Hepatocellular carcinoma (HCC) is an aggressive form of primary liver cancer that occurs more frequently in men than women. This malignancy is different from metastatic liver cancer which originates in another organ (such as the breast or colon) and then spreads to the liver. Even though the incidence of this malignancy is exceptionally high in Asia and Africa, the number of new cases in America and Europe is rapidly increasing, making HCC a worldwide health problem. In spite of improvements in treatment, patients with HCC continue to have a poor prognosis, with 5-year survival rates of only 18%. Therefore, in order to formulate sustained therapeutic strategies, detailed understanding of the molecular network of aggressive HCC is required.
In addition to significant genomic and proteomic alterations, cancer cells also exhibit highly unique metabolic phenotype which is characterized by increased glucose uptake, enhanced glycolytic activity, decreased mitochondrial activity, low bioenergetic status, and aberrant phospholipid metabolism. This suggests that metabolism may also play a significant role in differentiating normal cells from neoplastic tissues. Several metabolic markers of malignancy are described in particular tumors, such as N-acetyl aspartate and myo-inositol in brain cancers, citrate in prostate cancer, or triglycerides in liposarcomas, based on tissue-specific biochemistry. Cancer metabolite profiling, or cancer metabolomics, is a promising novel approach to help understand the biological events associated with cancer development and progression. A systemic analysis of the pathways in which these genes and biochemical molecules interact may assist in the identification of key biomarkers or drug targets for clinical intervention. Metabolite detection and quantification is usually carried out by nuclear magnetic resonance (NMR) spectroscopy, while mass spectrometry (MS) provides another highly sensitive metabolomics technology.
Using a combination of gene expression and metabolic profile analysis, a recent study by Budhu et al. (2013) reported identification of lipid biomarkers, monounsaturated lipid metabolite (MUPA) and stearoyl-CoA-desaturase (SCD), as key role players in a subset of HCC termed as hepatic stem cell HCC (HpSC-HCC). HpSC-HCC was found to exhibit stem cell–like gene expression traits and associated with poor prognosis as reported by Yamashita and colleagues. By performing metabolomics profiling of tumor and non-tumor tissue samples from 356 patients, Budhu et al. identified 28 metabolites and 169 genes associated with aggressive HCC. Using an integrative data analysis approach to determine gene-metabolite interconnections, this study suggested genes associated with fatty-acid metabolites may play roles in overall survival, stem cell-like HCC and metastasis-related prognosis. Higher expression of one of the genes stearoyl-CoA-desaturase (SCD) was found to be associated with worse survival and disease-free survival. SCD codes for an enzyme responsible for conversion of saturated palmitic acid (SPA) to its monounsaturated form, palmitoleic acid (MUPA). Based on these results, Budhu and colleagues sought to determine the mechanism by which SCD and its related fatty acids, MUPA and SPA, functionally contribute to aggressive HCC and how altering SCD activity may improve this effect. They noted elevated levels of MUPA in aggressive HCCs, and that MUPA enhanced migration and invasion of cultured HCC cells and colony formation by HCC cells, Huh7. Furthermore, HCC cells that had reduced SCD had decreased migration and colony formation in culture and reduced tumorigenicity in mice. Collectively this study suggested that SCD and its related metabolites may be valuable biomarkers and prognostic indicators for molecular re-staging of HCC.
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