title: Oncogenesis: An "Off-Target" Effect of Radiofrequency Ablation.
abstract: OBJECTIVE
  To compare hepatocellular carcinoma (HCC) development after radiofrequency (RF) ablation, partial surgical hepatectomy, and a sham operation and to inhibit HCC recurrence after RF ablation in a mouse model of spontaneously forming HCC in the setting of chronic inflammation (ie, the MDR2 knockout model).
  
  
  METHODS
  Animal experiments were performed according to an approved animal care committee protocol. The authors compared the survival of MDR2 knockout mice (an inflammation-induced HCC model) that underwent RF ablation, 35% partial hepatectomy (ie, left lobectomy), or a sham operation (controls) by using Kaplan-Meier survival curve analysis. Tumor load and tumor frequency in mice that underwent sham operation were further compared with those of mice treated with RF ablation at 1 month after therapy by using a two-tailed Student t test. Liver slices from mice treated with RF ablation were stained for α-smooth muscle actin and Ki-67 to establish the role of liver regeneration in the tumorigenic effect of RF ablation. Finally, tumor load and tumor incidence were evaluated in mice treated with a c-met inhibitor after RF ablation by using the Mann-Whitney U test.
  
  
  RESULTS
  Ablation of 3.5% ± 0.02 of the MDR2 knockout mice liver induced increased tumor load (P = .007) and reduced survival (P = .03) in comparison to that of controls, with no significant difference to the 10-fold volume removal of partial hepatectomy. Seven days after RF treatment, the border zone of the coagulation zone was surrounded by α-smooth muscle actin-positive activated myofibroblasts. A significant elevation of hepatocyte proliferation was also seen 7 days after RF ablation in the distant liver (ablated lobe: P = .003; untreated lobe: P = .02). A c-met inhibitor significantly attenuated HCC development in MDR2 knockout mice treated with RF ablation (P = .001).
  
  
  CONCLUSIONS
  Liver regeneration induced by RF ablation facilitates c-met/hepatocyte growth factor axis-dependent HCC tumor formation after treatment in the MDR2 knockout model. Blockage of the c-met/hepatocyte growth factor axis attenuates HCC recurrence, raising the potential for therapeutic intervention to reverse this potentially deleterious tumorigenic effect.
authors.affiliation: From the Goldyne Saved Institute for Gene Therapy (N.R., E.Z., B.B., S.G., H.Y., E.G., S.N.G.) and Department of Radiology (S.N.G.), Hadassah Hebrew University Medical Center, Jerusalem 91120, Israel; Institute for Drug Research, School of Pharmacy, Faculty of Medicine, The Hebrew University of Jerusalem, Jerusalem, Israel (V.S.); and Laboratory for Minimally Invasive Tumor Therapies, Department of Radiology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Mass (S.N.G.).
authors.forename: Nir
authors.initials: N
authors.lastname: Rozenblum
authors.affiliation: From the Goldyne Saved Institute for Gene Therapy (N.R., E.Z., B.B., S.G., H.Y., E.G., S.N.G.) and Department of Radiology (S.N.G.), Hadassah Hebrew University Medical Center, Jerusalem 91120, Israel; Institute for Drug Research, School of Pharmacy, Faculty of Medicine, The Hebrew University of Jerusalem, Jerusalem, Israel (V.S.); and Laboratory for Minimally Invasive Tumor Therapies, Department of Radiology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Mass (S.N.G.).
authors.forename: Evelyne
authors.initials: E
authors.lastname: Zeira
authors.affiliation: From the Goldyne Saved Institute for Gene Therapy (N.R., E.Z., B.B., S.G., H.Y., E.G., S.N.G.) and Department of Radiology (S.N.G.), Hadassah Hebrew University Medical Center, Jerusalem 91120, Israel; Institute for Drug Research, School of Pharmacy, Faculty of Medicine, The Hebrew University of Jerusalem, Jerusalem, Israel (V.S.); and Laboratory for Minimally Invasive Tumor Therapies, Department of Radiology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Mass (S.N.G.).
authors.forename: Viviana
authors.initials: V
authors.lastname: Scaiewicz
authors.affiliation: From the Goldyne Saved Institute for Gene Therapy (N.R., E.Z., B.B., S.G., H.Y., E.G., S.N.G.) and Department of Radiology (S.N.G.), Hadassah Hebrew University Medical Center, Jerusalem 91120, Israel; Institute for Drug Research, School of Pharmacy, Faculty of Medicine, The Hebrew University of Jerusalem, Jerusalem, Israel (V.S.); and Laboratory for Minimally Invasive Tumor Therapies, Department of Radiology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Mass (S.N.G.).
authors.forename: Baruch
authors.initials: B
authors.lastname: Bulvik
authors.affiliation: From the Goldyne Saved Institute for Gene Therapy (N.R., E.Z., B.B., S.G., H.Y., E.G., S.N.G.) and Department of Radiology (S.N.G.), Hadassah Hebrew University Medical Center, Jerusalem 91120, Israel; Institute for Drug Research, School of Pharmacy, Faculty of Medicine, The Hebrew University of Jerusalem, Jerusalem, Israel (V.S.); and Laboratory for Minimally Invasive Tumor Therapies, Department of Radiology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Mass (S.N.G.).
authors.forename: Svetlana
authors.initials: S
authors.lastname: Gourevitch
authors.affiliation: From the Goldyne Saved Institute for Gene Therapy (N.R., E.Z., B.B., S.G., H.Y., E.G., S.N.G.) and Department of Radiology (S.N.G.), Hadassah Hebrew University Medical Center, Jerusalem 91120, Israel; Institute for Drug Research, School of Pharmacy, Faculty of Medicine, The Hebrew University of Jerusalem, Jerusalem, Israel (V.S.); and Laboratory for Minimally Invasive Tumor Therapies, Department of Radiology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Mass (S.N.G.).
authors.forename: Hagit
authors.initials: H
authors.lastname: Yotvat
authors.affiliation: From the Goldyne Saved Institute for Gene Therapy (N.R., E.Z., B.B., S.G., H.Y., E.G., S.N.G.) and Department of Radiology (S.N.G.), Hadassah Hebrew University Medical Center, Jerusalem 91120, Israel; Institute for Drug Research, School of Pharmacy, Faculty of Medicine, The Hebrew University of Jerusalem, Jerusalem, Israel (V.S.); and Laboratory for Minimally Invasive Tumor Therapies, Department of Radiology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Mass (S.N.G.).
authors.forename: Eithan
authors.initials: E
authors.lastname: Galun
authors.affiliation: From the Goldyne Saved Institute for Gene Therapy (N.R., E.Z., B.B., S.G., H.Y., E.G., S.N.G.) and Department of Radiology (S.N.G.), Hadassah Hebrew University Medical Center, Jerusalem 91120, Israel; Institute for Drug Research, School of Pharmacy, Faculty of Medicine, The Hebrew University of Jerusalem, Jerusalem, Israel (V.S.); and Laboratory for Minimally Invasive Tumor Therapies, Department of Radiology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Mass (S.N.G.).
authors.forename: S Nahum
authors.initials: SN
authors.lastname: Goldberg
mesh_terms: D055011:Ablation Techniques / Q000009:adverse effects*; D000818:Animals; D063646:Carcinogenesis; D006528:Carcinoma, Hepatocellular / Q000209:etiology* / Q000601:surgery*; D004598:Electrosurgery / Q000009:adverse effects*; D006498:Hepatectomy / Q000379:methods*; D008113:Liver Neoplasms / Q000209:etiology* / Q000601:surgery*; D051379:Mice; D009364:Neoplasm Recurrence, Local / Q000517:prevention & control