Affiliation:
1. The Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital), Hangzhou, China
2. Institute of Basic Medicine and Cancer (IBMC), Chinese Academy of Sciences, Hangzhou, China
3. Zhejiang Key Laboratory of Diagnosis&Treatment Technology on Thoracic Oncology(Lung and Esophagus), Hangzhou, China
4. Zhejiang Chinese Medical University, Hangzhou, China
Abstract
Background
Malignant mesothelioma (MM) is a rare and highly aggressive cancer. Despite advances in multidisciplinary treatments for cancer, the prognosis for MM remains poor with no effective diagnostic biomarkers currently available. The aim of this study was to identify plasma metabolic biomarkers for better MM diagnosis and prognosis by use of a MM cell line-derived xenograft (CDX) model.
Methods
The MM CDX model was confirmed by hematoxylin and eosin staining and immunohistochemistry. Twenty female nude mice were randomly divided into two groups, 10 for the MM CDX model and 10 controls. Plasma samples were collected two weeks after tumor cell implantation. Gas chromatography-mass spectrometry analysis was conducted. Both univariate and multivariate statistics were used to select potential metabolic biomarkers. Hierarchical clustering analysis, metabolic pathway analysis, and receiver operating characteristic (ROC) analysis were performed. Additionally, bioinformatics analysis was used to investigate differential genes between tumor and normal tissues, and survival-associated genes.
Results
The MM CDX model was successfully established. With VIP > 1.0 and P-value < 0.05, a total of 23 differential metabolites were annotated, in which isoleucine, 5-dihydrocortisol, and indole-3-acetamide had the highest diagnostic values based on ROC analysis. These were mainly enriched in pathways for starch and sucrose metabolism, pentose and glucuronate interconversions, galactose metabolism, steroid hormone biosynthesis, as well as phenylalanine, tyrosine and tryptophan biosynthesis. Further, down-regulation was observed for amino acids, especially isoleucine, which is consistent with up-regulation of amino acid transporter genes SLC7A5 and SLC1A3 in MM. Overall survival was also negatively associated with SLC1A5, SLC7A5, and SLC1A3.
Conclusion
We found several altered plasma metabolites in the MM CDX model. The importance of specific metabolic pathways, for example amino acid metabolism, is herein highlighted, although further investigation is warranted.
Funder
The National Natural Science Foundation of China
Key R&D Program Projects in Zhejiang Province
Natural Science Foundation of Zhejiang Province of China
Excellent Youth Talent Program of Traditional Chinese medicine of Zhejiang province science and technology plan project
Subject
General Agricultural and Biological Sciences,General Biochemistry, Genetics and Molecular Biology,General Medicine,General Neuroscience
Reference25 articles.
1. Biomarkers in malignant pleural mesothelioma: current status and future directions;Ahmadzada;Journal of Thoracic Disease,2018
2. Branched-chain amino acid metabolism in cancer;Ananieva;Current Opinion in Clinical Nutrition and Metabolic Care,2018
3. A review of applications of metabolomics in cancer;Beger;Metabolites,2013
4. Amino acid transporters as targets for cancer therapy: why, where, when, and how;Bröer;International Journal of Molecular Sciences,2020
5. Mesothelioma: scientific clues for prevention, diagnosis, and therapy;Carbone;CA: A Cancer Journal for Clinicians,2019