The role of the endoplasmic reticulum in in vivo cancer FDG kinetics

Abstract

2A very recent result obtained by means of an in vitro experiment with cancer cultured cells 3 has configured the endoplasmic reticulum as the preferential site for the accumulation of 2-4 deoxy-2-[ 18 F]fluoro-D-glucose (FDG). Such a result is coherent with cell biochemistry and is 5 made more significant by the fact that reticular accumulation rate of FDG is dependent upon 6 extracellular glucose availability. The objective of the present paper was to confirm this result 7 in vivo, using small animal models of CT26 cancer tissues. Specifically, assuming that the 8 endoplasmic reticulum plays a specific functional role in the framework of a three-compartment 9 model for FDG kinetics, we are able to explain positron emission tomography dynamic data in a 10 more reliable way than by means of a standard Sokoloff two-compartment system. This result is 11 made more solid from a computational viewpoint by means of some identifiability considerations 12 based on a mathematical analysis of the compartmental equations. 13 Keywords: cancer glucose metabolism, endoplasmic reticulum, in vivo models, FDG kinetics, compartmental analysis 14 1 INTRODUCTION 2-deoxy-2-[ 18 F]fluoro-D-glucose (FDG) is widely used as a glucose analogue tracer to evaluate glucose 15 metabolism in living organisms. As glucose, FDG is first transported into cells, where it is phosphorylated 16to FDG-6-phosphate (FDG6P) by hexokinase (HK) and then accumulates intracellularly. The measured 17 amount of emitted radiation is considered an accurate marker of overall glucose uptake by cells and tissues 18 (Cherry et al., 2012). In addition, FDG consumption by cancer cells is increased by the Warburg effect for 19 glucose (Vander et al., 2009); consequently, FDG may be employed in cancer detection and staging, and to 20 determine the effectiveness of medical treatments (Cairns et al., 2011). 21A recent result concerning the characterization of FDG kinetics in cultured cancer cells (Scussolini et 22 al., 2019) showed that the endoplasmic reticulum (ER) is the preferential site of FDG accumulation and 23 that, even more importantly, FDG reticular accumulation rate is dependent upon extracellular glucose 24 availability. This result is coherent with recent progress in cell biochemistry, which clarified that the 25 glucose-6-phosphatase (G6Pase), responsible for the dephosphorylation, is compartmentalized within the 26 endoplasmic reticulum (ER) (Ghosh et al., 2002; Marini et al., 2016). 27 1 Scussolini et al. The role of the endoplasmic reticulum The investigation in (Scussolini et al., 2019) relied on two methodological tools, one experimental 28 and one computational. In fact, on the one hand, FDG kinetics in cells cultured over a Petri dish, was 29 evaluated using the dedicated Ligand Tracer device (Björke and Andersson, 2006), which is able to count 30 electron/positron events without contaminating the counting rate of the cultured cells. On the other hand, 31 the data analysis was performed within the framework of a novel compartmental model, which extend...

Computational approaches for parametric imaging of dynamic PET data

“…On the other hand reg-GN seems to systematically underestimate the parameter values within region 1. Furthermore and as expected, for all methods the quality of the parametric reconstructions deteriorates with increasing noise levels; this is more clear from the k 3 and k 4 parametric images, probably due to the different sensitivities of the data with respect to the model parameters [37]. In reg-GN and lsqcurvefit some artifacts can be observed at the edges of the homogeneous regions, especially around region 1 and region 2, whereas the effect of regularization in reg-AS-TR results in a reduced presence of artifacts while the structure of the regions is preserved.…”