[(Methyl)1-11C]-Acetate Metabolism in Hepatocellular Carcinoma

Abstract

Purpose Studies have established the value of [(methyl)1-11C]-acetate ([11C]Act) combined with 2-deoxy-2[18F]fluoro-d-glucose (FDG) for detecting hepatocellular carcinoma (HCC) using positron emission tomography (PET). In this study, the metabolic fate of [11C]Act in HCC was characterized. Methods Experiments with acetic acid [1-14C] sodium salt ([14C]Act) were carried out on WCH-17 cells and freshly derived rat hepatocytes. PET scans with [11C]Act were also carried out on woodchucks with HCC before injection of [14C]Act. The radioactivity levels in different metabolites were quantified with thin-layer chromatography. Results In WCH-17 cells, the predominant metabolite was phosphatidylcholine (PC). Regions of HCCs with the highest [11C]Act uptake had higher radioactivity accumulation in lipid-soluble compounds than surrounding hepatic tissues. In those regions, PC and triacylglycerol (TG) accumulated more radioactivity than in surrounding hepatic tissues. Conclusions High [11C]Act uptake in HCC is associated with increased de novo lipogenesis. PC and TG are the main metabolites into which the radioactive label from [11C]Act is incorporated in HCC.

Functional imaging techniques in hepatocellular carcinoma

“…In the woodchuck HCC animal model 11 C-Act uptake is associated with de-novo tumoral lipogenesis [23] and fatty acid synthase activity. Phosphatidylcholine and triacylglycerol are the main metabolites into which the radioactive label from 11 C-Act accumulates in HCC.…”

Metabolic positron emission tomography imaging of cancer: Pairing lipid metabolism with glycolysis

“…This and other observations support speculation that imaging of choline metabolism can be used to monitor tumor lipogenesis[12,18]. The reason why choline-based tracers may be needed to assess tumor lipogenic activity despite 11C-acetate being available is that acetyl-CoA formed from acetate can also serve as a metabolic substrate for a variety of metabolic processes, including oxidative metabolism, histone modification, and cholesterol biosynthesis[19].…”

“…Upregulated FAS expression is a frequently observed phenomenon in many tumor types[4]. However, while the constitutive role of FAS in liver and adipose tissue is to create stored energy in the form of triglycerides, the primary role for FAS in cancer cells appears to be to supply fatty acids for phospholipid membrane synthesis[11,12]. Glycolysis, which is also frequently upregulated in cancer[1], can not only fuel this process by providing ATP, but also contribute substrate for de-novo lipogenesis by producing acetyl-CoA.…”

“…On the basis of this mechanism, fluorine-18 fluorocholine PET/CT was tested in HCC, and found to be significantly more sensitive than FDG PET/CT, with a sensitivity of 84% vs 67%, respectively ( P = 0.01)[16]. As the most abundant membrane phospholipid, PtC is believed to be the primary metabolic destination of most fatty acids synthesized de-novo by cancer cells[11,12]. Fatty acids produced by FAS may be distinguished by their relatively high saturation, and while humans lack the desaturase enzymes required to produce certain unsaturated fatty acids ( i.e ., essential fatty acids), de-novo synthesized fatty acids undergo sufficient modification by elongase and desaturase enzymes to still give rise to broad structural and functional variations among phospholipids such as phosphatidylcholine (PtC)[17].…”

[18F]Fluorocholine PET/CT Imaging of Liver Cancer: Radiopathologic Correlation with Tissue Phospholipid Profiling

“…Increased rates of de-novo fatty acid synthesis have been observed in many cancers (28), and pre-clinical experiments using radiolabeled acetate have shown that a significant proportion of de-novo fatty acids are incorporated by PtC in HCC (29). Indeed, [ 11 C]-acetate has been proposed as a PET tracer for detecting HCC on the basis of imaging de-novo fatty acid synthesis, with clinical studies supporting its potential diagnostic efficacy (30).…”