Hepatic radiofrequency ablation-induced stimulation of distant tumor growth is suppressed by c-Met inhibition

Purpose: To elucidate how hepatic radiofrequency (RF) ablation affects distant extrahepatic tumor growth by means of two key molecular pathways. Materials and Methods: Rats were used in this institutional animal care and use committee-approved study. First, the effect of hepatic RF ablation on distant subcutaneous in situ R3230 and MATBIII breast tumors was evaluated. Animals were randomly assigned to standardized RF ablation, sham procedure, or no treatment. Tumor growth rate was measured for 3 1/2 to 7 days. Then, tissue was harvested for Ki-67 proliferative indexes and CD34 microvascular density. Second, hepatic RF ablation was performed for hepatocyte growth factor (HGF), vascular endothelial growth factor (VEGF), and c-Met receptor expression measurement in periablational rim, serum, and distant tumor 24 hours to 7 days after ablation. Third, hepatic RF ablation was combined with either a c-Met inhibitor (PHA-665752) or VEGF receptor inhibitor (semaxanib) and compared with sham or drug alone arms to assess distant tumor growth and growth factor levels. Finally, hepatic RF ablation was performed in rats with c-Met-negative R3230 tumors for comparison with the native c-Met-positive line. Tumor size and immunohistochemical quantification at day 0 and at sacrifice were compared with analysis of variance and the two-tailed Student t test. Tumor growth curves before and after treatment were analyzed with linear regression analysis to determine mean slopes of pre- and posttreatment growth curves on a per-tumor basis and were compared with analysis of variance and paired two-tailed t tests. Results: After RF ablation of normal liver, distant R3230 tumors were substantially larger at 7 days compared with tumors treated with the sham procedure and untreated tumors, with higher growth rates and tumor cell proliferation. Similar findings were observed in MATBIII tumors. Hepatic RF ablation predominantly increased periablational and serum HGF and downstream distant tumor VEGF levels. Compared with RF ablation alone, RF ablation combined with adjuvant PHA-665752 or semaxanib reduced distant tumor growth, proliferation, and microvascular density. For c-Met-negative tumors, hepatic RF ablation did not increase distant tumor growth, proliferation, or microvascular density compared with sham treatment. Conclusion: RF ablation of normal liver can stimulate distant subcutaneous tumor growth mediated by HGF/c-Met pathway and VEGF activation. This effect was not observed in c-Met- negative tumors and can be blocked with adjuvant c-Met and VEGF inhibitors.