Thermal Ablation Induces Transitory Metastatic Growth by Means of the STAT3/c-Met Molecular Pathway in an Intrahepatic Colorectal Cancer Mouse Model.

ABSTRACT

Background Systemic protumorigenic effects have been noted after radiofrequency ablation (RFA) of normal liver and have been linked to an interleukin 6/signal transducer and activator of transcription 3 (STAT3)/hepatocyte growth factor (HGF)/tyrosine-protein kinase Met (c-Met)/vascular endothelial growth factor (VEGF) cytokinetic pathway. Purpose To elucidate kinetics of RFA protumorigenic effects on intrahepatic metastatic implantation and growth and determine potential molecular targets for pharmacologic suppression of these effects. Materials and Methods An intrahepatic metastasis model was established by implanting CT26 and MC38 tumor cells into 216 7-8-week-old male Balb/C and C57BL6 mice, respectively, by means of splenic injection. Between June 2017 and March 2019, mice underwent tumor injection, followed 24 hours later by either standardized RFA (70°C ± 1, 5 minutes, 1-cm tip) or a sham procedure (needle placement without heating) (12 animals per arm, n = 48). Next, RFA or sham procedures were performed, followed by splenic tumor cell injection at 1 day, 3 days, or 7 days later (six animals per arm, n = 72). Finally, PHA-665752 and S3I-201 were used to block c-Met or STAT3, respectively, prior to either RFA or sham treatment (six animals per arm, n = 96). Livers were harvested at 14 days for CT26 and 21days for MC38 for tumor quantification. Ki-67 and CD34 immunohistochemistry measured proliferative indexes and microvascular density, respectively. Data were compared with analysis of variance and the two-tailed Student t test. Results RFA performed after tumor cell injection induced increased metastatic tumor number (103 ± 45 vs 52 ± 44 [CT26], P = .009 and 87 ± 51 vs 39 ± 20 [MC38], P = .007), cellular proliferation (P < .001 for both), and intratumoral neovascularization (P < .001 for both), compared with the sham procedure. Tumor cell injection performed 1 day and 3 days after RFA also increased these indexes (P < .05), while no difference was demonstrated for cell injection 7 days after RFA (P > .05). Adjuvant c-Met or STAT3 inhibition reduced intrahepatic metastatic parameters after RFA to baseline (P < .03), equivalent to the sham group (P > .05). Conclusion Radiofrequency ablation of normal liver promotes intrahepatic metastatic implantation and increased growth over a short-lived (1-3 days) temporal window in animal models. This phenomenon can be potentially neutralized with specific inhibition of pathways including hepatocyte growth factor/tyrosine-protein kinase Met and signal transducer and activator of transcription 3. © RSNA, 2019 Online supplemental material is available for this article. See also the editorial by Nikolic in this issue.