18F-Fluorodeoxyglucose Uptake and Tumor Hypoxia: Revisit 18F-Fluorodeoxyglucose in Oncology Application

Abstract

This study revisited 18F-fluorodeoxyglucose (18F-FDG) uptake and its relationship to hypoxia in various tumor models. METHODS: We generated peritoneal carcinomatosis and subcutaneous xenografts of colorectal cancer HT29, breast cancer MDA-MB-231, and non–small cell lung cancer A549 cell lines in nude mice. The partial oxygen pressure (pO2) of ascites fluid was measured. 18F-FDG accumulation detected by digital autoradiography was related to tumor hypoxia visualized by pimonidazole binding and glucose transporter-1 (GLUT-1) in frozen tumor sections. RESULTS: Ascites pO2 was 0.90 ± 0.53 mm Hg. Single cancer cells and clusters suspended in ascites fluid as well as submillimeter serosal tumors stained positive for pimonidazole and GLUT-1 and had high 18F-FDG uptake. In contrast, 18F-FDG uptake was significantly lower in normoxic portion (little pimonidazole binding or GLUT-1 expression) of larger serosal tumors or subcutaneous xenografts, which was not statistically different from that in the liver. CONCLUSIONS: Glucose demand (18F-FDG uptake) in severely hypoxic ascites carcinomas and hypoxic portion of larger tumors is significantly higher than in normoxic cancer cells. Warburg effect originally obtained from Ehrlich ascites carcinoma may not apply to normoxic cancer cells. Our findings may benefit the better understanding of 18F-FDG PET in oncology application.

The Reverse Warburg Effect and 18F-FDG Uptake in Non–Small Cell Lung Cancer A549 in Mice: A Pilot Study

“…In a separate group of mice, 5 fasted mice and 5 fed mice (total 10 mice) were included. A mixture of 18 F-FDG (7.4 MBq) and pimonidazole (2 mg) was injected via the tail vein 1 h before animal euthanasia (total injection volume, 0.2 mL) as described previously (3,4). Blood glucose levels were measured.…”

“…We and others have recently documented that hypoxic cancer cells have significantly higher 18 F-FDG uptake than aerobic ones in vivo animal studies (3)(4)(5)(6)(7) as well as in in vitro cell culture studies (8)(9)(10)(11) in various cancer cell lines. Therefore, in the absence of oxygen, cancer cells seem to have increased demand for glucose or 18 F-FDG uptake, and this may be more logically explained by anaerobic glycolysis or the Pasteur effect (3,4,7).…”

“…In operational terms, the Warburg effect increases the relative uptake of 18 F-FDG in tumors said to be unrelated to the microdistribution of hypoxia. However, growing evidence indicates that 18 F-FDG uptake is significantly higher in hypoxic cancer cells than normoxic cancer cells (3)(4)(5)(6)(7)(8)(9)(10)(11), and 18 F-FDG uptake in the latter is typically low and not statistically different from stromal or necrotic regions (3). These findings raise the question of whether the Warburg effect actually applies to normoxic cancer cells (4).…”

“…Therefore, in the absence of oxygen, cancer cells seem to have increased demand for glucose or 18 F-FDG uptake, and this may be more logically explained by anaerobic glycolysis or the Pasteur effect (3,4,7).…”

Is Carbonic Anhydrase IX a Validated Target for Molecular Imaging of Cancer and Hypoxia?

“…Results from scintigrams of the abdomen of the patient either 5 days after injection of 111 In-cG250 or 5 days after injection of 131 I-cG250, showed no apparent accumulation of radiolabeled cG250 in tumors. Immunohistochemical analyses revealed the expression of CAIX in tumor tissues of all three Figure 5) [21,[73][74][75][76]. In addition, hypoxic portion of colorectal cancer HCT-8 xenografts had increased 18 F-FDG accumulation [21], but CAIX expression in hypoxic zones was undetectable by immunohistochemistry [36].…”