Low uptake of fluorodeoxyglucose in positron emission tomography/computed tomography in ovarian clear cell carcinoma may reflect glutaminolysis of its cancer stem cell-like properties

Abstract

The characteristics of ovarian cancers that showed low activation of glycolysis were investigated. Using medical records of patients with ovarian cancers who had undergone fluorodeoxyglucose positron emission tomography/computed tomography (FDG-PET/CT) prior to their primary surgery at the University of Tokyo Hospital between 2010 and 2015, we identified cases with a low uptake of FDG in PET/CT. We considered the maximum standardized uptake value (SUVmax) as the degree of glucose uptake. We investigated the properties which may account for the low activation of glycolysis in vitro. The expression level of alanine, serine, cysteine-preferring transporter 2 (ASCT2, a glutamine influx transporter), system L-type amino acid transporter 1 (LAT1, a glutamine efflux transporter) and glucose transporter 1 (GLUT1, a glucose influx transporter) were investigated by western blotting. The phosphorylation level of AMP-activated protein kinase (AMPK), which is one of the metabolic sensors, was also investigated. Most of the cases with a low uptake SUVmax were limited to patients with ovarian clear cell carcinoma (CCC). We obtained cancer stem cell (CSC)-like properties from CCC cell lines, and compared the expression levels of transporters between non-CSCs and CSCs. Whereas the expression level of ASCT2 was nearly unchanged between non-CSCs and CSCs, the expression levels of LAT1 and GLUT1 were decreased in CSCs compared to non-CSCs. The phosphorylation level of AMPK was reduced in CSCs compared to non-CSCs. In conclusion, we suggested that ovarian CCC showed low activation of glycolysis, and this may reflect glutaminolysis of its CSC-like properties.

Para-aortic Lymph Node Invasion in High-risk Endometrial Cancer: Performance of 18FDG PET-CT

“…The cellular uptake of 18 FDG appears to depend partly on cellular grade (17). In ovarian cancer, patients with clear-cell carcinoma have been shown to have a lower mean maximal standardized uptake value than patients with serous adenocarcinoma or endometrioid adenocarcinoma (18)(19)(20). Clear-cell carcinomas seem to prefer the glutaminolysis pathway over glycolysis, resulting in lower 18 F-FDG concentrations in cells and a weaker signal (19).…”

Therapeutic Targeting of Glutaminolysis as a Novel Strategy to Combat Cancer Stem Cells

“…Research demonstrated lower uptake of glucose in ovarian clear cell carcinoma with CSC-like properties on fluorodeoxyglucose positron emission tomography/computed tomography, indicating a low activation of glycolysis [ 123 ]. Further in vitro evaluation found that, in comparison to non-CSCs, CSCs have lower expression levels of LAT1, a transporter of glutamine efflux, and GLUT1, a transporter of glucose influx [ 123 ]. The expression level of SLC1A5 shows no difference, suggesting a comparable glutamine influx between CSCs and non-CSCs [ 123 ].…”

“…Further in vitro evaluation found that, in comparison to non-CSCs, CSCs have lower expression levels of LAT1, a transporter of glutamine efflux, and GLUT1, a transporter of glucose influx [ 123 ]. The expression level of SLC1A5 shows no difference, suggesting a comparable glutamine influx between CSCs and non-CSCs [ 123 ]. Taken together, these lines of evidence depict a glutamine-accumulating feature and indicate the metabolic diversion toward glutaminolysis from glycolysis in ovarian CSCs ( Figure 2 ).…”

Potential Therapies Targeting Metabolic Pathways in Cancer Stem Cells

“…Assays of glycolysis and glutamine transporters indicate that ovarian clear cell carcinoma (CCC) displayed low glycolytic flux, which may be related to the high glutaminolysis and its CSC-like properties [ 116 ]. Especially, higher expression levels of ASCT2 and GLS were observed in CSCs, which implicated that ASCT2 and GLS are important for the proliferation and maintenance of the redox state in CSCs [ 114 ].…”