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    Home > Active Ingredient News > Antitumor Therapy > Science: review of metabolic remodeling and cancer progress

    Science: review of metabolic remodeling and cancer progress

    • Last Update: 2020-06-19
    • Source: Internet
    • Author: User
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    Translation: scopolamine, editing: Xie Yi, Jiang shunyao< br / > < br / > metabolic remodeling (also known as metabolic reprogramming) is a characteristic of malignant tumorsWith the increasing understanding of the complexity of tumor biology, our understanding of the complexity of tumor metabolism is also improvingThe metabolic heterogeneity between human tumors challenges the development and utilization of therapies with metabolic characteristics < br / >Recent studies have shown that in the process of cancer progression, tumor metabolic characteristics and preferences will changeEven in the same patient or experimental model, primary cancer and metastatic cancer have different metabolic characteristicsThis article reviews the latest viewpoints in the field of cancer metabolism, focusing on the changes of metabolism during the development of cancer, and how to use these information to develop better treatment strategies< br / > < br / > the flexible changes of cell metabolism meet the needs of homeostasis and growth of tissueIn cancer, malignant cells respond to various exogenous and endogenous signals to obtain metabolic adaptation (Figure 1)Some of these adaptations initiate the transformation process, others promote the growth of malignant cells and make them susceptible to key pathway inhibitorsMost cancer metabolism studies focus on tumor phenotypes observed in clinical or experimental modelsTherefore, the terms "cancer metabolism" and "metabolic remodeling" are often used to refer to a set of shared pathways observed in highly proliferating tumors or cancer cellsWarburg effect is a kind of effect that still prefers glycolysis and lactate secretion in the presence of oxygenIt is the metabolic characteristic of many proliferative cancer cells and cancer genes controlling tumor cells independentlyIf cancer cells are fixedly dependent on Warburg effect or other conservative pathways, and non malignant cells adapt to their inhibition, there may be treatment opportunities< br / > < br / > Advanced metabolic analysis technology and more and more attention to tumor metabolism in vivo indicate that it is necessary to conduct more detailed research on metabolic remodelingFirst of all, tumor cells need many of the same pathways and adaptations as non malignant tissues, indicating that few metabolic activities are really limited to tumors Secondly, with the increasing information of metabolic phenotype test results, it has been clear that tumor metabolism is heterogeneous Therefore, metabolic characteristics and defects are not consistent in all cancers This is consistent with the variable efficacy of treatments for metabolic defects that are common on the surface of cancer cells, including antifolates and other drugs Finally, with the progression from precancerous lesions to localized, clinically visible malignancies to metastatic cancers, the phenotype and dependence of cell metabolism are also changing In order to understand the metabolism of cancer and identify the metabolic characteristics, we need to have a deep understanding of the changes of metabolic phenotype over time It is valuable to know which metabolic activities allow cells to grow and proliferate to the maximum extent, and how these activities are activated in cancer for a long time The emerging view is that cancer metabolism is flexible and varies according to the environment, and some of the most promising therapeutic targets are different from the pathways supporting cell growth in locally invasive tumors This article reviews the latest concepts related to metabolism in tumor progression, and pays special attention to the relationship between the changing metabolic dependence and treatment opportunity < br / > < br / > intrinsic factors include the characteristics of parental tissues and new characteristics in malignant cells due to changes in signal and transcription networks External factors include patients' microenvironment and metabolic pressure The organ specific metabolic phenotype of < br / > < br / > < br / > < br / > 1 < br / > precancerous lesions < br / > < br / > non malignant tissues is the result of the combined effect of internal and external factors These factors include gene expression, cell composition, tissue structure regulated by epigenetics and, in some cases, symbiotic microbial population Different tissue influencing factors and metabolic phenotypes are also different (Figure 1) Metabolic disorder induces tissue specific response and regulates homeostasis Fasting stress in mammals induces lipolysis of adipose tissue, ketone production in the liver, and ketone consumption in the brain and other organs Understanding tissue-specific metabolic phenotypes is an important basis for understanding cancer metabolism < br / > First of all, although tumors are easily recognized by gene expression features, they retain the transcriptional features of their parent tissues, so tumors produced in the same organ are more similar than those produced in different organs A study that classifies thousands of human tumors has found that the primary determinants of DNA methylation and gene expression patterns are the tissues of origin The similarity of gene expression characteristics in the same organ is greater than that in different organs Secondly, although different oncogenes remodel metabolism in different ways, the tissues expressing oncogenes also affect the implementation of metabolic remodelling The expression of human myc oncogene in mice is a good example Transgenic myc can induce metabolic changes in both liver and lung tumors, but activate glutamine catabolism in lung tumors and glutamine synthesis in liver tumors Therefore, the classification of tumors based on tumor drivers rather than tissue sources may mask the metabolic differences caused by the original metabolic state of tissues The origin and development environment of < br / > < br / > tissue also determine whether the potential transformation mutation will lead to the occurrence of cancer Familial cancer syndrome is an example of this phenomenon In these diseases, patients inherit the germline mutations in tumor suppressor genes When other alleles are mutated, deleted or silenced, patients will develop cancer For the classical tumor suppressor gene TP53, the distribution of cancer tissue caused by the mutation is different from that caused by the sporadic mutation in the patients without the mutation This indicates that the result of TP53 mutation depends on the development environment < br / > But only a small number of cells are susceptible Despite the prevalence of metabolic enzyme succinate dehydrogenase (SDH), the germline mutations of this complex subunit cause cancer in only a few sites, including neuroendocrine tissue (paraganglioma), adrenal gland (pheochromocytoma), and stomach and small intestine (gastrointestinal stromal tumor) Similarly, mutations in the widely expressed fumaric hydratase (FH) strain can lead to hereditary leiomyomatosis and renal cell carcinoma, a family syndrome of uterine, skin leiomyoma and renal cancer, which is not susceptible to other common tumors Other cancers are caused by inborn metabolic errors The metabolic homeostasis is caused by the double allele mutation of metabolic enzymes, but cancer is limited to the specific tissues of each enzyme The basis of tissue specificity in these syndromes is not clear One possibility is that the molecular level required for metabolic enzyme mutations to cause malignancies is tissue-specific In other words, some tissues may induce adaptive response to limit the occurrence of tumors, or only a few cell types may respond to metabolic disorders through transformation Another possibility is that most cells simply can't tolerate this kind of disorder and can only deal with it through aging or death, rather than transformation These rare familial cancer syndromes are important because they provide examples of understanding tissue-specific mechanisms by which cells respond to genetically determined metabolic defects and why these reactions include tumorigenesis in some cases < br / > < br / > metabolic remodeling is a sign of cancer Mutations that lead to cancer make tumor cells obtain the metabolic characteristics of supporting cell survival, avoiding immune surveillance and proliferative growth This concept has been proved to be a classical carcinogen with the ability to regulate metabolism in an autonomous way However, it is not clear whether these mutations are necessary for the establishment of metabolic characteristics to support tumorigenesis Some tumors lack of typical tumor suppressor and re mutation of oncogene, but they still have metabolic characteristics different from non malignant tissues Clear cell papillary renal cell carcinoma (ccpap) is a typical low-grade renal tumor The metabonomics of these tumors suggest oxidative stress, inhibition of oxidative metabolism, and deletion of mitochondrial DNA and RNA However, a detailed molecular analysis shows that the genomic burden of point mutation and copy number mutation is low, there is no recurrent non synonymous mutation, and DNA methylation pattern similar to that of non malignant kidney Ccpap tumors may contain an undetected initial mutation, or the mutation disappears before it can be clinically detected But another possibility is that potential metabolic disorders mask the effects of classic mutations For example, chronic mitochondrial dysfunction may result in the phenotype loss of von Hippel Lindau (VHL), the most common mutant tumor suppressor gene in clear cell renal cell carcinoma (ccrcc) The accumulation of metabolites during mitochondrial dysfunction can inhibit the degradation of hypoxia inducible factor - α (HIF - α) dependent on VHL, and form a pseudo hypoxia state similar to the loss of VHL < br / > < br / > it is challenging to describe metabolic abnormalities in precancerous lesions First of all, these tumors are usually not clinically noticed, so the literature on their metabolism is limited; for those studies that fail to observe differences in parental tissues, there may be bias Secondly, systemic metabolism affects the risk of cancer and may affect the metabolism of precancerous lesions Many epidemiological studies report a link between obesity and cancer, and a large prospective analysis of more than 900000 Americans found that cancer mortality increased by more than 50% in patients with the highest body mass index The mechanism of association between cancer and obesity, diabetes and other metabolic disorders is multifactorial But because these diseases affect the metabolism of the whole body, it is difficult to identify specific carcinogenic pathways in precancerous lesions Despite these challenges, some mechanism studies have been reported that diabetes may increase the frequency of KRAS variation in human pancreas through the effect of chronic hyperglycemia on nucleotide balance In addition, high saturated fat diet can enhance the transcription of myc in human and mouse prostate cancer, and promote cell proliferation < br / > < br / > there are also several examples of specific metabolic changes in precancerous lesions relative to parental tissues In mice, the metabolic remodeling of pancreatic acinar cells in response to carcinogenic KRAS promotes acinar ductal metaplasia (ADM), a precursor of pancreatic ductal adenocarcinoma (PDAC) The oncogene KRAS increased the levels of acetyl CoA and ROS before ADM, and inhibition of these phenotypes could block Adm Other studies in humans and mice have reported metabolic changes in precancerous colonic polyps, some of which remain in adenocarcinoma Metabolic remodeling made the mouse hepatoma expressing myc in hepatocytes disappear In the early stage of precancerous lesions, myc can promote the conversion of pyruvate to alanine, while in the late stage of malignant lesions, pyruvate to lactate < br / > In atypical pulmonary adenomatous hyperplasia (aahs), SGLT2 was overexpressed in precancerous lesions SGLT2 does not transport common cancer imaging tracers < br / > 18 < br / > FDG, so these diseases
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