Evaluation of [18F]FDG/[18F]FLT/[18F]FMISO-based micro-positron emission tomography in detection of liver metastasis in human colorectal cancer

Abstract

Introduction: Positron emission tomography (PET) is extensively used in clinical oncology for tumor detection. This study aimed to explore the application of the radiotracers [¹⁸F]fluorodeoxyglucose ([¹⁸F]FDG), 3'-deoxy-3'- [¹⁸F]fluorothymidine ([¹⁸F]FLT), and [¹⁸F]fluoromisonidazole ([¹⁸F]FMISO) in the diagnosis and monitoring of hepatic metastasis in human colorectal cancer (CRC).

Methods: A mouse model of human CRC with hepatic metastasis was established by intrasplenic implantation of human CRC cell lines LoVo or HCT8. Metastatic potential of these two cell lines was evaluated by wound healing assay in vitro and survival analysis. Uptake of radiotracers between LoVo and HCT8 cells and uptake of radiotracers in the resulting mouse tumor models were examined by in vivo and in vitro experiments. Uptake of each radiotracer in hepatic metastatic lesions was quantified and expressed as standard uptake value (SUV). Protein expression of multiple tumor biomarkers was determined in metastatic lesions. The correlation between tracer uptake and tumor marker expression was evaluated using linear regression.

Results: LoVo cells exhibited a stronger metastatic potential and a higher radiotracer uptake ability than HCT8 cells, as evidenced by significantly greater wound closure percentage, shorter survival, higher incidence of liver metastases, and higher cellular radiotracer levels in LoVo cells or LoVo cell-xenografted mice. SUV values of [¹⁸F]FLT and [¹⁸F]FMISO, but not [¹⁸F]FDG, in LoVo cell-derived metastatic lesions were significantly greater than those in HCT8 lesions. Mechanistically, the expression of MACC1, HIF-1α, and GLUT-1(metastasis associated in colon cancer 1, MACC1; hypoxia-inducible factor 1-alpha, HIF-1α; and glucose transporter 1, GLUT-1, respectively) in LoVo cell-derived metastatic lesions was more effectively induced than in HCT8-derived ones. A linear regression analysis demonstrated significant positive correlations between [¹⁸F]FLT/[¹⁸F]FMISO uptake and tumor biomarker expression in metastatic tissues.

Conclusions: [¹⁸F]FLT and [¹⁸F]FMISO-based PET imaging may serve as a promising method for early detection and monitoring of hepatic metastasis in patients with CRC.

Keywords: 3′-deoxy-3′- [(18)F]fluorothymidine ([(18)F]FLT); Human colorectal cancer with liver metastasis; Positron emission tomography; [(18)F]fluorodeoxyglucose ([(18)F]FDG); [(18)F]fluoromisonidazole ([(18)F]FMISO).