Accelerated Perinecrotic Outgrowth of Colorectal Liver Metastases Following Radiofrequency Ablation is a Hypoxia-Driven Phenomenon

In Brief Objective: The aim of this study was to assess how thermal ablation of colorectal liver metastases affects the outgrowth of micrometastases in the transition zone (TZ) between ablated tissue and the unaffected reference zone (RZ) in 2 different murine models. Background: Thermal destruction therapies of nonresectable colorectal liver metastases, including radiofrequency ablation (RFA), can provide tumor clearance, but local recurrences are common. Methods: Three days after intrasplenic injection of C26 colon carcinoma cells, RFA was applied to the left liver lobe. Perinecrotic microcirculation, tissue hypoxia, hypoxia inducible factor (HIF)-1α and HIF-2α, and the outgrowth of micrometastases both in the TZ and in the RZ were evaluated over time. Results: In 2 different animal models, the outgrowth of micrometastases in the TZ following RFA was stimulated approximately 4-fold compared to tumor growth in the RZ. Accelerated tumor growth in the TZ was associated with microcirculatory disturbances, prolonged hypoxia, and stabilization of HIF-1α and HIF-2α in the tumor cells. In addition, RFA induced the formation of new hepatic vessels that sprouted from existing sinusoids and grew into the generated necrotic lesion. Surprisingly, the accelerated tumor growth was not associated with these vessels. Treatment with 17DMAG prevented HIF-1α and HIF-2α stabilization and selectively reduced tumor growth in the TZ by ∼40% without affecting tumor growth in sham-operated mice or in the RZ of RFA-treated mice. PTK787/ZK-222584, a nonselective Vascular Endothelial Growth Factor (VEGF)-receptor inhibitor, reduced RFA-stimulated tumor growth and tumor growth in the RZ to a similar extent. Conclusions: We conclude that RFA stimulates the outgrowth of tumor cells at the lesion periphery. Angiogenesis is not the driving force behind RFA-stimulated tumor growth, but other hypoxia/HIF-activated pathways are likely to be important. Radiofrequency ablation in the liver accelerates the outgrowth of microscopic tumor cell deposits immediately adjacent to the generated necrotic lesion. Prolonged tissue hypoxia contributes to the altered behavior of these micrometastases, possibly through stabilization of hypoxia inducible factor-1α and hypoxia inducible factor-2α. However, accelerated tumor growth is not associated with stimulation of tissue angiogenesis.