Metastasis and angiogenesis: preclinical PET study on hepatocellular carcinoma (He/De) tumor models

The use of animal models to study tumorigenesis and metastatic spread seems crucial to discover novel diagnostic and therapeutic targets that inhibit tumor development and progression. In this study a preclinical metastasis model of hepatocellular carcinoma (He/De) was established to explore metastases formation and related angiogenic processes using positron emission tomography (PET) and angiogenesis specific radiopharmaceuticals. Approximately 8 ± 1 days after the subrenal capsule assay-based generation of the primary, secondary and tertiary transplanted metastatic He/De tumors in Fischer-344 rats, we used [¹⁸F]FDG, [⁶⁸Ga]Ga-NOTA-c(NGR) and [⁶⁸Ga]Ga-NODAGA-[c(RGD)]₂ for the in vivo PET imaging of tumor development and angiogenesis. [¹⁸F]FDG displayed the highest level of radioactivity among all investigated tracers. This pattern was consistent across all neoplastic lesions in each of the three transplantations. Comparing the two ⁶⁸Ga-labelled probes, the NGR compound showed significantly higher accumulation in the subrenally growing primary/secondary/tertiary He/De tumors (p ≤ 0.05) and related parathymic lymph node metastases (PTLNs, p ≤ 0.01) that could indicate higher expression level for aminopeptidase N/CD13 than for RGD-binding α_vβ₃ integrin. Progressive increase in the [¹⁸F]FDG, [⁶⁸Ga]Ga-NOTA-c(NGR) and [⁶⁸Ga]Ga-NODAGA-[c(RGD)]₂ uptakes of both the subrenally growing He/De tumors and the PTLNs during the serial transplantations may imply increasing aggressivity. Overall, the currently developed experimental system provides a feasible platform for further investigation of metastatic spread.