Gesteigerte Aktivierung der Matrix-Metalloproteinasen 2 und 9 nach Kryotherapie und Radiofrequenzablation von kolorektalen Lebermetastasen

Abstract

Background: Cryosurgery (CRYO) and radiofrequency ablation (RFA), which represent established local ablative techniques, are associated with a high rate of local and intrahepatic tumor recurrence. Furthermore, matrix metalloproteinases (MMPs) have been reported to play an important role in tumor cell invasion and metastasis. Therefore, we studied in a standardized rat model the time-dependent effect of CRYO and RFA on the bioactivity of MMP 2 and 9 in colorectal liver metastases. Methods: According to an established liver metastasis model, CC531 colon cancer cells were implanted in the left liver lobe of syngeneic Wag-Rij rats. After 14 days, animals were randomized to CRYO or RFA ablation of the metastatic lesion. Sham-treated tumors served as controls. Hepatic lesions were analyzed after 1h, 3h and 6h using histology and immunohistochemistry. Latent and active forms of MMP 2 and 9 were measured in tissue extracts by means of quantitative gelatin zymography. Means ± SEM; ANOVA and post-hoc test; p < 0.05. Results: MMP 2 and 9 activities were higher in the center of the metastases compared to the border and normal liver tissue. Compared to controls, only at 6h after CRYO, MMP 2 and 9 activities were significantly increased at the border of the lesions and the neighboring liver tissue, whereas no changes could be observed in the center of the lesions. After RFA, MMP 2 was only significantly increased after 1h at the border of the lesion without any changes in the normal liver tissue and a significant decrease of the MMP 2 and 9 activities at the center of the ablation compared to controls. Comparing the ablation techniques, at the border of the lesion and the neighboring liver tissue activity of MMP2 was significantly higher 1h after RFA whereas the activities of MMP 2 and 9 were significantly increased 6h after CRYO. Conclusion: The present study shows for the first time, that CRYO and RFA activates MMP 2 and 9 at an early time point after ablation of colorectal liver metastases. The MMP-activity at the border of the lesions could represent a potential mechanism for local tumor recurrence after hepatic ablation.