The role of endoplasmic reticulum in in vivo cancer FDG kinetics

Abstract

A recent result obtained by means of an in vitro experiment with cancer cultured cells has configured the endoplasmic reticulum as the preferential site for the accumulation of 2-deoxy-2-[18F]fluoro-D-glucose (FDG). Such a result is coherent with cell biochemistry and is made more significant by the fact that the reticular accumulation rate of FDG is dependent upon extracellular glucose availability. The objective of the present paper is to confirm in vivo the result obtained in vitro concerning the crucial role played by the endoplasmic reticulum in FDG cancer metabolism. This study utilizes data acquired by means of a Positron Emission Tomography scanner for small animals in the case of CT26 models of cancer tissues. The recorded concentration images are interpreted within the framework of a three-compartment model for FDG kinetics, which explicitly assumes that the endoplasmic reticulum is the dephosphorylation site for FDG in cancer cells. The numerical reduction of the compartmental model is performed by means of a regularized Gauss-Newton algorithm for numerical optimization. This analysis shows that the proposed three-compartment model equals the performance of a standard Sokoloff’s two-compartment system in fitting the data. However, it provides estimates of some of the parameters, such as the phosphorylation rate of FDG, more consistent with prior biochemical information. These results are made more solid from a computational viewpoint by proving the identifiability and by performing a sensitivity analysis of the proposed compartment model.

Mathematical Models for FDG Kinetics in Cancer: A Review

“…Driven by biochemical reactions involving FDG molecules, a 3-compartment model (3-CM) has been developed, which is formed by the following compartments: , accounting for free tracer in the cytosol and possibly in the interstitial space, for phosphorylated FDG in cytosol, and for phosphorylated FDG in ER [ 13 , 33 ]. The resulting compartment model is depicted in Figure 2 .…”

“…3-CM has been applied to the reduction of data coming from in vitro [ 13 ] and in vivo [ 33 ] experiments. Although we deal with the same set of three compartments, the resulting models and the related approaches differ in various significant aspects.…”

“…Although we deal with the same set of three compartments, the resulting models and the related approaches differ in various significant aspects. For example, the process of data acquisition in vitro requires the use of a dedicated device (Ligand Tracer) with a properly defined calibration process, while activities replace concentrations as state variables [ 13 , 33 ]. However, the most outstanding result obtained from the mathematical analysis of data via 3-CM, i.e., that tracer is accumulated in ER, holds both in vitro and in vivo, and this has been confirmed by the localization of fluorescent FDG analogues in the case of in vitro experiments [ 13 ].…”

“…The connection between the tracer concentration estimated over a suitable ROI and the formal solution of the ODEs (13)–(15) is obtained as follows [ 33 ]. The volume of the ROI is partitioned as where and denote the volume occupied by blood and interstitial fluid, respectively; and denote the total volumes of cytosol and ER in tissue cells.…”

“…For example, consider the system of ODE for 3-CM and suppose that is almost constant. Indeed, repeated applications of 3-CM have shown that reaches a stationary value after a very short transition time [ 13 , 33 ]. In that case, Equation (14) reduces to (as a consequence, also becomes constant, consistent with simulations).…”