In vivo MRSI of hyperpolarized [1-13C]pyruvate metabolism in rat hepatocellular carcinoma

• Published in: NMR in biomedicine 2011-06, Vol.24 (5), p.506-513
• Main Authors: Darpolor, Moses M., Yen, Yi-Fen, Chua, Mei-Sze, Xing, Lei, Clarke-Katzenberg, Regina H., Shi, Wenfang, Mayer, Dirk, Josan, Sonal, Hurd, Ralph E., Pfefferbaum, Adolf, Senadheera, Lasitha, So, Samuel, Hofmann, Lawrence V., Glazer, Gary M., Spielman, Daniel M.
• Format: Article
• Language: English
• Subjects: [1-13C]pyruvate; Alanine - metabolism; alanine transaminase; Animals; Carbon Isotopes; Carcinoma, Hepatocellular - enzymology; Carcinoma, Hepatocellular - genetics; Carcinoma, Hepatocellular - metabolism; Carcinoma, Hepatocellular - pathology; Gene Expression Regulation, Neoplastic; hepatocellular carcinoma; Humans; hyperpolarized three-dimensional 13C MRSI; Immunohistochemistry; Lactic Acid - metabolism; Liver Neoplasms - enzymology; Liver Neoplasms - genetics; Liver Neoplasms - metabolism; Liver Neoplasms - pathology; Magnetic Resonance Spectroscopy - methods; Pyruvic Acid - metabolism; Rats; Reverse Transcriptase Polymerase Chain Reaction
• ISSN: 0952-3480; 1099-1492; 1099-1492
• DOI: 10.1002/nbm.1616

Hepatocellular carcinoma (HCC), the primary form of human adult liver malignancy, is a highly aggressive tumor with average survival rates that are currently less than 1 year following diagnosis. Most patients with HCC are diagnosed at an advanced stage, and no efficient marker exists for the prediction of prognosis and/or response(s) to therapy. We have reported previously a high level of [1‐13C]alanine in an orthotopic HCC using single‐voxel hyperpolarized [1‐13C]pyruvate MRS. In the present study, we implemented a three‐dimensional MRSI sequence to investigate this potential hallmark of cellular metabolism in rat livers bearing HCC (n = 7 buffalo rats). In addition, quantitative real‐time polymerase chain reaction was used to determine the mRNA levels of lactate dehydrogenase A, nicotinamide adenine (phosphate) dinucleotide dehydrogenase quinone 1 and alanine transaminase. The enzyme levels were significantly higher in tumor than in normal liver tissues within each rat, and were associated with the in vivo MRSI signal of [1‐13C]alanine and [1‐13C]lactate after a bolus intravenous injection of [1‐13C]pyruvate. Histopathological analysis of these tumors confirmed the successful growth of HCC as a nodule in buffalo rat livers, revealing malignancy and hypervascular architecture. More importantly, the results demonstrated that the metabolic fate of [1‐13C]pyruvate conversion to [1‐13C]alanine significantly superseded that of [1‐13C]pyruvate conversion to [1‐13C]lactate, potentially serving as a marker of HCC tumors. Copyright © 2010 John Wiley & Sons, Ltd. The data herein suggest that the conversion of exogenous [1‐13C]pyruvate to [1‐13C]lactate and [1‐13C]alanine is a characteristic marker of this hepatocellular carcinoma (HCC) model in vivo. Coupled with this finding, the associated enzymes (lactate dehydrogenase A, NAD(P)H dehydrogenase quinone 1 and alanine transaminase) are significantly elevated in this HCC model when compared with normal liver. Therefore, hyperpolarized 13C three‐dimensional MRSI may be a diagnostic tool for the detection of HCC, and a potentially useful imaging tool as a surrogate marker.