TY - JOUR
T1 - Accelerated perinecrotic outgrowth of colorectal liver metastases following radiofrequency ablation is a hypoxia-driven phenomenon
AU - Nijkamp, Maarten W.
AU - Van Der Bilt, Jarmila D.W.
AU - De Bruijn, Menno T.
AU - Molenaar, I. Quintus
AU - Voest, Emile E.
AU - van Diest, Paulus Joannes
AU - Kranenburg, Onno
AU - Borel Rinkes, Inne H.M.
PY - 2009/5
Y1 - 2009/5
N2 - 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)-1± and HIF-2±, 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-1± and HIF-2± 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-1± and HIF-2± stabilization and selectively reduced tumor growth in the TZ by 1/440% 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.
AB - 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)-1± and HIF-2±, 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-1± and HIF-2± 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-1± and HIF-2± stabilization and selectively reduced tumor growth in the TZ by 1/440% 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.
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U2 - 10.1097/SLA.0b013e3181a38ef5
DO - 10.1097/SLA.0b013e3181a38ef5
M3 - Article
C2 - 19387320
AN - SCOPUS:67649586929
SN - 0003-4932
VL - 249
SP - 814
EP - 823
JO - Annals of surgery
JF - Annals of surgery
IS - 5
ER -