Tumor uptake of 14C-thymidine in rodent breast cancer: Interrelationship with perfusion, hypoxia, glycolysis and glucose transporter expression

Objectives It is widely believed that FDG uptake in tumors is affected by many factors, like perfusion, proliferation, GLUT-1 expression, inflammation and others. The goal of this study is to compare 14C-thymidine uptake with hypoxia, Proliferation, Glut-1 expression and FDG uptake.

Methods Rats bearing syngeneic mammary tumor (RMT) in their interscapular subcutaneous regions were prepared. One of the well-established hypoxia markers, pimonidazole (60mg/kg) was injected intraperitoneally six hours before sacrifice. A mixture of 18FDG (1mCi) and 14C-thymidine (5μCi), and subsequently a perfusion marker, Hoechst 33342, were injected intravenously two hours and one minute before sacrifice, respectively. Immunofluorescent staining using a confocal microscope on frozen sections was performed after autoradiography for 18F and 14C. Images of the four tracers (two radioactive) and GLUT-1 were quantitatively assessed for density in tumor sections using ImageJ. Correlation among the tracers was statistically analyzed.

Results 14C-thymidine accumulation showed a strong positive correlation with Hoechst 33342 (r=0.72, p<0.000001) (flow) and negative correlations with pimonidazole (r=-0.68, p<0.000001) and GLUT-1 (r=-0.52, p<0.000001) (hypoxia). 14C-thymidine and 18FDG uptake showed a positive correlation up to a middle level of 14C-thymidine uptake. 18FDG uptake started to decrease in the area of the highest 14C-thymidine uptake. Therefore, the areas with moderate 14C-thymidine uptake showed the highest 18FDG uptake.

Conclusions 14C-thymidine uptake in RMT was highly correlated with tumor perfusion. Areas with low 14C-thymidine uptake were often hypoxic. 18FDG uptake was affected both by proliferation (perfusion) and GLUT-1 expression. The influence of proliferation is apparent in low proliferation and the decrease of 18FDG uptake in high proliferation may be due to low GLUT-1 expression. Non thymidine-avid but FDG-avid lesions were not uncommon