Molecular mechanisms of [18F]fluorodeoxyglucose accumulation in liver cancer

Abstract

To elucidate the molecular mechanisms underlying the insufficient sensitivity in the detection of hepatocellular carcinoma (HCC) by [18F] 2-fluoro-2-deoxy-D-glucose positron emission tomography (FDG-PET), the characteristics of glucose metabolism-related protein expression in HCC were examined in liver metastasis from colorectal cancer (Meta). Thirty-four patients (14 Meta and 20 HCC) who underwent FDG-PET and hepatectomy were studied. The relationships between the maximum standardized uptake value (SUV) in tumors and the mRNA expression of glucose metabolism-related proteins [hexokinase (HK), glucose transporter 1 (GLUT1), and glucose-6-phosphatase (G6Pase)] and proliferating cell nuclear antigen (PCNA) were examined in snap-frozen specimens with quantitative PCR. Tumor detection rates were lower in HCC (15/20) compared to Meta (13/14) patients. HK and GLUT1 expression was lower and G6Pase expression was higher in HCC compared to Meta. In particular, GLUT1 overexpression was 92-fold in Meta and 11-fold in HCC compared to the surrounding liver. The SUV correlated with GLUT1 and PCNA expression in HCC, but not Meta patients. Of note, four cases of poorly differentiated (P/D) HCC compared to moderately differentiated (M/D) HCC produced completely different results for FDG uptake (SUV, 14.4 vs. 4.0) and mRNA expression (G6Pase expression, 0.007 vs. 1.5). Variations in the expression of glucose metabolism-related enzymes between HCC and Meta patients are attributed to origin or degree of differentiation. Low FDG uptake in M/D HCC reflected low GLUT1 and high G6Pase expression, while high FDG accumulation in P/D HCC could reflect increased GLUT1 and decreased G6Pase expression. These results may explain why M/D HCC is not detected as sensitively by FDG-PET.

The uptake exploration of 68Ga-labeled NGR in well-differentiated hepatocellular carcinoma xenografts: Indication for the new clinical translational of a tracer based on NGR

“…However, the high expression rate of CD13 has already been confirmed not only in a variety of HCC cell lines, but also clinical samples (23,24), which suggests that 68 Ga-NGR may have high specificity and sensitivity for further clinical diagnosis of well-differentiated HCCs. Poor-differentiated HCCs have relatively low expression of G6Pase and high expression of GLUT1 (17), which may contribute to the low uptake of 18 F-FDG by poor-differentiated HCC. The uptake performance of 68 Ga-NGR, in poor-differentiated HCC, warrants further investigation.…”

“…In well-differentiated HCC, it is widely accepted that the low uptake of 18 F-FDG mainly results from the overexpression of glucose-6-phosphatase (G6Pase), which leads to the release of 18 F-FDG from the tumor cells by converting the 6-phosphoric acid-FDG back to the FDG prototype (12,16). However, the low expression of glucose transporter 1 (GLUT1), which serves as the primary transporter of FDG, also decreases the uptake of 18 F-FDG to some degree (17). Therefore, a new PET/CT tracer that targets other molecular biomarkers rather than those related to glucose metabolism should be developed to improve the clinical applications of PET/CT for the detection of well-differentiated HCC.…”

An FDG-PET/CT-Positive Lesion Mimicking Local Recurrence of Colon Cancer 5 Years after Radical Colectomy

“…FDG accumulation is observed in cases of accelerated glucose absorption and/or delayed glucose metabolism. However, these conditions are not specific to malignant lesions [ 25 ]. Since it is impossible even for FDG-PET to distinguish malignant from benign disease in all cases, further advancement of the PET technology is needed and more useful modalities should be established.…”

Hepatocyte nuclear factor 1α-inactivated hepatocellular adenomas exhibit high18F-fludeoxyglucose uptake associated with glucose-6-phosphate transporter inactivation

“…Most HCCs with fat deposition are well differentiated, 29 and because of G6Pase expression, the FDG uptake in well-differentiated HCCs was reported to equal that in the background liver. 6 Therefore, HCCs with fat deposition may not exhibit increased FDG uptake. Angiomyolipoma sometimes exhibits increased FDG uptake in association with the infiltration of inflammatory cells, although this is an atypical Figure 4.…”

“…5 However, the sensitivity of FDG-PET for the detection of HCC, especially well-differentiated or moderately differentiated HCC, is limited because glucose-6-phosphatase (G6Pase) expression in HCC cells leads to the rapid disappearance of FDG from these cells in a manner similar to that observed in the surrounding hepatocytes. 6 Benign hepatocellular nodules, such as focal nodular hyperplasia and HCA, also commonly exhibit a similar FDG uptake and retention pattern as the normal liver tissue owing to the same mechanism. 7 Therefore, FDG-PET has been considered as less useful for not only detecting hepatocellular lesions but also differentiating well to moderately differentiated HCCs from benign hepatocellular lesions.…”