Highly malignant intra-hepatic metastatic hepatocellular carcinoma in rats

Intra-hepatic metastasis is one of the major modalities that lead to the recurrence of advanced HCC. Research efforts to investigate HCC metastasis/recurrence and therapy response will require appropriate models. For our study, the main purpose was to compare two different rodent syngenic orthotopic HCC models using MRI and pathologic evidence; we specifically sought to investigate the intra-hepatic metastatic properties of HCC in Buffalo rats. Methods: 12 female Buffalo rats and 16 male Sprague Dawley (SD) rats were used in these studies. Subcapsular implantation of 1×106 McA-RH7777 and 1×106 N1-S1 rat hepatoma cells into the left hepatic lobe was carried out in Buffalo and SD rats, respectively. Buffalo hepatoma rats (n=5/6) and SD hepatoma rats (n=6/8) were imaged using MRI at 6-8 days after implantation. Then, another group of Buffalo HCC rats (n=6/6) and SD HCC (n=6/8) rats were scanned at 21-25 days interval post-implantation. After image acquisition, tumor sections were evaluated with H&E and CD34 staining. Results: Tumor induction rate for Buffalo rats was 92% (11/12) compared to 75% (12/16) for SD rats. The mean tumor size of McA-RH7777 hepatoma rats at 6-8 day interval was 1.32±0.56cm, but progressed to multiple intra-hepatic metastasis at 21-25 day interval in 6/6 rats (100%). In contrast, the mean tumor size of N1-S1 rats at early interval was 1.06±0.32cm, these progressed to only a single solid mass of 2.35±0.69cm at later interval without obvious intra-hepatic metastasis. H&E staining showed that McA-RH7777 cell induced Morris hepatoma exhibited typical trabecular growth pattern, better representative of human HCC compared to the sheet pattern of N1-S1 cell induced Novikoff hepatoma. Conclusion: The McA-Rh7777 rat hepatoma model was demonstrated to be a highly malignant intra-hepatic metastasis model of potential utility for HCC research.