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

View Article: PubMed Central - PubMed

ABSTRACT

The limitations of fluorine-18 fluorodeoxy-D-glucose (FDG) in detecting some cancers has prompted a longstanding search for other positron emission tomography (PET) tracers to complement the imaging of glycolysis in oncology, with much attention paid to lipogenesis based on observations that the production of various lipid and lipid-containing compounds is increased in most cancers. Radiolabeled analogs of choline and acetate have now been used as oncologic PET probes for over a decade, showing convincingly improved detection sensitivity over FDG for certain cancers. However, neither choline nor acetate have been thoroughly validated as lipogenic biomarkers, and while acetyl-CoA produced from acetate is used in de-novo lipogenesis to synthesize fatty acids, acetate is also consumed by various other synthetic and metabolic pathways, with recent experimental observations challenging the assumption that lipogenesis is its predominant role in all cancers. Since tumors detected by acetate PET are also frequently detected by choline PET, imaging of choline metabolism might serve as an alternative albeit indirect marker of lipogenesis, particularly if the fatty acids produced in cancer cells are mainly destined for membrane synthesis through incorporation into phosphatidylcholines. Aerobic glycolysis may or may not coincide with changes in lipid metabolism, resulting in combinatorial metabolic phenotypes that may have different prognostic or therapeutic implications. Consequently, PET imaging using dual metabolic tracers, in addition to being diagnostically superior to imaging with individual tracers, could eventually play a greater role in supporting precision medicine, as efforts to develop small-molecule metabolic pathway inhibitors are coming to fruition. To prepare for this advent, clinical and translational studies of metabolic PET tracers must go beyond simply estimating tracer diagnostic utility, and aim to uncover potential therapeutic avenues associated with these metabolic alterations.

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Corresponding 18F-fluorodeoxy-D-glucose positron emission tomography/computed tomography (A) and 18F-fluorocholine positron emission tomography/computed tomography (B) images of hepatocellular carcinoma obtained from the same patient on different days. The tumor is not at all evident on transaxial images of the liver from FDG PET/CT (A). Corresponding transaxial images of the liver from 18F-fluorocholine PET/CT (B) shows a 5-cm diameter circumscribed area of increased uptake in the left hepatic lobe (B) This tumor contained within the left hepatic lobe was histopathologically confirmed to be a well-differentiated HCC. FDG: 18F-fluorodeoxy-D-glucose; PET: Positron emission tomography; CT: Computed tomography; HCC: Hepatocellular carcinoma.
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Figure 3: Corresponding 18F-fluorodeoxy-D-glucose positron emission tomography/computed tomography (A) and 18F-fluorocholine positron emission tomography/computed tomography (B) images of hepatocellular carcinoma obtained from the same patient on different days. The tumor is not at all evident on transaxial images of the liver from FDG PET/CT (A). Corresponding transaxial images of the liver from 18F-fluorocholine PET/CT (B) shows a 5-cm diameter circumscribed area of increased uptake in the left hepatic lobe (B) This tumor contained within the left hepatic lobe was histopathologically confirmed to be a well-differentiated HCC. FDG: 18F-fluorodeoxy-D-glucose; PET: Positron emission tomography; CT: Computed tomography; HCC: Hepatocellular carcinoma.

Mentions: Increases in lipid metabolism and glucose metabolism can be observed to coincide in the same tumor. Among several clinical comparisons between acetate PET and FDG PET, over 90% of poorly differentiated or metastatic HCC tumors demonstrated increased uptake of both 11C-acetate and FDG, leading to the conclusion that the diagnostic advantage of acetate PET over FDG PET stems from its ability to detect more well-differentiated tumors[20-22]. In a study involving earlier stage HCC, the overall sensitivity of 11C-acetate PET for all grades of tumor was 87.3%, while the sensitivity of 18F-FDG was 47.3% in the same group of patients[6]. A similar pattern of dual tracer uptake in well- vs poorly-differentiated tumors was noted in a clinical trial that compared 18F-fluorocholine against FDG, with 18F-fluorocholine showing higher sensitivity for well-differentiated HCC, and both tracers showing similar sensitivity for less-differentiated HCC[16]. The detection by 18F-fluorocholine PET/CT of a well-differentiated HCC tumor that was not found by FDG PET is illustrated in Figure 3. Along these lines, in a tissue microarray of 157 HCC tumors, we found associations with overall survival for both CK expression and HK expression, but only HK expression correlated with tumor differentiation[23]. Thus, while choline and acetate affords PET with better overall sensitivity for HCC, only FDG PET shows promise for assessing tumor differentiation in HCC.


Metabolic positron emission tomography imaging of cancer: Pairing lipid metabolism with glycolysis
Corresponding 18F-fluorodeoxy-D-glucose positron emission tomography/computed tomography (A) and 18F-fluorocholine positron emission tomography/computed tomography (B) images of hepatocellular carcinoma obtained from the same patient on different days. The tumor is not at all evident on transaxial images of the liver from FDG PET/CT (A). Corresponding transaxial images of the liver from 18F-fluorocholine PET/CT (B) shows a 5-cm diameter circumscribed area of increased uptake in the left hepatic lobe (B) This tumor contained within the left hepatic lobe was histopathologically confirmed to be a well-differentiated HCC. FDG: 18F-fluorodeoxy-D-glucose; PET: Positron emission tomography; CT: Computed tomography; HCC: Hepatocellular carcinoma.
© Copyright Policy - open-access
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC5120244&req=5

Figure 3: Corresponding 18F-fluorodeoxy-D-glucose positron emission tomography/computed tomography (A) and 18F-fluorocholine positron emission tomography/computed tomography (B) images of hepatocellular carcinoma obtained from the same patient on different days. The tumor is not at all evident on transaxial images of the liver from FDG PET/CT (A). Corresponding transaxial images of the liver from 18F-fluorocholine PET/CT (B) shows a 5-cm diameter circumscribed area of increased uptake in the left hepatic lobe (B) This tumor contained within the left hepatic lobe was histopathologically confirmed to be a well-differentiated HCC. FDG: 18F-fluorodeoxy-D-glucose; PET: Positron emission tomography; CT: Computed tomography; HCC: Hepatocellular carcinoma.
Mentions: Increases in lipid metabolism and glucose metabolism can be observed to coincide in the same tumor. Among several clinical comparisons between acetate PET and FDG PET, over 90% of poorly differentiated or metastatic HCC tumors demonstrated increased uptake of both 11C-acetate and FDG, leading to the conclusion that the diagnostic advantage of acetate PET over FDG PET stems from its ability to detect more well-differentiated tumors[20-22]. In a study involving earlier stage HCC, the overall sensitivity of 11C-acetate PET for all grades of tumor was 87.3%, while the sensitivity of 18F-FDG was 47.3% in the same group of patients[6]. A similar pattern of dual tracer uptake in well- vs poorly-differentiated tumors was noted in a clinical trial that compared 18F-fluorocholine against FDG, with 18F-fluorocholine showing higher sensitivity for well-differentiated HCC, and both tracers showing similar sensitivity for less-differentiated HCC[16]. The detection by 18F-fluorocholine PET/CT of a well-differentiated HCC tumor that was not found by FDG PET is illustrated in Figure 3. Along these lines, in a tissue microarray of 157 HCC tumors, we found associations with overall survival for both CK expression and HK expression, but only HK expression correlated with tumor differentiation[23]. Thus, while choline and acetate affords PET with better overall sensitivity for HCC, only FDG PET shows promise for assessing tumor differentiation in HCC.

View Article: PubMed Central - PubMed

ABSTRACT

The limitations of fluorine-18 fluorodeoxy-D-glucose (FDG) in detecting some cancers has prompted a longstanding search for other positron emission tomography (PET) tracers to complement the imaging of glycolysis in oncology, with much attention paid to lipogenesis based on observations that the production of various lipid and lipid-containing compounds is increased in most cancers. Radiolabeled analogs of choline and acetate have now been used as oncologic PET probes for over a decade, showing convincingly improved detection sensitivity over FDG for certain cancers. However, neither choline nor acetate have been thoroughly validated as lipogenic biomarkers, and while acetyl-CoA produced from acetate is used in de-novo lipogenesis to synthesize fatty acids, acetate is also consumed by various other synthetic and metabolic pathways, with recent experimental observations challenging the assumption that lipogenesis is its predominant role in all cancers. Since tumors detected by acetate PET are also frequently detected by choline PET, imaging of choline metabolism might serve as an alternative albeit indirect marker of lipogenesis, particularly if the fatty acids produced in cancer cells are mainly destined for membrane synthesis through incorporation into phosphatidylcholines. Aerobic glycolysis may or may not coincide with changes in lipid metabolism, resulting in combinatorial metabolic phenotypes that may have different prognostic or therapeutic implications. Consequently, PET imaging using dual metabolic tracers, in addition to being diagnostically superior to imaging with individual tracers, could eventually play a greater role in supporting precision medicine, as efforts to develop small-molecule metabolic pathway inhibitors are coming to fruition. To prepare for this advent, clinical and translational studies of metabolic PET tracers must go beyond simply estimating tracer diagnostic utility, and aim to uncover potential therapeutic avenues associated with these metabolic alterations.

No MeSH data available.


Related in: MedlinePlus