resistance. Effector immune cells are recruited and activated but they are blocked by the strong immunosuppressive nature of the tumor microenvironment (TME). Immune evasion and deregulation of energy metabolism are two hallmarks of cancer that may be functionally linked. Malignant cells which present a high glycolytic phenotype, besides creating metabolic demanding environments that encroach on the function of tumor-infiltrating immune cells, also release immunosuppressive metabolites and by-products, such as lactate, forming a metabolic symbiosis with immune cells. This acidic TME has a strong impact in the profile of tumor-infiltrating immune cells, being instrumental for immunosuppression. Therefore, in this review, we focus on key molecular mechanisms by which lactate metabolically modulates immune cell response during tumor development and progression.

Abstract 1693: Prediction of the efficacy of nivolumab using resting energy expenditure in metastatic non-small cell lung cancer (mNSCLC) patients

Abstract Background: Immune evasion and deregulation of energy metabolism play a pivotal role in cancer progression. Immunosuppression in the tumor microenvironment can be based on the mutual metabolic requirements of immune and tumor cells. We evaluated the value of resting energy expenditure (REE) as a predictor of outcome, in mNSCLC patients under Nivolumab, an immune checkpoint inhibitor. Methods: We studied the relation between REE, clinical and biological markers of cachexia and inflammation, and response to Nivolumab in 82 consecutive mNSCLC patients. Efficacy was assessed every 2 months according to Response Evaluation Criteria in Solid Tumors (RECIST) criteria. REE was measured using indirect calorimetry, before the initiation of Nivolumab. According to their REE and with the use of Boothby's standard, patients were categorized as hypermetabolic, normometabolic and hypometabolic. Body mass index (BMI), performance status (PS), C-reactive protein (CRP), albumin, Neutrophil Lymphocyte R Ratio (NLR) and PD-L1 tumor expression were also recorded. Results: Patients characteristics were: 62% males, median age of 65 years (range 37-78), 61% PS 0-1, median BMI of 24 kg.m-² (range 17-39), 78% nonsquamous NSCLC. The analysis of REE was available for 69 out of 82 consecutive pts: 37.7% were hypermetabolic, 47.8% were normometabolic, and 14.5% were hypometabolic. In univariate analysis, hypometabolism was a strong predictive marker of disease progression (Table 1), with positive and negative predictive values of 0.80 and 0.52 respectively. In multivariate analysis, independent parameters associated with disease progression were baseline hypometabolism (vs normometabolism: OR 1.77 [1.31-2.39] p= 0.0004) and albumin (per 1pt increase: OR 0.96 [0.94-0.99] p= 0.005). Conclusion: Rest energy expenditure assessed by calorimetry appears as a biomarker of nivolumab clinical activity independently of PD1/PDL1 status. Table 1Disease control (best response) n (%)<85% calculated REE n=10 (14.5%) Hypometabolic85-115% calculated REE n=33 (47.8%) Normometabolic>115% calculated REE n=26 (37.7%) Hypermetabolicunivariate OR (Hypometabolic vs normometabolic)pProgression8 (80%)11 (33%)17 (65%)8 [1.4-44.2]0.0007Disease control rate2 (20%)22 (67%)9 (35%) Citation Format: Claire Gervais, Pascaline Boudou-Rouquette, Anne Jouinot, Jeanne Chapron, Jennifer Arrondeau, Marco Alifano, Frédérique Giraud, Olivier Huillard, Jérôme Alexandre, Clara Vazeille, Jean-Philippe Durand, Karen Leroy, Marie-Pierre Revel, Jean-Pascal de Bandt, Luc Cynober, Diane Damotte, Audrey Lupo-Mansuet, François Goldwasser. Prediction of the efficacy of nivolumab using resting energy expenditure in metastatic non-small cell lung cancer (mNSCLC) patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1693.

Abstract P4-07-05: MicroRNA-27b mediates deregulation of energy metabolism in breast cancer

Abstract MicroRNAs (miRNAs) are a class of small, non-coding RNA which participate in gene regulation by targeted silencing of specific mRNA transcripts. Recently, it has become clear that dysfunctional miRNA expression is an important contributor to the deregulation of key signaling pathways underlying carcinogenesis. MicroRNA-27b is an example of one such pro-oncogenic miRNA, and correspondingly, its expression has been found to be upregulated in breast cancer cells and tissues. In this regard, several targets of miR-27b have previously been verified, and implicate miR-27b in multiple neoplastic processes including migration, invasion and metastasis. In order to enable future development of miRNA-based cancer therapies, the putative targets of each miRNA must be mapped more comprehensively. Such awareness is necessary in order to make informed choices regarding whether a miRNA-based therapy is likely to be effective and what side-effects should be anticipated. Therefore, this project seeks to further establish the role of miR-27b in the context of breast cancer, specifically by identifying novel target transcripts under its control. Using target prediction algorithms and breast cancer cell culture models, initial evidence has implicated Pyruvate Dehydrogenase Protein X (PDHX) to be a probable target. As a structural component of the Pyruvate Dehydrogenase Complex, the role of PDHX in linking the end products of glycolytic reactions with subsequent oxidative phosphorylation pathways is indispensable. However, a hallmark of cancer cell metabolism is the propensity to consume glucose aerobically, which liberates additional carbon skeletons for use in biosynthetic reactions that are crucial for tumor growth. In this way, miR-27b overexpression appears to sever the link between glycolysis and subsequent catabolic pathways, thus conferring a pro-growth advantage to the cancer cells. Expression profiling of PDHX using both breast cancer cell lines and human breast tissues (which overexpress miR-27b) reveal that PDHX levels are indeed significantly reduced, thus supporting the notion that miR-27b alters cancer cell metabolism specifically by targeting this gene in breast cancer. Improving the current understanding of miR-27b's functions will lay the necessary ground work to evaluate its potential as a novel target for cancer therapy. Similarly, the awareness of the expression status of miR-27b and its targets in breast cancer tumors will further efforts to find suitable miRNA tissue biomarkers to enhance screening and prognosis. In this way, microRNA-based approaches offer the distinct potential to improve cancer detection as well as treatment, making them a dynamic method to improve management of breast cancer patients in the future. Citation Format: Eastlack SC, Alahari SK, Dong S, Cole JT. MicroRNA-27b mediates deregulation of energy metabolism in breast cancer [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P4-07-05.

Deregulation of Energy Metabolism as a Cause and Consequence of Oncogenic Process: Review of Literature

The reprogramming of energy metabolism is an emerging hallmark of cancer that has not yet been demonstrated in all tumor models, and there are aspects which still not entirely clear. This review enrolled and analyzed data from the last 20 years regarding the proposed theme; and it allowed to conclude that the deregulation of energy metabolism is a key factor in the initiation and progression of tumors, behaving as a cause and consequence.

Metabolomics and In-Silico Analysis Reveal Critical Energy Deregulations in Animal Models of Parkinson’s Disease

Parkinson’s disease (PD) is a multifactorial disease known to result from a variety of factors. Although age is the principal risk factor, other etiological mechanisms have been identified, including gene mutations and exposure to toxins. Deregulation of energy metabolism, mostly through the loss of complex I efficiency, is involved in disease progression in both the genetic and sporadic forms of the disease. In this study, we investigated energy deregulation in the cerebral tissue of animal models (genetic and toxin induced) of PD using an approach that combines metabolomics and mathematical modelling. In a first step, quantitative measurements of energy-related metabolites in mouse brain slices revealed most affected pathways. A genetic model of PD, the Park2 knockout, was compared to the effect of CCCP, a complex I blocker. Model simulated and experimental results revealed a significant and sustained decrease in ATP after CCCP exposure, but not in the genetic mice model. In support to data analysis, a mathematical model of the relevant metabolic pathways was developed and calibrated onto experimental data. In this work, we show that a short-term stress response in nucleotide scavenging is most probably induced by the toxin exposure. In turn, the robustness of energy-related pathways in the model explains how genetic perturbations, at least in young animals, are not sufficient to induce significant changes at the metabolite level.

Enigma, a mitochondrial protein affecting lifespan and oxidative stress response in Drosophila

Deregulation of energy metabolism by external interventions or mutations in metabolic genes can extend lifespan in a wide range of species. We describe mutations in Drosophila melanogaster that confer resistance to oxidative stress and display a longevity phenotype. These phenotypes are associated with molecular lesions in a hitherto uncharacterized gene we named Enigma. We show that Enigma encodes a mitochondrial protein with homology to enzymes of the beta-oxidation of fatty acids and that mutations in this locus affect lipid homeostasis. Our analysis provides further support to the notion that lipid metabolism may play a central role in metazoan lifespan regulation.