Hepatocellular carcinoma (HCC) is a leading cause of cancer-related deaths worldwide. HCC, a slowly progressing disease, results from an accumulation of mutations arising out of chronic liver diseases such as hepatitis or cirrhosis.1,2 Our knowledge surrounding high-risk groups and the disease’s slow progression, however, point to opportunities for early diagnosis that may drastically improve survival rates for patients.
Liu et al. were able to determine the metabolic profile of HCC and identify new biomarker prospects for further research using a human tissue metabolics approach.3 They took samples from 10 hepatitis-B HCC patients. The samples came from three areas: central tumor tissue, adjacent tissue 1–2 cm from the tumor, and distant tissue 5 cm from the tumor. All samples were taken prior to radiation or chemotherapy.
The researchers identified metabolites using an Accela LC System (Thermo Scientific) to perform chromatography studies, followed by mass spectrometry on an LTQ Orbitrap XL hybrid ion trap-Orbitrap mass spectrometer (Thermo Scientific).
One of the aims of the study was to establish a model for predicting the metabolic profile of HCC tissue. The investigators performed statistical analysis of the metabolites using Pareto scaling followed by principal component analysis and an orthogonal partial least-squares discriminant analysis. The clustering of metabolites in the aforementioned analysis enabled the researchers to identify endogenous metabolites highly related to HCC.
Liu et al. found 215 metabolites in the HCC samples; they selected 14 metabolites that were characteristic metabolites, as identified by the Human Metabolome Database. Nine of the 14 they selected had been previously suggested as serum metabolite biomarkers in HCC diagnosis. The remaining five metabolites—beta-sitosterol, quinaldic acid, arachidyl carnitine, tetradecanal and oleamide—had not been reported in other literature, providing potential new targets for further research.
Overall, the up- and down-regulation of metabolites changed dramatically as the distance between the tumor tissue and normal tissue increased. The results showed that the greatest changes to metabolite levels were between distant tissue and tissue samples adjacent to the tumor. Beta-sitosterol and quinaldic acid were both unregulated in adjacent samples as compared to distant tissue samples, while oleamide was down-regulated. These metabolites then maintained very similar levels when comparing the adjacent and central tumor samples. Arachidyl carnitine and tetradecanal on the other hand, maintained very similar levels when comparing distant and adjacent samples, but were down-regulated by tumor progression.
The levels of 11 metabolites were significantly elevated in the distant tissue group as compared with the central tumor tissue group. These were beta-sitosterol, L-phenylalanine, lysoPCs, glycerophosphocholine, lysoPEs, chenodeoxycholic acid glycine conjugate, and quinaldic acid.
It is reasonable to speculate that changes in metabolites in the central tumor samples correlate with and are relevant to tumor progression and development of HCC. The changes in metabolites between tumor and distant samples—in particular, the five previously unreported metabolites—show their potential as biomarkers for HCC diagnosis. Further investigation into the role of those metabolites and their related pathways may yield exciting results for predicting development of HCC.
1. Patel, M., et al. (2012) “Hepatocellular carcinoma: Diagnostics and screening,” Journal of Evaluation in Clinical Practice, 18 (pp. 335–42).
2. Thorgeirsson, S.S., and Grimshaw, A.W. (2002) “Molecular pathogenesis of human hepatocellular carcinoma,” Nature Genetics, 31(4) (pp. 339–46).
3. Liu, S.Y., et al. (2013) “Human liver tissue metabolic profiling research on hepatitis B virus-related hepatocellular carcinoma,” World Journal of Gastroenterology, 19(22) (pp. 3423–32).