bims-glucam Biomed News
on Glutamine cancer metabolism
Issue of 2024–01–14
fiveteen papers selected by
Sreeparna Banerjee, Middle East Technical University
  1. Identification of breast cancer subgroups and immune characterization based on glutamine metabolism-related genes.
  2. Design strategies and recent development of bioactive modulators for glutamine transporters.
  3. Role of long non-coding RNAs in metabolic reprogramming of gastrointestinal cancer cells.
  4. Augmented drug resistance of osteosarcoma cells within decalcified bone matrix scaffold: The role of glutamine metabolism.
  5. Immunosurveillance encounters cancer metabolism.
  6. The nonessential amino acid cysteine is required to prevent ferroptosis in acute myeloid leukemia.
  7. Genetic estimation of correlations between circulating glutamine and cancer.
  8. Assessing the effect of oral glutamine on the MELAS phenotype requires appropriate study designs.
  9. Recreating metabolic interactions of the tumour microenvironment.
  10. Ferroptosis, Metabolic Rewiring, and Endometrial Cancer.
  11. Norovirus NS1/2 protein increases glutaminolysis for efficient viral replication.
  12. Isocitrate Dehydrogenase Mutations in Cancer: Mechanisms of Transformation and Metabolic Liability.
  13. p66ShcA promotes malignant breast cancer phenotypes by alleviating energetic and oxidative stress.
  14. GLUD1 inhibits hepatocellular carcinoma progression via ROS-mediated p38/JNK MAPK pathway activation and mitochondrial apoptosis.
  15. Amino Acid Profiles in the Biological Fluids and Tumor Tissue of CRC Patients.
  1. BMC Med Genomics. 2024 Jan 10. 17(1): 17
    Identification of breast cancer subgroups and immune characterization based on glutamine metabolism-related genes.
    Hongjing Yu, Junchen Liu.
      Immunotherapy is a promising treatment for breast cancer (BC). However, due to individual differences and tumor heterogeneity, immunotherapy is only applicable to some BC patients. Glutamine metabolism plays a role in inhibiting immunotherapy, but its role in BC is limitedly studied. Therefore, we aimed to identify different BC subgroups based on glutamine metabolism and characterize the features of different subgroups to provide guidance for personalized immunotherapy for BC patients. Using unsupervised clustering analysis, we classified BC patients in The Cancer Genome Atlas (TCGA) with glutamine metabolism-related genes and obtained low-risk (LR) and high-risk (HR) subgroups. Survival analysis revealed that prognosis of LR subgroup was notably better than HR subgroup. Through ssGSEA and CIBERSORT methods, we disclosed that infiltration levels of B cells, Mast cells, T helper cells, and Th2 cells, and Type II IFN Response immune function were notably higher in LR subgroup than in HR subgroup. The Wilcox algorithm comparison denoted that DEPTH of LR subgroup was significantly lower than HR subgroup. The TIDE of LR subgroup was significantly higher than HR subgroup. Functional annotation of differentially expressed genes revealed that channel activity and the Estrogen signaling pathway may be related to BC prognosis. Ten hub genes were selected between the subgroups through the STRING database and Cytoscape, and their correlation with drugs was predicted on the CellMiner website. This study analyzed the immune characteristics of BC subgroups based on glutamine metabolism and provided reference for prognosis prediction and personalized immunotherapy.
    Keywords:  Breast cancer; Gene mutation; Glutamine metabolism; Immune; Subgroups
    DOI:  https://doi.org/10.1186/s12920-023-01792-5
  2. Drug Discov Today. 2024 Jan 10. pii: S1359-6446(24)00005-9. [Epub ahead of print] 103880
    Design strategies and recent development of bioactive modulators for glutamine transporters.
    Xinying Cheng, Yezhi Wang, Guangyue Gong, Pei Shen, Zhiyu Li, Jinlei Bian.
      Glutamine transporters are integral to the metabolism of glutamine in both healthy tissues and cancerous cells, playing a pivotal role in maintaining amino acid balance, synthesizing biomolecules, and regulating redox equilibrium. Their critical functions in cellular metabolism make them promising targets for oncological therapies. Recent years have witnessed substantial progress in the field of glutamine transporters, marked by breakthroughs in understanding of their protein structures and the discovery of novel inhibitors, prodrugs, and radiotracers. This review provides a comprehensive update on the latest advancements in modulators targeting the glutamine transporter, with special attention given to LAT1 and ASCT2. It also discusses innovative approaches in drug design aimed at these transporters.
    Keywords:  antitumor, drug discovery; glutamine transporter; strategy
    DOI:  https://doi.org/10.1016/j.drudis.2024.103880
  3. Cancer Cell Int. 2024 Jan 06. 24(1): 15
    Role of long non-coding RNAs in metabolic reprogramming of gastrointestinal cancer cells.
    Kang Wang, Yan Lu, Haibin Li, Jun Zhang, Yongle Ju, Manzhao Ouyang.
      Metabolic reprogramming, which is recognized as a hallmark of cancer, refers to the phenomenon by which cancer cells change their metabolism to support their increased biosynthetic demands. Tumor cells undergo substantial alterations in metabolic pathways, such as glycolysis, oxidative phosphorylation, pentose phosphate pathway, tricarboxylic acid cycle, fatty acid metabolism, and amino acid metabolism. Latest studies have revealed that long non-coding RNAs (lncRNAs), a group of non-coding RNAs over 200 nucleotides long, mediate metabolic reprogramming in tumor cells by regulating the transcription, translation and post-translational modification of metabolic-related signaling pathways and metabolism-related enzymes through transcriptional, translational, and post-translational modifications of genes. In addition, lncRNAs are closely related to the tumor microenvironment, and they directly or indirectly affect the proliferation and migration of tumor cells, drug resistance and other processes. Here, we review the mechanisms of lncRNA-mediated regulation of glucose, lipid, amino acid metabolism and tumor immunity in gastrointestinal tumors, aiming to provide more information on effective therapeutic targets and drug molecules for gastrointestinal tumors.
    Keywords:  Gastrointestinal tract tumors; Long non-coding RNAs; Metabolic enzymes; Metabolic reprogramming; Prognosis; Therapeutic targets; Tumor microenvironment; microRNA
    DOI:  https://doi.org/10.1186/s12935-023-03194-0
  4. Int J Cancer. 2024 Jan 09.
    Augmented drug resistance of osteosarcoma cells within decalcified bone matrix scaffold: The role of glutamine metabolism.
    Jiaxin Ren, Cheng Zhao, Ruizhu Sun, Jian Sun, Laiya Lu, Jun Wu, Shuaijun Li, Lei Cui.
      Due to the lack of a precise in vitro model that can mimic the nature microenvironment in osteosarcoma, the understanding of its resistance to chemical drugs remains limited. Here, we report a novel three-dimensional model of osteosarcoma constructed by seeding tumor cells (MG-63 and MNNG/HOS Cl no. 5) within demineralized bone matrix scaffolds. Demineralized bone matrix scaffolds retain the original components of the natural bone matrix (hydroxyapatite and collagen type I), and possess good biocompatibility allowing osteosarcoma cells to proliferate and aggregate into clusters within the pores. Growing within the scaffold conferred elevated resistance to doxorubicin on MG-63 and MNNG/HOS Cl no. 5 cell lines as compared to two-dimensional cultures. Transcriptomic analysis showed an increased enrichment for drug resistance genes along with enhanced glutamine metabolism in osteosarcoma cells in demineralized bone matrix scaffolds. Inhibition of glutamine metabolism resulted in a decrease in drug resistance of osteosarcoma, which could be restored by α-ketoglutarate supplementation. Overall, our study suggests that microenvironmental cues in demineralized bone matrix scaffolds can enhance osteosarcoma drug responses and that targeting glutamine metabolism may be a strategy for treating osteosarcoma drug resistance.
    Keywords:  decalcified bone matrix; drug resistance; glutamine metabolism; osteosarcoma
    DOI:  https://doi.org/10.1002/ijc.34841
  5. EMBO Rep. 2024 Jan 12.
    Immunosurveillance encounters cancer metabolism.
    Yu-Ming Chuang, Sheue-Fen Tzeng, Ping-Chih Ho, Chin-Hsien Tsai.
      Tumor cells reprogram nutrient acquisition and metabolic pathways to meet their energetic, biosynthetic, and redox demands. Similarly, metabolic processes in immune cells support host immunity against cancer and determine differentiation and fate of leukocytes. Thus, metabolic deregulation and imbalance in immune cells within the tumor microenvironment have been reported to drive immune evasion and to compromise therapeutic outcomes. Interestingly, emerging evidence indicates that anti-tumor immunity could modulate tumor heterogeneity, aggressiveness, and metabolic reprogramming, suggesting that immunosurveillance can instruct cancer progression in multiple dimensions. This review summarizes our current understanding of how metabolic crosstalk within tumors affects immunogenicity of tumor cells and promotes cancer progression. Furthermore, we explain how defects in the metabolic cascade can contribute to developing dysfunctional immune responses against cancers and discuss the contribution of immunosurveillance to these defects as a feedback mechanism. Finally, we highlight ongoing clinical trials and new therapeutic strategies targeting cellular metabolism in cancer.
    Keywords:  Cancer Evolution; Immunoediting; Immunometabolism
    DOI:  https://doi.org/10.1038/s44319-023-00038-w
  6. Blood Adv. 2024 Jan 09. 8(1): 56-69
    The nonessential amino acid cysteine is required to prevent ferroptosis in acute myeloid leukemia.
    Alan Cunningham, Lieve L Oudejans, Marjan Geugien, Diego Antonio Pereira-Martins, Albertus T J Wierenga, Ayşegül Erdem, Dominique Sternadt, Gerwin Huls, Jan Jacob Schuringa.
       ABSTRACT: Cysteine is a nonessential amino acid required for protein synthesis, the generation of the antioxidant glutathione, and for synthesizing the nonproteinogenic amino acid taurine. Here, we highlight the broad sensitivity of leukemic stem and progenitor cells to cysteine depletion. By CRISPR/CRISPR-associated protein 9-mediated knockout of cystathionine-γ-lyase, the cystathionine-to-cysteine converting enzyme, and by metabolite supplementation studies upstream of cysteine, we functionally prove that cysteine is not synthesized from methionine in acute myeloid leukemia (AML) cells. Therefore, although perhaps nutritionally nonessential, cysteine must be imported for survival of these specific cell types. Depletion of cyst(e)ine increased reactive oxygen species (ROS) levels, and cell death was induced predominantly as a consequence of glutathione deprivation. nicotinamide adenine dinucleotide phosphate hydrogen oxidase inhibition strongly rescued viability after cysteine depletion, highlighting this as an important source of ROS in AML. ROS-induced cell death was mediated via ferroptosis, and inhibition of glutathione peroxidase 4 (GPX4), which functions in reducing lipid peroxides, was also highly toxic. We therefore propose that GPX4 is likely key in mediating the antioxidant activity of glutathione. In line, inhibition of the ROS scavenger thioredoxin reductase with auranofin also impaired cell viability, whereby we find that oxidative phosphorylation-driven AML subtypes, in particular, are highly dependent on thioredoxin-mediated protection against ferroptosis. Although inhibition of the cystine-glutamine antiporter by sulfasalazine was ineffective as a monotherapy, its combination with L-buthionine-sulfoximine (BSO) further improved AML ferroptosis induction. We propose the combination of either sulfasalazine or antioxidant machinery inhibitors along with ROS inducers such as BSO or chemotherapy for further preclinical testing.
    DOI:  https://doi.org/10.1182/bloodadvances.2023010786
  7. Am J Cancer Res. 2023 ;13(12): 6072-6089
    Genetic estimation of correlations between circulating glutamine and cancer.
    Kai Zhang, Hongjin Liang.
      The controversy regarding the causal relationship between circulating glutamine and cancer risk remains unresolved. Here, we aim to assess the causal impact of glutamine on the risk of six prevalent cancer types and their respective subtypes including breast, lung, ovarian, thyroid, prostate, and endometrial cancers. A Mendelian randomization (MR) analysis was conducted to evaluate the causal effect of circulating glutamine on cancers risk. Data on circulating glutamine were extracted from the UK Biobank (UKB), comprising 114,750 European patients. To ensure the validity of our findings, we employed several analytical approaches, such as inverse variance weighting, weighted median, weighted mode test, MR-Egger regression, and MR-PRESSO method. Both univariable and multivariable MR analyses were conducted. Additionally, we employed a large-scale summary-level study on circulating glutamine involving 24,925 European participants for validation purposes. Our MR analysis reveals a causal association between circulating glutamine and thyroid cancer in both the UKB cohort (IVW: OR = 0.667, 95% CI [0.541-0.822], P = 1.52×10-4) and the validated cohort (IVW: OR = 0.577, 95% CI [0.421-0.790], P = 6.14×10-4). Sensitivity analysis, including multivariable MR analyses, consistently supports this finding (P < 0.05), affirming the reliability and robustness of our study. Our findings indicate an inverse correlation between circulating glutamine and the incidence of thyroid cancer in European populations. However, further research encompassing diverse ancestries is necessary to validate this causal relationship.
    Keywords:  Circulating glutamine; GWAS; Mendelian randomization; UK Biobank; cancer; genetics
  8. Neuroradiology. 2024 Jan 09.
    Assessing the effect of oral glutamine on the MELAS phenotype requires appropriate study designs.
    Josef Finsterer.
      
    DOI:  https://doi.org/10.1007/s00234-024-03284-4
  9. Trends Endocrinol Metab. 2024 Jan 10. pii: S1043-2760(23)00250-3. [Epub ahead of print]
    Recreating metabolic interactions of the tumour microenvironment.
    Rodrigo Curvello, Nikolaus Berndt, Sandra Hauser, Daniela Loessner.
      Tumours are heterogeneous tissues containing diverse populations of cells and an abundant extracellular matrix (ECM). This tumour microenvironment prompts cancer cells to adapt their metabolism to survive and grow. Besides epigenetic factors, the metabolism of cancer cells is shaped by crosstalk with stromal cells and extracellular components. To date, most experimental models neglect the complexity of the tumour microenvironment and its relevance in regulating the dynamics of the metabolism in cancer. We discuss emerging strategies to model cellular and extracellular aspects of cancer metabolism. We highlight cancer models based on bioengineering, animal, and mathematical approaches to recreate cell-cell and cell-matrix interactions and patient-specific metabolism. Combining these approaches will improve our understanding of cancer metabolism and support the development of metabolism-targeting therapies.
    Keywords:  cancer metabolism; cancer models; mathematical models; tumour microenvironment
    DOI:  https://doi.org/10.1016/j.tem.2023.12.005
  10. Int J Mol Sci. 2023 Dec 20. pii: 75. [Epub ahead of print]25(1):
    Ferroptosis, Metabolic Rewiring, and Endometrial Cancer.
    Eglė Žalytė.
      Ferroptosis is a newly discovered form of regulated cell death. The main feature of ferroptosis is excessive membrane lipid peroxidation caused by iron-mediated chemical and enzymatic reactions. In normal cells, harmful lipid peroxides are neutralized by glutathione peroxidase 4 (GPX4). When GPX4 is inhibited, ferroptosis occurs. In mammalian cells, ferroptosis serves as a tumor suppression mechanism. Not surprisingly, in recent years, ferroptosis induction has gained attention as a potential anticancer strategy, alone or in combination with other conventional therapies. However, sensitivity to ferroptosis inducers depends on the metabolic state of the cell. Endometrial cancer (EC) is the sixth most common cancer in the world, with more than 66,000 new cases diagnosed every year. Out of all gynecological cancers, carcinogenesis of EC is mostly dependent on metabolic abnormalities. Changes in the uptake and catabolism of iron, lipids, glucose, and glutamine affect the redox capacity of EC cells and, consequently, their sensitivity to ferroptosis-inducing agents. In addition to this, in EC cells, ferroptosis-related genes are usually mutated and overexpressed, which makes ferroptosis a promising target for EC prediction, diagnosis, and therapy. However, for a successful application of ferroptosis, the connection between metabolic rewiring and ferroptosis in EC needs to be deciphered, which is the focus of this review.
    Keywords:  endometrial cancer; ferroptosis; metabolism; resistance
    DOI:  https://doi.org/10.3390/ijms25010075
  11. bioRxiv. 2023 Dec 19. pii: 2023.12.19.572316. [Epub ahead of print]
    Norovirus NS1/2 protein increases glutaminolysis for efficient viral replication.
    Adam Hafner, Noah Meurs, Ari Garner, Elaine Azar, Karla D Passalacqua, Deepak Nagrath, Christiane E Wobus.
      Viruses are obligate intracellular parasites that rely on host cell metabolism for successful replication. Thus, viruses rewire host cell pathways involved in central carbon metabolism to increase the availability of building blocks for replication. However, the underlying mechanisms of virus-induced alterations to host metabolism are largely unknown. Noroviruses (NoVs) are highly prevalent pathogens that cause sporadic and epidemic viral gastroenteritis. In the present study, we uncovered several strain-specific and shared host cell metabolic requirements of three murine norovirus (MNV) strains, the acute MNV-1 strain and the persistent CR3 and CR6 strains. While all three strains required glycolysis, glutaminolysis, and the pentose phosphate pathway for optimal infection of macrophages, only MNV-1 relied on host oxidative phosphorylation. Furthermore, the first metabolic flux analysis of NoV-infected cells revealed that both glycolysis and glutaminolysis are upregulated during MNV-1 infection of macrophages. Glutamine deprivation affected the MNV lifecycle at the stage of genome replication, resulting in decreased non-structural and structural protein synthesis, viral assembly, and egress. Mechanistic studies further showed that MNV infection and overexpression of the MNV non-structural protein NS1/2 increased the enzymatic activity of the rate-limiting enzyme glutaminase. In conclusion, the inaugural investigation of NoV-induced alterations to host glutaminolysis identified the first viral regulator of glutaminolysis for RNA viruses, which increases our fundamental understanding of virus-induced metabolic alterations.
    Author Summary: All viruses critically depend on the host cells they infect to provide the necessary machinery and building blocks for successful replication. Thus, viruses often alter host metabolic pathways to increase the availability of key metabolites they require. Human noroviruses (HNoVs) are a major cause of acute non-bacterial gastroenteritis, leading to significant morbidity and economic burdens. To date, no vaccines or antivirals are available against NoVs, which demonstrates a need to better understand NoV biology, including the role host metabolism plays during infection. Using the murine norovirus (MNV) model, we show that host cell glutaminolysis is upregulated and required for optimal virus infection of macrophages. Additional data point to a model whereby the viral non-structural protein NS1/2 upregulates the enzymatic activity of glutaminase, the rate-limiting enzyme in glutaminolysis. Insights gained through investigating the role host metabolism plays in MNV replication may assist with improving HNoV cultivation methods and development of novel therapies.
    DOI:  https://doi.org/10.1101/2023.12.19.572316
  12. Cold Spring Harb Perspect Med. 2024 Jan 08. pii: a041537. [Epub ahead of print]
    Isocitrate Dehydrogenase Mutations in Cancer: Mechanisms of Transformation and Metabolic Liability.
    Kathryn Gunn, Julie-Aurore Losman.
      Isocitrate dehydrogenase 1 and 2 (IDH1 and IDH2) are metabolic enzymes that interconvert isocitrate and 2-oxoglutarate (2OG). Gain-of-function mutations in IDH1 and IDH2 occur in a number of cancers, including acute myeloid leukemia, glioma, cholangiocarcinoma, and chondrosarcoma. These mutations cripple the wild-type activity of IDH and cause the enzymes to catalyze a partial reverse reaction in which 2OG is reduced but not carboxylated, resulting in production of the (R)-enantiomer of 2-hydroxyglutarate ((R)-2HG). (R)-2HG accumulation in IDH-mutant tumors results in profound dysregulation of cellular metabolism. The most well-characterized oncogenic effects of (R)-2HG involve the dysregulation of 2OG-dependent epigenetic tumor-suppressor enzymes. However, (R)-2HG has many other effects in IDH-mutant cells, some that promote transformation and others that induce metabolic dependencies. Herein, we review how cancer-associated IDH mutations impact epigenetic regulation and cellular metabolism and discuss how these effects can potentially be leveraged to therapeutically target IDH-mutant tumors.
    DOI:  https://doi.org/10.1101/cshperspect.a041537
  13. Redox Biol. 2024 Jan 05. pii: S2213-2317(24)00004-1. [Epub ahead of print]70 103028
    p66ShcA promotes malignant breast cancer phenotypes by alleviating energetic and oxidative stress.
    Kyle Lewis, Rachel La Selva, Elias Maldonado, Matthew G Annis, Ouafa Najyb, Eduardo Cepeda Cañedo, Stephanie Totten, Steven Hébert, Valérie Sabourin, Caitlynn Mirabelli, Emma Ciccolini, Camille Lehuédé, Luc Choinière, Mariana Russo, Daina Avizonis, Morag Park, Julie St-Pierre, Claudia L Kleinman, Peter M Siegel, Josie Ursini-Siegel.
      Significant efforts have focused on identifying targetable genetic drivers that support the growth of solid tumors and/or increase metastatic ability. During tumor development and progression to metastatic disease, physiological and pharmacological selective pressures influence parallel adaptive strategies within cancer cell sub-populations. Such adaptations allow cancer cells to withstand these stressful microenvironments. This Darwinian model of stress adaptation often prevents durable clinical responses and influences the emergence of aggressive cancers with increased metastatic fitness. However, the mechanisms contributing to such adaptive stress responses are poorly understood. We now demonstrate that the p66ShcA redox protein, itself a ROS inducer, is essential for survival in response to physiological stressors, including anchorage independence and nutrient deprivation, in the context of poor outcome breast cancers. Mechanistically, we show that p66ShcA promotes both glucose and glutamine metabolic reprogramming in breast cancer cells, to increase their capacity to engage catabolic metabolism and support glutathione synthesis. In doing so, chronic p66ShcA exposure contributes to adaptive stress responses, providing breast cancer cells with sufficient ATP and redox balance needed to withstand such transient stressed states. Our studies demonstrate that p66ShcA functionally contributes to the maintenance of aggressive phenotypes and the emergence of metastatic disease by forcing breast tumors to adapt to chronic and moderately elevated levels of oxidative stress.
    Keywords:  Anoikis; Breast cancer; Glutathione; Metabolic plasticity; Oxidative stress; p66ShcA
    DOI:  https://doi.org/10.1016/j.redox.2024.103028
  14. Discov Oncol. 2024 Jan 12. 15(1): 8
    GLUD1 inhibits hepatocellular carcinoma progression via ROS-mediated p38/JNK MAPK pathway activation and mitochondrial apoptosis.
    Qianwei Zhao, Mengdan Yu, Jinxia Li, Yaoyu Guo, Zexuan Wang, Kefei Hu, Fang Xu, Yixian Liu, Lili Li, Didi Wan, Ying Zhao, Jian Shang, Jintao Zhang.
      Glutamate dehydrogenase 1 (GLUD1) is an important enzyme in glutamine metabolism. Previously, we found GLUD1 was down-regulated in tumor tissues of hepatocellular carcinoma (HCC) patients by proteomics study. To explore its role in the progression of HCC, the expressional level of GLUD1 was firstly examined and presented as that both the protein and mRNA levels were down-regulated in tumor tissues compared to the normal liver tissues. GLUD1 overexpression significantly inhibited HCC cells proliferation, migration, invasion and tumor growth both in vitro and in vivo, while GLUD1 knocking-down promoted HCC progression. Metabolomics study of GLUD1 overexpressing and control HCC cells showed that 129 differentially expressed metabolites were identified, which mainly included amino acids, bases, and phospholipids. Moreover, metabolites in mitochondrial oxidative phosphorylation system (OXPHOS) were differentially expressed in GLUD1 overexpressing cells. Mechanistic studies showed that GLUD1 overexpression enhanced mitochondrial respiration activity and reactive oxygen species (ROS) production. Excessive ROS lead to mitochondrial apoptosis that was characterized by increased expression levels of p53, Cytochrome C, Bax, Caspase 3 and decreased expression level of Bcl-2. Furthermore, we found that the p38/JNK MAPK pathway was activated in GLUD1 overexpressing cells. N-acetylcysteine (NAC) treatment eliminated cellular ROS and blocked p38/JNK MAPK pathway activation, as well as cell apoptosis induced by GLUD1 overexpression. Taken together, our findings suggest that GLUD1 inhibits HCC progression through regulating cellular metabolism and oxidative stress state, and provide that ROS generation and p38/JNK MAPK pathway activation as promising methods for HCC treatment.
    Keywords:  Apoptosis; GLUD1; Metabolism; ROS; p38/JNK MAPK pathway
    DOI:  https://doi.org/10.1007/s12672-024-00860-1
  15. Cancers (Basel). 2023 Dec 22. pii: 69. [Epub ahead of print]16(1):
    Amino Acid Profiles in the Biological Fluids and Tumor Tissue of CRC Patients.
    Marisa Domingues Santos, Ivo Barros, Pedro Brandão, Lúcia Lacerda.
      Amino acids are the building blocks of proteins and essential players in pathways such as the citric acid and urea cycle, purine and pyrimidine biosynthesis, and redox cell signaling. Therefore, it is unsurprising that these molecules have a significant role in cancer metabolism and its metabolic plasticity. As one of the most prevalent malign diseases, colorectal cancer needs biomarkers for its early detection, prognostic, and prediction of response to therapy. However, the available biomarkers for this disease must be more powerful and present several drawbacks, such as high costs and complex laboratory procedures. Metabolomics has gathered substantial attention in the past two decades as a screening platform to study new metabolites, partly due to the development of techniques, such as mass spectrometry or liquid chromatography, which have become standard practice in diagnostic procedures for other diseases. Extensive metabolomic studies have been performed in colorectal cancer (CRC) patients in the past years, and several exciting results concerning amino acid metabolism have been found. This review aims to gather and present findings concerning alterations in the amino acid plasma pool of colorectal cancer patients.
    Keywords:  amino acids; biomarkers; colorectal cancer; diagnosis; laboratorial findings; metabolomics; prognosis; treatment response
    DOI:  https://doi.org/10.3390/cancers16010069
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