This study revisited (18)F-fluorodeoxyglucose ((18)F-FDG) uptake and its relationship to hypoxia in various tumor models. 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. (18)F-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. 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 (18)F-FDG uptake. In contrast, (18)F-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. Glucose demand ((18)F-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 (18)F-FDG PET in oncology application.

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The role of microRNAs (miRNAs) in regulating gene expression is currently an area of intense interest. Previous studies have shown that miRNA‑372 plays crucial roles in gastric tumorigenesis by targeting the mRNA of tumor necrosis factor, α‑induced protein 1 (TNFAIP1). The present study showed that miR‑373 is upregulated in gastric adenocarcinoma tissue and gastric carcinoma cell lines when compared to normal gastric tissues. The overexpression of miR‑373 in the gastric cancer cells increased cell proliferation. A bioinformatics search revealed a conserved target site within the 3' untranslated region (UTR) of TNFAIP1, an immediate‑early response gene of the endothelium induced by TNF‑α. The overexpression of miR‑373 caused the suppression of a luciferase reporter containing the TNFAIP1 3'UTR in the HEK293 cells and reduced the levels of TNFAIP1 protein in the AGS cells. The mRNA levels of TNFAIP1 in the gastric cancer and normal gastric tissues were negatively correlated with the expression levels of miR‑373 in these tissues. Moreover, the knockdown of TNFAIP1 had a similar effect to the overexpression of miR‑373. The overexpression of TNFAIP1 may partly rescue the inhibition of proliferation caused by the inhibitor, miR‑373‑ASO. Taken together, these findings demonstrate an oncogenic role for miR‑373, similar to that of miR‑372, in controlling cell growth through the downregulation of TNFAIP1.

The presence of hypoxia is a general feature of most solid malignancies, and hypoxia is considered as one of major factors for anticancer therapy failure. Carbonic anhydrase IX (CAIX) has been reported to be an endogenous hypoxia marker, CAIX monoclonal antibodies, their segments and inhibitors are developed for CAIX imaging. However, growing evidence indicates that CAIX expression under hypoxia condition may be cancer cell lines or cancer-type dependent. Here we review the current literature on CAIX and discuss the advantage and limitation of CAIX as a target for tumor hypoxia imaging. Accordingly, CAIX would be unreliable as a universal target for cancer and tumor hypoxia visualization.

The purpose of this study was to observe the effect of fasting and feeding on ¹⁸F-FDG uptake in a mouse model of human non–small cell lung cancer. Methods: In in vivo studies, ¹⁸F-FDG small-animal PET scans were acquired in 5 mice bearing non–small cell lung cancer A549 xenografts on each flank with continuous feeding and after overnight fasting to observe the changes in intratumoral distribution of ¹⁸F-FDG and tumor ¹⁸F-FDG standardized uptake value (SUV). In ex vivo studies, intratumoral spatial ¹⁸F-FDG distribution assessed by autoradiography was compared with the tumor microenvironment (including hypoxia by pimonidazole and stroma by hematoxylin and eosin stain). Five overnight-fasted mice and 5 fed mice with A549 tumors were observed. Results: Small-animal PET scans were obtained in fed animals on day 1 and in the same animals after overnight fasting; the lapse was approximately 14 h. Blood glucose concentration after overnight fasting was not different from fed mice (P = 0.42), but body weight loss was significant after overnight fasting (P = 0.001). Intratumoral distribution of ¹⁸F-FDG was highly heterogeneous in all tumors examined, and change in spatial intratumoral distribution of ¹⁸F-FDG between 2 sets of PET images from the same mouse was remarkably different in all mice. Tumor ¹⁸F-FDG mean SUV and maximum SUV were not significantly different between fed and fasted animals (all P > 0.05, n = 10). Only tumor mean SUV weakly correlated with blood glucose concentration (R² = 0.17, P = 0.03). In ex vivo studies, in fasted mice, there was spatial colocalization between high levels of ¹⁸F-FDG uptake and pimonidazole-binding hypoxic cancer cells; in contrast, pimonidazole-negative normoxic cancer cells and noncancerous stroma were associated with low ¹⁸F-FDG uptake. However, high ¹⁸F-FDG uptake was frequently observed in noncancerous stroma of tumors but rarely in viable cancer cells of the tumors in fed animals. Conclusion: Host dietary status may play a key role in intratumoral distribution of ¹⁸F-FDG. In the fed animals, ¹⁸F-FDG accumulated predominantly in noncancerous stroma in the tumors, that is, reverse Warburg effect. In contrast, in fasted status, ¹⁸F-FDG uptake was found in hypoxic cancer cells component (Pasteur effect). Our findings may provide a better understanding of competing cancer glucose metabolism hypotheses: the Warburg effect, reverse Warburg effect, and Pasteur effect.