“Facilitated” Amino Acid Transport is Upregulated in Brain Tumors

Abstract

The goal of this study was to determine the magnitude of "facilitated" amino acid transport across tumor and brain capillaries and to evaluate whether amino acid transporter expression is "upregulated" in tumor vessels compared to capillaries in contralateral brain tissue. Aminocyclopentane carboxylic acid (ACPC), a non-metabolized [14C]-labeled amino acid, and a reference molecule for passive vascular permeability, [67Ga]-gallium-diethylenetriaminepentaacetic acid (Ga-DTPA), were used in these studies. Two experimental rat gliomas were studied (C6 and RG2). Brain tissue was rapidly processed for double label quantitative autoradiography 10 minutes after intravenous injection of ACPC and Ga-DTPA. Parametric images of blood-to-brain transport (K1ACPC and K1Ga-DTPA, microL/min/g) produced from the autoradiograms and the histology were obtained from the same tissue section. These three images were registered in an image array processor; regions of interest in tumor and contralateral brain were defined on morphologic criteria (histology) and were transferred to the autoradiographic images to obtain mean values. The facilitated component of ACPC transport (deltaK1ACPC) was calculated from the K1ACPC and K1Ga-DTPA data, and paired comparisons between tumor and contralateral brain were performed. ACPC flux, K1ACPC, across normal brain capillaries (22.6 +/- 8.1 microL/g/min) was >200-fold greater than that of Ga-DTPA (0.09 +/- 0.04 microL/g/min), and this difference was largely (approximately 90%) due to facilitated ACPC transport. Substantially higher K1ACPC values compared to corresponding K1DTPA values were also measured in C6 and RG2 gliomas. The deltaK1ACPC values for C6 glioma were more than twice that of contralateral brain cortex. K1ACPC and deltaK1ACPC values for RG2 gliomas was not significantly higher than that of contralateral cortex, although a approximately 2-fold difference in facilitated transport is obtained after normalization for differences in capillary surface area between RG2 tumors and contralateral cortex. K1ACPC, deltaK1ACPC, and K DTPA were directly related to tumor cell density, were higher in regions of "impending" necrosis, and the tumor/contralateral brain ACPC radio-activity ratios (0 to 10 minutes) were very similar to that obtained with 0 to 60 minutes experiments. These results indicate that facilitated transport of ACPC is upregulated across C6 and RG2 glioma capillaries, and that tumors can induce upregulation of amino acid transporter expression in their supporting vasculature. They also suggest that early imaging (e.g., 0 to 20 minutes) with radiolabeled amino acids in a clinical setting may be optimal for defining brain tumors.

Analysis of11C-methionine Uptake in Low-Grade Gliomas and Correlation with Proliferative Activity

“…Increased uptake of MET is present in most low-grade gliomas despite the absence of damage to the BBB. 13,[29][30][31] In malignant gliomas with BBB damage, passive diffusion also contributes to total uptake of MET. 32 We hypothesize that the MET uptake, especially in DAs without BBB disruption, may be closely associated with tumor viability, which itself is dependent on increased amino acid transport.…”

Dynamic 18F‐FET PET in suspected WHO grade II gliomas defines distinct biological subgroups with different clinical courses

“…Differential expression of LAT-1 in low-grade and high-grade gliomas has been regarded as one of the possible key factors for distinct influx and efflux patterns of 18 F-FET in gliomas of different grade. 10,[14][15][16][17] Faster delivery of the amino acid to the tumor tissue of high-grade gliomas has been also linked to increased angiogenesis, microvessel densitiy and increased perfusion; the influence of a disturbed blood-brain barrier is considered of limited importance, as an increasing/decreasing TAC pattern can be seen in both gadolinium enhancing and nonenhancing gliomas. 11,18,19 For characterization of MRI-suspected low-grade gliomas by 18 F-FET PET, we had previously mapped the tumor volumes using dynamic 18 F-FET uptake analyses.…”

Multimodality Assessment of Brain Tumors and Tumor Recurrence

“…Labeled amino acids and their analogs-L-[methyl-11 C]-methionine ( 11 C-MET), 11 C-tyrosine, 18 F-fluorotyrosine, 18 F-deoxyphenylalanine (F-DOPA) and O-2 18 F-fluoroethyltyrosine-are particularly attractive for imaging brain tumors because of the high uptake in tumor tissue and low uptake in normal brain and, as a consequence, higher tumor-to-normal-tissue contrast. This increased amino acid uptake, especially in gliomas, is not a direct measure of protein synthesis or dependent on BBB breakdown but rather is related to increased transport mediated by type L amino acid carriers: facilitated transport is upregulated because tumors increase transporter expression in their vasculature (24). Additionally, the countertransport system A is overexpressed in neoplastic cells and seems to be positively correlated with the rate of tumor cell growth (25).…”