Dual-tracer positron emission tomography/computed tomography as an imaging probe of de novo lipogenesis in preclinical models of hepatocellular carcinoma

Abstract

BackgroundDe novo lipogenesis is upregulated in many cancers, and targeting it represents a metabolic approach to cancer treatment. However, the treatment response is unpredictable because lipogenic activity varies greatly among individual tumors, thereby necessitating the assessment of lipogenic activity before treatment. Here, we proposed an imaging probe, positron emission tomography/computed tomography (PET/CT) with dual tracers combining 11C-acetate and 18F-fluorodeoxyglucose (18F-FDG), to assess the lipogenic activity of hepatocellular carcinoma (HCC) and predict the response to lipogenesis-targeted therapy.MethodsWe investigated the association between 11C-acetate/18F-FDG uptake and de novo lipogenesis in three HCC cell lines (from well-differentiated to poorly differentiated: HepG2, Hep3B, and SkHep1) by examining the expression of lipogenic enzymes: acetyl-CoA synthetase 2 (ACSS2), fatty acid synthase (FASN), and ATP citrate lyase (ACLY). The glycolysis level was determined through glycolytic enzymes: pyruvate dehydrogenase expression (PDH). On the basis of the findings of dual-tracer PET/CT, we evaluated the treatment response to a lipase inhibitor (orlistat) in cell culture experiments and xenograft mice.ResultsDual-tracer PET/CT revealed the lipogenic activity of various HCC cells, which was positively associated with 11C-acetate uptake and negatively associated with 18F-FDG uptake. This finding represents the negative association between 11C-acetate and 18F-FDG uptake. Because these two tracers revealed the lipogenic and glycolytic activity, respectively, which implies an antagonism between lipogenic metabolism and glucose metabolism in HCC. In addition, dual-tracer PET/CT not only revealed the lipogenic activity but also predicted the treatment response to lipogenesis-targeted therapy. For example, HepG2 xenografts with high 11C-acetate but low 18F-FDG uptake exhibited high lipogenic activity and responded well to orlistat treatment, whereas SkHep1 xenografts with low 11C-acetate but high 18F-FDG uptake exhibited lower lipogenic activity and poor response to orlistat.ConclusionThe proposed non-invasive dual-tracer PET/CT imaging can reveal the lipogenesis and glycolysis status of HCC, thus providing an ideal imaging probe for predicting the therapeutic response of HCC to lipogenesis-targeted therapy.

Tracers and Imaging of Fatty Acid and Energy Metabolism of Human Adipose Tissues

“…We initially used a simple mono-exponential decay modeling of BAT [ 11 C]acetate time-activity curve as a semiquantitative measure of BAT oxidative metabolism ( 83 ). However, multicompartmental modeling now offers the potential to assess nonoxidative [ 11 C]acetate metabolism in BAT ( 96 ) by estimating the rate of TG droplet repletion from de novo lipogenesis ( 92 , 97 ).…”

“…One important gap of in vivo lipid pathophysiological investigation is our limited capacity to specifically measure de novo lipogenesis and fatty acid esterification, which are important lipotoxic processes at the organ level. While [ 11 C]acetate ( 92 , 97 ) and [ 11 C]palmitate ( 72 – 74 ) PET dynamic scanning can derive estimates of these rates, these methods assume that the slow tissue retention rate of these tracers is entirely from lipogenesis and esterification, respectively. In vivo 2 H magnetic resonance spectroscopy (i.e., deuterium imaging) using 2 H-labeled water and fatty acids has the potential to directly address this question using high-field magnetic resonance scanners given the very low natural tissue abundance of 2 H and capacity to measure 2 H enrichment specifically in tissue TG.…”

Current and Future Use of Long Axial Field-of-View Positron Emission Tomography/Computed Tomography Scanners in Clinical Oncology

“…For example, the combination of 18 F and 11 C tracers, as well as 18 F and 68 Ga tracers, have emerged as particularly valuable in providing insights into different disease characteristics. The pair of 18 F and 11 C enables the assessment of neurochemical changes and glucose metabolism in neurodegenerative disorders such as Parkinson's disease [76], while also offering valuable information on metabolic alterations associated with de novo lipogenesis in hepatocellular carcinoma studies [77]. On the other hand, the combination of 18 F and 68 Ga allows for the visualization of somatostatin receptor expression ([ 68 Ga]DOTATOC) and assessment of the dopaminergic system ([ 18 F]FDOPA), which can be used to determine the characteristics of pulmonary carcinoids and guide the selection of the most suitable therapy [78].…”