Dataset Information

Lactic Acid Accumulation in the Tumor Microenvironment Suppresses 18F-FDG Uptake.

ABSTRACT: The process by which tumor cells take up 2-[18F]fluoro-2-deoxy-D-glucose (FDG) is heterogeneous and influenced by a multitude of factors. In mouse tumor grafts, the core of the tumor often presents lower FDG uptake than the periphery. Whether this pattern is caused by the intrinsic avidity of individual cells for FDG, the density of viable cells in the tumor, or the perfusion of the radiotracer remains unknown. In this study, we used radioluminescence microscopy to measure FDG uptake in single cells isolated from the core and periphery of the tumor and found that differences in FDG uptake persist on the level of single cells. Single cells from the core of 4T1 and MDA-MB-231 tumors grafts took up 26% to 84% less FDG than those from the periphery. These differences were observed in mice with large tumors (>8 mm diameter) but not in those with smaller tumors. To explain the origin of these differences, we examined the influence of three microenvironmental factors on FDG uptake. Hypoxia was ruled out as a possible explanation because its presence in the core would increase and not decrease FDG uptake. Higher cell proliferation in the periphery was consistent with higher FDG uptake, but there was no evidence of a causal relationship. Finally, lactate was higher in the core of the tumor, and it suppressed FDG uptake in a dose-dependent fashion. We therefore conclude that lactic acidosis-the combination of lactate ion buildup and acidic pH-can increase the heterogeneity of FDG uptake in MDA-MB-231 and 4T1 tumor grafts. SIGNIFICANCE: Analysis of single cells from heterogeneous tumors reveals the role played by the tumor microenvironment, lactic acidosis in particular, on the uptake by tumor cells of 18F-FDG, a PET imaging agent.

SUBMITTER: Turkcan S

PROVIDER: S-EPMC6335173 | biostudies-literature | 2019 Jan

REPOSITORIES: biostudies-literature

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Lactic Acid Accumulation in the Tumor Microenvironment Suppresses <sup>18</sup>F-FDG Uptake.

Türkcan Silvan S Kiru Louise L Naczynski Dominik J DJ Sasportas Laura S LS Pratx Guillem G

Cancer research 20181203 2

The process by which tumor cells take up 2-[<sup>18</sup>F]fluoro-2-deoxy-D-glucose (FDG) is heterogeneous and influenced by a multitude of factors. In mouse tumor grafts, the core of the tumor often presents lower FDG uptake than the periphery. Whether this pattern is caused by the intrinsic avidity of individual cells for FDG, the density of viable cells in the tumor, or the perfusion of the radiotracer remains unknown. In this study, we used radioluminescence microscopy to measure FDG uptake ...[more]

PMID: 30510121

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Project description:A family of fluorine-18 ((18)F)-fluorodeoxyglucose ((18)F-FDG) positron-emission tomography (PET) features based on histogram distances is proposed for predicting pathologic tumor response to neoadjuvant chemoradiotherapy (CRT). These features describe the longitudinal change of FDG uptake distribution within a tumor.Twenty patients with esophageal cancer treated with CRT plus surgery were included in this study. All patients underwent PET/CT scans before (pre-) and after (post-) CRT. The two scans were first rigidly registered, and the original tumor sites were then manually delineated on the pre-PET/CT by an experienced nuclear medicine physician. Two histograms representing the FDG uptake distribution were extracted from the pre- and the registered post-PET images, respectively, both within the delineated tumor. Distances between the two histograms quantify longitudinal changes in FDG uptake distribution resulting from CRT, and thus are potential predictors of tumor response. A total of 19 histogram distances were examined and compared to both traditional PET response measures and Haralick texture features. Receiver operating characteristic analyses and Mann-Whitney U test were performed to assess their predictive ability.Among all tested histogram distances, seven bin-to-bin and seven crossbin distances outperformed traditional PET response measures using maximum standardized uptake value (AUC = 0.70) or total lesion glycolysis (AUC = 0.80). The seven bin-to-bin distances were: L(2) distance (AUC = 0.84), χ(2) distance (AUC = 0.83), intersection distance (AUC = 0.82), cosine distance (AUC = 0.83), squared Euclidean distance (AUC = 0.83), L(1) distance (AUC = 0.82), and Jeffrey distance (AUC = 0.82). The seven crossbin distances were: quadratic-chi distance (AUC = 0.89), earth mover distance (AUC = 0.86), fast earth mover distance (AUC = 0.86), diffusion distance (AUC = 0.88), Kolmogorov-Smirnov distance (AUC = 0.88), quadratic form distance (AUC = 0.87), and match distance (AUC = 0.84). These crossbin histogram distance features showed slightly higher prediction accuracy than texture features on post-PET images.The results suggest that longitudinal patterns in (18)F-FDG uptake characterized using histogram distances provide useful information for predicting the pathologic response of esophageal cancer to CRT.

Project description:BACKGROUND:Anti-programmed cell death 1 (PD-1) antibody is an immune checkpoint inhibitor, and anti-PD-1 therapy improves the anti-tumor functions of T cells and affects tumor microenvironment. We previously reported that anti-PD-1 treatment affected tumor glycolysis by using 2-deoxy-2-[18F]fluoro-D-glucose ([18F]FDG) positron emission tomography (PET). That study showed that anti-PD-1 therapy in a mouse B16F10 melanoma model increased glucose metabolism in cancer cells at the point where anti-PD-1 therapy did not cause a significant inhibition of tumor growth. However, the B16F10 melanoma model is poorly immunogenic, so it is not clear how anti-PD-1 treatment affects glucose metabolism in highly immunogenic cancer models. In this study, we used a cyclic dinucleotide GMP-AMP (cGAMP)-injected B16F10 melanoma model to investigate the effect of anti-PD-1 therapy on [18F]FDG uptake in a highly immune activated tumor in mice. RESULTS:To compare the cGAMP-injected B16F10 model with the B16F10 model, experiments were performed as described in our previous manuscript. [18F]FDG-PET was measured before treatment and 7 days after the start of treatment. In this study, [18F]FDG uptake in tumors in the cGAMP/anti-PD-1 combination group was lower than that in the anti-PD-1 treatment group tumors on day 7, as shown by PET and ex vivo validation. Flow-cytometry was performed to assess immune cell populations and glucose metabolism. Anti-PD-1 and/or cGAMP treatment increased the infiltration level of immune cells into tumors. The cGAMP/anti-PD-1 combination group had significantly lower levels of GLUT1high cells/hexokinase IIhigh cells in CD45- cancer cells compared with tumors in the anti-PD-1 treated group. These results suggested that if immune responses in tumors are higher than a certain level, glucose uptake in cancer cells is reduced depending on that level. Such a change of glucose uptake might be caused by the difference in infiltration or activation level of immune cells between the anti-PD-1 treated group and the cGAMP/anti-PD-1 combination group. CONCLUSIONS:[18F]FDG uptake in cancer cells after anti-PD-1 treatment might be affected by the tumor immune microenvironment including immune cell infiltration, composition, and activation status.

Project description:PurposeTo quantify the post-radiotherapy 2-[(18)F]-fluoro-2-deoxyglucose (FDG) pulmonary uptake dose-response in lung cancer patients and determine its relationship with radiation pneumonitis symptoms.Methods and materialsThe data from 24 patients treated for lung cancer with thoracic radiotherapy who received restaging PET/CT imaging between 4 and 12 weeks after radiotherapy completion were evaluated. Their radiation dose distribution was registered with the post-treatment restaging PET/CT. Using histogram analysis, the voxel average FDG-PET uptake vs. radiation dose was obtained for each case and linear regression was performed. The resulting slope, the pulmonary metabolic radiation response (PMRR), was used to characterize the dose-response. The Common Toxicity Criteria version 3 was used to score clinical pulmonary toxicity symptoms. Receiver operating characteristic (ROC) curves were used to determine the level of FDG uptake vs. dose, MLD, V(5), V(10), V(20), and V(30) that can best predict symptomatic and asymptomatic patients.ResultsThe median time between radiotherapy completion and FDG-PET imaging was 59 days (range, 26-70 days). The median of the mean SUV from lung that received 0-5 Gy was 1.00 (range, 0.37-1.48), 5-10 Gy was 1.01 (range, 0.37-1.77), 10-20 Gy was 1.04 (0.42-1.53), and >20 Gy was 1.29 (range, 0.41-8.01). Using the dose range of 0 Gy to the maximum dose minus 10 Gy, hierarchical linear regression model of the radiation dose and normalized FDG uptake per case found an adequate fit with the linear model. Pneumonitis scores were: Grade 0 for 13, Grade 1 for 5, Grade 2 for 6, and Grade 3, 4 or 5 for none. Using a PMRR threshold of 0.017 yields an associated true positive rate of 0.67 and false positive rate of 0.15 with average error of 30%. A V(5) threshold of 57.6 gives an associated true positive rate of 0.67 and false positive rate of 0.05 with a 20% average error.ConclusionThe metabolic radiation pneumonitis dose-response was evaluated from post-treatment FDG-PET/CT imaging. Statistical modeling found a linear relationship. The FDG uptake dose-response and V(5) correlated with symptomatic radiation pneumonitis.

Project description:BackgroundAssessment of dual time point (DTP) positron emission tomography was carried out with the aim of a quantitative determination of Km, the metabolic uptake rate of [18F]fluorodeoxyglucose as a measure of glucose consumption.MethodsStarting from the Patlak equation, it is shown that Km?mt/ca0+V?r/?a, where mt is the secant slope of the tissue response function between the dual time point measurements centered at t?=?t0. ca0=ca(t0) denotes arterial tracer concentration, V?r is an estimate of the Patlak intercept, and ?a is the time constant of the ca(t) decrease. We compared the theoretical predictions with the observed relation between Ks=mt/ca0 and Km in a group of nine patients with liver metastases of colorectal cancer for which dynamic scans were available, and Km was derived from conventional Patlak analysis. Twenty-two lesion regions of interest (ROIs) were evaluated. ca(t) was determined from a three-dimensional ROI in the aorta. Furthermore, the correlation between Km and late standard uptake value (SUV) as well as retention index was investigated. Additionally, feasibility of the approach was demonstrated in a whole-body investigation.ResultsPatlak analysis yielded a mean Vr of V?r=0.53±0.08 ml/ml. The patient averaged ?a was 99?±?23 min. Linear regression between Patlak-derived Km and DTP-derived Ks according to Ks?=?b?·?Km?+?a yielded b?=?0.98?±?0.05 and a?=?-0.0054?±?0.0013 ml/min/ml (r?=?0.98) in full accordance with the theoretical predictions b?=?1 and a?-V?r/?a. Ks exhibits better correlation with Km than late SUV and retention index, respectively. Ks(c)=Ks+V?r/?a is proposed as a quantitative estimator of Km which is independent of patient weight, scan time, and scanner calibration.ConclusionQuantification of Km from dual time point measurements compatible with clinical routine is feasible. The proposed approach eliminates the issues of static SUV and conventional DTP imaging regarding influence of chosen scanning times and inter-study variability of the input function. Ks and Ks(c) exhibit improved stability and better correlation with the true Km. These properties might prove especially relevant in the context of radiation treatment planning and therapy response control.

Dataset Information

Lactic Acid Accumulation in the Tumor Microenvironment Suppresses 18F-FDG Uptake.

Publications

Lactic Acid Accumulation in the Tumor Microenvironment Suppresses <sup>18</sup>F-FDG Uptake.

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