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Liao, Haixing; Ahmed, Muneeb; Markezana, Aurelia; Zeng, Guohua; Stechele, Matthias; Galun, Eithan; Goldberg, S. Nahum (2020): Thermal Ablation Induces Transitory Metastatic Growth by Means of the STAT3 / c-Met Molecular Pathway in an Intrahepatic Colorectal Cancer Mouse Model. In: Radiology, Vol. 294, No. 2: pp. 464-472
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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-proteinkinase 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 2167-8-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 degrees 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 21 days 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. (C) RSNA, 2019