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

Abstract

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 a year following diagnosis. Most patients with HCC are diagnosed at an advanced stage, and no efficient marker exists for predicting prognosis and/or response(s) to therapy. We previously reported a high level of [1-13 C] alanine in an orthotopic HCC using single-voxel hyperpolarized [1-13 C] pyruvate magnetic resonance spectroscopy (MRS). In the present study, we implemented a 3D-magnetic resonance spectroscopic imaging (MRSI) sequence to investigate this potential hallmark of cellular metabolism in rat livers bearing HCC (N=7 buffalo rats). In addition, quantitative realtime PCR was used to determine the mRNA levels of lactate dehydrogenase A, NAD(P)H dehydrogenase quinone 1, and alanine transaminase. The enzymes levels were significantly higher in the tumor than the normal liver tissues within each rat, which is associated with the in vivo MRSI signal of [1-13 C]alanine and [1-13 C]lactate after a bolus intravenous injection of [1-13 C]pyruvate. Histopathological analysis of these tumors confirms successful growth of HCC as a nodule in buffalo rats' livers revealing malignancy and hyper-vascular architecture. More importantly, the results demonstrate that the metabolic fate of [1-13 C]pyruvate conversion to [1-13 C]alanine significantly supersedes that of [1-13 C]pyruvate conversion to [1-13 C]lactate potentially serving as a marker of HCC tumors.

Hyperpolarized [1,3‐13C2]ethyl acetoacetate is a novel diagnostic metabolic marker of liver cancer

“…With this hyperpolarized substrate it was shown how a liver cancer implanted in rat could be detected due to a higher substrate-to-product ratio in the cancer tissue compared with the surrounding healthy tissue. The signal-tonoise ratio (SNR) in the images, was comparable to the SNR obtained in a reported liver cancer study using hyperpolarized [1][2][3][4][5][6][7][8][9][10][11][12][13] C]pyruvate, 16 the most widely used d-DNP-MR substrate. 17 is a popular animal model.…”

Multimodal Assessment of In Vivo Metabolism with Hyperpolarized [1-13C]MR Spectroscopy and 18F-FDG PET Imaging in Hepatocellular Carcinoma Tumor–Bearing Rats

“…The liver is a highly perfused organ, and HCC tumors that are growing in the orthotopic location are well vascularized (32). Growth of these tumors in an ectopic location, with a different microenvironment and at a higher growth rate (700 mm 3 in 12-14 d, compared with 100-200 mm 3 as reported by Darpolor et al), is likely to lead to a different grade of vascularization (31,33). Restricted vascularization in our model could explain the low amount of [1-13 C]pyruvate detected in the tumor region, compared with other organs in the FOV (GIT) and in the vena cava.…”

“…They reported equal amounts of [1-13 C] pyruvate being delivered to healthy liver and to tumor tissue as opposed to the reduced delivery of pyruvate to the ectopic tumor model we observed. The manifold higher turnover to [1-13 C]lactate and [1-13 C]alanine in tumor, therefore, resulted in clearly distinguishable peaks (31). The liver is a highly perfused organ, and HCC tumors that are growing in the orthotopic location are well vascularized (32).…”

Plasma metabolomic analysis of human hepatocellular carcinoma: Diagnostic and therapeutic study

“…Such observation is possibly due to enhanced lipid metabolism in response to liver injury caused by HCC. The increased levels of alanine, lactate, and pyruvate in intermediates of glycolysis and TCA cycle suggest high consumption of glucose by HCC in response to the stimulated aerobic glycolysis or the Warburg effect with conversion through pyruvate to alanine and lactate [27, 28]. Notably, higher consumption of glucose and lactate production in TACE group than any other groups implied that recurrence or metastasis HCC is more active in conversion of glucose to lactic acid during mitochondrial citric acid cycle and oxidative phosphorylation.…”