| Purpose:Biological behavior plays an important role in tumor research. Positron emission tomography (PET) could capture interior characteristic information of tumor cell, and supply a visualization technique. The aim of current study is to discuss the value of multi-tracers PET imaging in hepatocellular carcinoma (HCC) with different biological behavior.Methods:Four kinds of human HCC cell lines (HepG2, QGY7701, MHCC97-H and MHCC97-L) were cultured and administered into nude mice to establish subcutaneous tumor-bearing and metastatic models. In vitro cell migration and invasion assay were performed to judge migration and invasion ability. Uptake of 18F-FDG,18F-FAC and 18F-FLT in the four kinds of cells were assessed after incubation with each radiotracer for 60 min. Then a multi-tracers classification model was established for HCC with different biological behavior, binding of pattern recognition technology. In vivo imaging of MHCC97-H and MHCC97-L mice models were obtained using small animal PET at 60min after injection of each tracer. ROI (region of interest) was drawn over tumor and lung to calculate T/NT (tumor/non-tumor). Tumor growth, metastasis status and survival time were assessed in model mice. The biomarkers (HSP27, CD44, VEGFR-2 and MMP9) were determined by immunohistochemistry, Western Blot and PT-PCR, respectively. The correlation between uptake of the tracers, metastasis capability, survival time and biomarkers expression were determined by linear regression analyses.Results:Cell migration/invasion ability:HepG2> QGY7701> MHCC97-H> MHCC97-L. 18F-FDG uptake of cells:HepG2> QGY7701> MHCC97-H> MHCC97-L (P<0.01), 18F-FAC uptake:HepG2> MHCC97-H> MHCC97-L> QGY7701, (P<0.01),18F-FLT uptake:HepG2> QGY7701> MHCC97-H> MHCC97-L, (P<0.05). Higher 18F-FDG or 18F-FLT uptake was found to correlate with higher migration or invasion capability. 18F-FDG uptake correlated with HSP27 and VEGFR-2 protein expression (P<0.01). 18F-FAC uptake correlated with CD44 protein expression (P<0.05).18F-FLT uptake correlated with HSP27 and VEGFR-2 protein expression (P<0.01). In addition, there was a correlation between 18F-FDG and 18F-FLT uptake (P<0.01).The results of classification showed the error rate of three features (18F-FDG+18F-FAC+18F-FLT) was lower than that of two features (18F-FDG+18F-FAC,18F-FDG+18F-FLT or 18F-FAC+18F-FLT). So multi-parameter classifier provided more accurate information for discrimination of biological behavior. In Micro-PET study, the uptake of 18F-FDG or 18F-FLT in MHCC97-H tumor and MHCC97-L tumor were different significantly (P<0.05), but for the uptake of 18F-FAC in MHCC97-H and MHCC97-L tumor was not different (P>0.05) In Micro-PET imaging of metastatic models,18F-FDG uptake in MHCC97-H and MHCC97-L was different significantly (P<0.01). Whereas 18F-FLT uptake was not different in the two kinds of tumors (P>0.05). In correlation analysis, MMP9 mRNA level was correlated with 18F-FLT uptake (P<0.05), and with VEGFR-2 (P<0.05), but there was no correlation was found between three tracers uptake and biomarkers (CD44 and VEGFR-2) (P>0.05). There was also a significant correlation between survival time and 18F-FDG uptake (P<0.05), but not with 18F-FLT uptake (P>0.05).Conclusions:1. Establishing classification model based on multi-tracers would be helpful to discriminate HCC with different biological behaviour.2 There were linear correlation between three tracers' uptake and biomarkers expression in vitro and in vivo. It indicated that combining radiomarkers and biomarkers would be a better way to reflect tumor biological behavior 3. Binding 18F-FDG and 18F-FLT Micro-PET was useful for predicting and monitoring of metastasis and prognosis in HCC models.
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