Metabolomics Reveals That Tumor Xenografts Induce Liver Dysfunction

Abstract

Metabolomics, based on ultraperformance liquid chromatography coupled with electrospray ionization quadrupole mass spectrometry, was used to explore metabolic signatures of tumor growth in mice. Urine samples were collected from control mice and mice injected with squamous cell carcinoma (SCCVII) tumor cells. When tumors reached ϳ2 cm, all mice were killed and blood and liver samples collected. The urine metabolites hexanoylglycine, nicotinamide 1-oxide, and 11␤,20␣-dihydroxy-3-oxopregn-4-en-21-oic acid were elevated in tumor-bearing mice, as was asymmetric dimethylarginine, a biomarker for oxidative stress. Interestingly, SCCVII tumor growth resulted in hepatomegaly, reduced albumin/globulin ratios, and elevated serum triglycerides, suggesting liver dysfunction. Alterations in liver metabolites between SCCVII-tumor-bearing and control mice confirmed the presence of liver injury. Hepatic mRNA analysis indicated that inflammatory cytokines, tumor necrosis factor ␣, and transforming growth factor ␤ were enhanced in SCCVII-tumor-bearing mice, and the expression of cytochromes P450 was decreased in tumor-bearing mice. Further, genes involved in fatty acid oxidation were decreased, suggesting impaired fatty acid oxidation in SCCVII-tumor-bearing mice. Additionally, activated phospholipid metabolism and a disrupted tricarboxylic acid cycle were observed in SCCVIItumor-bearing mice. These data suggest that tumor growth imposes a global inflammatory response that results in liver dysfunction and underscore the use of metabolomics to temporally examine these changes and potentially use metabolite changes to monitor tumor treatment response. The combination of nuclear magnetic resonance and liquid and gas chromatography coupled to mass spectrometry has enabled the global analysis of metabolites in small volumes of biofluids and tissues. Using this technology, the emerging field of metabolomics seeks to elucidate how pathological conditions, genetic modifications, and xenobiotic exposure can lead to alterations in biochemical pathways of an organism as measured via metabolite profile analysis (1-4). The applications of this technology extend beyond those mentioned above (5) and further hold promise for identifying biomarkers that might provide early diagnostic information characterizing a variety of disease processes. Such biomarkers might also be most useful for following the course of therapy and perhaps predicting treatment outcomes.Cancer is a disease amenable to metabolite interrogation, as many human tumors are difficult to detect at an early stage of development, when they are most vulnerable to treatment. Moreover, many human tumors are unresponsive to a wide variety of therapies, and metabolite profile anomalies specific to cancer might provide targets or pathways for the development of new treatment strategies. A number of different types of human cancers have been subjected to metabolomic analysis (5), and specific metabolites were identified that may provide diagnostic information. Examples include urine sarcos...

Short overview on metabolomics approach to study pathophysiology of oxidative stress in cancer

“…//serum ↑(in prediagnosed serum) [89] Xanthine (HMDB00292) GC/MS, UPLC/MS-MS Clinical/ Hepatocellular carcinoma (HCC) arising from hepatitis C (HCV); HCC, hepatitis C cirrhosis, disease controls (DC) and healthy volunteers //serum ↑ (HCC vs DC) [88] GC-TOF Clinical/Adenocarcinoma a type of non-small-cell lung cancer (NSCLC) // tissue ↑ [94] NMTR Animal /rat model of gastric carcinogenesis//serum ↑ [102] GC-MS and LC-MS/MS Clinical / normal ovarian tissue vs. primary epithelial ovarian cancer (EOC) vs. metastatic tumors resulting from primary ovarian cancer (MOC)// tissue ↑EOC [86] Lauric acid (HMDB00638) GC-MS Clinical/melanoma Pilot study (small cohort)- //biopsied tissue melanoma and matched control non-neoplastic skin from the same patient (VOC) ↑ [103] Alkanes such as ethane and pentane GC-MS Review breath cancer/in vivo vs. in vitro hypoxic and hyperoxic cond// Volatile organic compounds (VOC) ↑ [104] Aldehydes, alcohols and ketones GC-MS Review breath cancer/in vivo vs. in vitro hypoxic and hyperoxic cond// Volatile organic compounds (VOC) ↑ [104] Indoxyl sulfate (HMDB00682) LC-MS Clinical/epithelial ovarian cancer (EOC) primary EOC vs post-operative EOC patients vs recurrent EOC//plasma samples ↑ (post operative)↓(relapsed) [95] H NMR Clinical/Esophageal adenocarcinoma (EAC) Barrett’s esophagus and EAC, // urine ↑ (EAC) [85] Asymmetric dimethylarginine (HMDB01539) UPLC-ESI-QTOF/MS Animal /rodent squamous cell carcinoma (SCCVII) injected into the subcutaneous space of female C3H/Hen mice temporal study//. serum, liver, and tumor ↑ [105] 24-nor−5 β -cholane-triol (NA) UPLC–MS Animal /Dicer-Pten double knockout (DKO) mice. Simulates High-grade serous carcinoma (HGSC) in women – early tumor (ET) //...…”

Bile acid signaling in lipid metabolism: Metabolomic and lipidomic analysis of lipid and bile acid markers linked to anti-obesity and anti-diabetes in mice

“…Lipidomics is a sub-metabolomics platform that provides a comprehensive analysis of lipid species within a cell or tissue, which plays an essential role in defining the biochemical mechanisms of lipid-related disease processes through identifying alterations in cellular lipid metabolism, trafficking and homeostasis [42, 43]. The current study of metabolomics and lipidomics profiling of CYP7A1-tg mice using ultra-performance liquid chromatography-coupled with electrospray ionization quadrupole time-of-flight mass spectrometry (UPLC-ESI-QTOFMS) detected and characterized small organic molecules in biological materials [44–47]. This study explores the involvement of metabolites such as phospholipids and bile acids in the regulation of metabolic homeostasis, and provides insights into the mechanism for the anti-obesity and anti-diabetic effect of increased bile acid pool and altered bile acid composition.…”

Celastrol Protects From Cholestatic Liver Injury Through Modulation of SIRT1-FXR Signaling

“…Mass spectrometry-based metabolomics has become a powerful tool for the characterization of metabolites in biological matrices and has been applied to studies in hepatology. Notably, metabolomic data for nonalcoholic steatohepatitis (5), cholestasis (6), viral hepatitis (7), liver dysfunction (8,9), and hepatocellular carcinoma (10) have been obtained in the recent years. These studies revealed that metabolic disorders involving BAs and phospholipids are a core phenotype for hepatobiliary diseases (5,10,11).…”