title: Accelerated perinecrotic outgrowth of colorectal liver metastases following radiofrequency ablation is a hypoxia-driven phenomenon.
abstract: 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)-1alpha and HIF-2alpha, 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-1alpha and HIF-2alpha 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-1alpha and HIF-2alpha stabilization and selectively reduced tumor growth in the TZ by approximately 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.
authors.affiliation: Department of Surgery, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: Maarten W
authors.initials: MW
authors.lastname: Nijkamp
authors.forename: Jarmila D W
authors.initials: JD
authors.lastname: van der Bilt
authors.forename: Menno T
authors.initials: MT
authors.lastname: de Bruijn
authors.forename: I Quintus
authors.initials: IQ
authors.lastname: Molenaar
authors.forename: Emile E
authors.initials: EE
authors.lastname: Voest
authors.forename: Paul J
authors.initials: PJ
authors.lastname: van Diest
authors.forename: Onno
authors.initials: O
authors.lastname: Kranenburg
authors.forename: Inne H M
authors.initials: IH
authors.lastname: Borel Rinkes
mesh_terms: D000818:Animals; D017115:Catheter Ablation / Q000009:adverse effects*; D045744:Cell Line, Tumor; D015179:Colorectal Neoplasms / Q000473:pathology / Q000503:physiopathology*; D004195:Disease Models, Animal; D000860:Hypoxia / Q000503:physiopathology*; D008099:Liver / Q000473:pathology* / Q000503:physiopathology; D008113:Liver Neoplasms / Q000503:physiopathology* / Q000556:secondary; D008297:Male; D051379:Mice; D009336:Necrosis; D009364:Neoplasm Recurrence, Local / Q000209:etiology* / Q000503:physiopathology; D051381:Rats