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

Abstract

The process by which tumor cells take up 2-[ 18 F]fluoro-2deoxy-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 18 F-FDG, a PET imaging agent.

Targeting Glucose Transporters for Breast Cancer Therapy: The Effect of Natural and Synthetic Compounds

“…In the interesting paper of Turkcan et al, single cells from the core of 4T1 and MDA-MB-231 mice large tumors (>8 mm diameter) grafts were found to take up less glucose than those from the periphery. The authors were able to show that this difference was attributed to an inhibitory effect of lactic acid on glucose uptake [123].…”

“…This compound induces angiogenesis [121], induces HIF1α, which is associated with cancer cell growth and poor prognosis [122], and stimulates folate uptake by breast cancer cells [38]. Lactic acid interferes also with glucose uptake by breast cancer cells, but either a stimulatory [38] or an inhibitory effect [123] were described (Table 2). In the interesting paper of Turkcan et al, single cells from the core of 4T1 and MDA-MB-231 mice large tumors (>8 mm diameter) grafts were found to take up less glucose than those from the periphery.…”

“…EGFR stimulation also increased T47D cell proliferation [127] (Table 2). Single cells from the core of tumors grafts took up less glucose than those from the periphery Lactic acid levels were higher in the core of the tumor ↓ glucose uptake - [123] Lactic acid 10 mM (26 min) T-47D ↑ glucose uptake - [38] Epidermal growth factor 100 ng/mL (24 h) T-47D, MDA-MB-468, MCF-7…”

Plasma metabolites related to cellular energy metabolism are altered in adults with Down syndrome and Alzheimer's disease

“…Lactic acid fermentation may serve this end even though it is bioenergetically suboptimal. It may also serve to alter the biochemical microenvironment of vulnerable cells and perhaps brain regions in a way that promotes disease progression more broadly (Romero-Garcia, Moreno-Altamirano, Prado-Garcia, & Sánchez-García, 2016;Turkcan, Kiru, Naczynski, Sasportas, & Pratx, 2019). This is an interesting possibility given recent literature suggesting that Aβ clearance can be rescued in astrocytes in which endosomal pH has been epigenetically alkalinized (Prasad & Rao, 2018).…”

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“…This metabolic reprogramming is controlled mainly by the transcriptional activity of HIFs. Elevated glucose uptake in cells is seen at reduced oxygen concentration in the mild hypoxia range [ 100 , 101 ]. Moreover, increased gene or protein expression of glucose transporter GLUT1 and key enzymes in the glycolytic pathway, including HK2, GAPDH, ALDOA and ENO1 has been reported at 1.5–1% O 2 , e.g., [ 100 , 102 , 103 , 104 ].…”