Hepatocellular carcinoma has a poor prognosis due to its rapid development and early metastasis. In this report, we characterized the metabolic features of hepatocellular carcinoma using a nontargeted metabolic profiling strategy based on liquid chromatography-mass spectrometry. Fifty pairs of liver cancer samples and matched normal tissues were collected from patients having hepatocellular carcinoma, including tumor tissues, adjacent noncancerous tissues, and distal noncancerous tissues, and 105 metabolites were filtered and identified from the tissue metabolome. The principal metabolic alternations in HCC tumors included elevated glycolysis, gluconeogenesis, and b-oxidation with reduced tricarboxylic acid cycle and D-12 desaturase. Furthermore, increased levels of glutathione and other antioxidative molecules, together with decreased levels of inflammatory-related polyunsaturated fatty acids and phospholipase A2, were observed. Differential metabolite levels in tissues were tested in 298 serum specimens from patients with chronic hepatitis, cirrhosis, and hepatocellular carcinoma. Betaine and propionylcarnitine were confirmed to confer good diagnostic potential to distinguish hepatocellular carcinoma from chronic hepatitis and cirrhosis. External validation of cirrhosis and hepatocellular carcinoma serum specimens further showed that this combination biomarker is useful for diagnosis of hepatocellular carcinoma with a supplementary role to a-fetoprotein. Cancer Res; 73(16); 4992-5002. Ó2013 AACR.

Prostate cancer is a highly prevalent tumor affecting millions of men worldwide, but poor understanding of its pathogenesis has limited effective clinical management of patients. In addition to transcriptional profiling or transcriptomics, metabolomics is being increasingly utilized to discover key molecular changes underlying tumorigenesis. In this study, we integrated transcriptomics and metabolomics to analyze 25 paired human prostate cancer tissues and adjacent noncancerous tissues, followed by further validation of our findings in an additional cohort of 51 prostate cancer patients and 16 benign prostatic hyperplasia patients. We found several altered pathways aberrantly expressed at both metabolic and transcriptional levels, including cysteine and methionine metabolism, nicotinamide adenine dinucleotide metabolism, and hexosamine biosynthesis. Additionally, the metabolite sphingosine demonstrated high specificity and sensitivity for distinguishing prostate cancer from benign prostatic hyperplasia, particularly for patients with low prostate specific antigen level (0 -10 ng/ml). We also found impaired sphingosine-1-phosphate receptor 2 signaling, downstream of sphingosine, representing a loss of tumor suppressor gene and a potential key oncogenic pathway for therapeutic targeting. By integrating metabolomics and transcriptomics, we have provided both a broad picture of the molecular perturbations underlying prostate cancer and a preliminary study of a novel metabolic signature, which may help to discriminate prostate cancer from normal tissue and benign prostatic hyperplasia. Molecular & Cellular Proteomics

In-depth delineation of lipid metabolism in prostate cancer (PCa) is significant to open new insights into prostate tumorigenesis and progression, and provide potential biomarkers with greater accuracy for improved diagnosis. Here, we performed lipidomics and transcriptomics in paired prostate cancer tumor (PCT) and adjacent nontumor (ANT) tissues, followed by external validation of biomarker candidates. We identified major dysregulated pathways involving lipogenesis, lipid uptake and phospholipids remodeling, correlated with widespread lipid accumulation and lipid compositional reprogramming in PCa. Specifically, cholesteryl esters (CEs) were most prominently accumulated in PCa, and significantly associated with cancer progression and metastasis. We showed that overexpressed scavenger receptor class B type I (SR-BI) may contribute to CEs accumulation. In discovery set, CEs robustly differentiated PCa from nontumor (area under curve (AUC) of receiver operating characteristics (ROC), 0.90–0.94). In validation set, CEs potently distinguished PCa and non-malignance (AUC, 0.84–0.91), and discriminated PCa and benign prostatic hyperplasia (BPH) (AUC, 0.90–0.96), superior to serum prostate-specific antigen (PSA) (AUC = 0.83). Cholesteryl oleate showed highest AUCs in distinguishing PCa from non-malignance or BPH (AUC = 0.91 and 0.96). Collectively, our results unravel the major lipid metabolic aberrations in PCa and imply the potential role of CEs, particularly, cholesteryl oleate, as molecular biomarker for PCa detection.

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ABSTRACT:The objective of present study was to offer insights into the metabolic responses of hepatocellular carcinoma (HCC) to surgical resection and the metabolic signatures latent in early HCC recurrence (one year after operation). Urinary metabolic profiling employing gas chromatography time-of-flight mass spectrometry (GC-TOF MS) was utilized to investigate the complex physiopathologic regulations in HCC after operational intervention. It was revealed that an intricate series of metabolic regulations including energy metabolism, amino acid metabolism, nucleoside metabolism, tricarboxylic acid (TCA) cycle, gut floral metabolism, etc., principally leading to the direction of biomass synthesis, could be observed after tumor surgical removal. Moreover, metabolic differences between recurrent and nonrecurrent patients had emerged 7 days after initial operation. The metabolic signatures of HCC recurrence principally comprised notable up-regulations of lactate excretion, succinate production, purine and pyrimidine nucleosides turnover, glycine, serine and threonine metabolism, aromatic amino acid turnover, cysteine and methionine metabolism, and glyoxylate metabolism, similar to metabolic behaviors of HCC burden. Sixteen metabolites were found to be significantly increased in the recurrent patients compared with those in nonrecurrent patients and healthy controls. Five metabolites (ethanolamine, lactic acid, acotinic acid, phenylalanine and ribose) were further defined; they were favorable to the prediction of early recurrence. KEYWORDS: urine, metabolomics, hepatocellular carcinoma, GC−MS, surgery, metabolic signature, recurrence ■ INTRODUCTION Hepatocellular carcinoma (HCC) is one of the most prevalent neoplasms worldwide especially in the eastern Asia and subSaharan Africa.1 It is characterized by a high mortality and a low 5-year survival rate, primarily due to high recurrence and metastasis rates.2 Prevention of both recurrence and metastasis could improve the efficacy of current treatment modalities and enhance survival rates. TNM staging of HCC, estimated using tumor size, tumor multiplicity, vessel invasion, lymph node metastasis, and distant metastasis is viewed as the most reliable indicator for early recurrence. However, TNM staging is often insufficient, even when combined with other established indicators.3 Therefore, discovery of biomarkers more reliably indicating the risk of recurrence is of the utmost importance.Metabolomics, as an emerging omics technique, pursues the comprehensive projection of dynamic multiple metabolic responses to biological disturbances or gene manipulations in living systems. 4,5 Hence, metabolomic approach has been broadly employed for intensive investigations of metabolic abnormalities in HCC and the potential biomarker discovery, besides the increasingly important roles in prognosis of cancer relapse and metastasis. 6−15 Taurocholic acid, lysophosphatidylcholine 22:5 and lysophosphoethanolamine were discovered as marker metabolites for different stages of hepatocarcinoge...

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