title: Hepatic Radiofrequency Ablation-induced Stimulation of Distant Tumor Growth Is Suppressed by c-Met Inhibition.
abstract: OBJECTIVE
  To elucidate how hepatic radiofrequency (RF) ablation affects distant extrahepatic tumor growth by means of two key molecular pathways.
  
  
  METHODS
  Rats were used in this institutional animal care and use committee-approved study. First, the effect of hepatic RF ablation on distant subcutaneous in situ R3230 and MATBIII breast tumors was evaluated. Animals were randomly assigned to standardized RF ablation, sham procedure, or no treatment. Tumor growth rate was measured for 3½ to 7 days. Then, tissue was harvested for Ki-67 proliferative indexes and CD34 microvascular density. Second, hepatic RF ablation was performed for hepatocyte growth factor (HGF), vascular endothelial growth factor (VEGF), and c-Met receptor expression measurement in periablational rim, serum, and distant tumor 24 hours to 7 days after ablation. Third, hepatic RF ablation was combined with either a c-Met inhibitor (PHA-665752) or VEGF receptor inhibitor (semaxanib) and compared with sham or drug alone arms to assess distant tumor growth and growth factor levels. Finally, hepatic RF ablation was performed in rats with c-Met-negative R3230 tumors for comparison with the native c-Met-positive line. Tumor size and immunohistochemical quantification at day 0 and at sacrifice were compared with analysis of variance and the two-tailed Student t test. Tumor growth curves before and after treatment were analyzed with linear regression analysis to determine mean slopes of pre- and posttreatment growth curves on a per-tumor basis and were compared with analysis of variance and paired two-tailed t tests.
  
  
  RESULTS
  After RF ablation of normal liver, distant R3230 tumors were substantially larger at 7 days compared with tumors treated with the sham procedure and untreated tumors, with higher growth rates and tumor cell proliferation. Similar findings were observed in MATBIII tumors. Hepatic RF ablation predominantly increased periablational and serum HGF and downstream distant tumor VEGF levels. Compared with RF ablation alone, RF ablation combined with adjuvant PHA-665752 or semaxanib reduced distant tumor growth, proliferation, and microvascular density. For c-Met-negative tumors, hepatic RF ablation did not increase distant tumor growth, proliferation, or microvascular density compared with sham treatment.
  
  
  CONCLUSIONS
  RF ablation of normal liver can stimulate distant subcutaneous tumor growth mediated by HGF/c-Met pathway and VEGF activation. This effect was not observed in c-Met-negative tumors and can be blocked with adjuvant c-Met and VEGF inhibitors.
authors.affiliation: From the Laboratory for Minimally Invasive Tumor Therapies, Department of Radiology, Beth Israel Deaconess Medical Center/Harvard Medical School, 1 Deaconess Rd, WCC 308-B, Boston, MA 02215 (M.A., G.K., M.M., Y.W., S.N.G.); and Goldyne Savad Institute of Gene Therapy (N.R., E.G.) and Division of Image-guided Therapy and Interventional Oncology, Department of Radiology (S.N.G.), Hadassah Hebrew University Hospital, Jerusalem, Israel.
authors.forename: Muneeb
authors.initials: M
authors.lastname: Ahmed
authors.affiliation: From the Laboratory for Minimally Invasive Tumor Therapies, Department of Radiology, Beth Israel Deaconess Medical Center/Harvard Medical School, 1 Deaconess Rd, WCC 308-B, Boston, MA 02215 (M.A., G.K., M.M., Y.W., S.N.G.); and Goldyne Savad Institute of Gene Therapy (N.R., E.G.) and Division of Image-guided Therapy and Interventional Oncology, Department of Radiology (S.N.G.), Hadassah Hebrew University Hospital, Jerusalem, Israel.
authors.forename: Gaurav
authors.initials: G
authors.lastname: Kumar
authors.affiliation: From the Laboratory for Minimally Invasive Tumor Therapies, Department of Radiology, Beth Israel Deaconess Medical Center/Harvard Medical School, 1 Deaconess Rd, WCC 308-B, Boston, MA 02215 (M.A., G.K., M.M., Y.W., S.N.G.); and Goldyne Savad Institute of Gene Therapy (N.R., E.G.) and Division of Image-guided Therapy and Interventional Oncology, Department of Radiology (S.N.G.), Hadassah Hebrew University Hospital, Jerusalem, Israel.
authors.forename: Marwan
authors.initials: M
authors.lastname: Moussa
authors.affiliation: From the Laboratory for Minimally Invasive Tumor Therapies, Department of Radiology, Beth Israel Deaconess Medical Center/Harvard Medical School, 1 Deaconess Rd, WCC 308-B, Boston, MA 02215 (M.A., G.K., M.M., Y.W., S.N.G.); and Goldyne Savad Institute of Gene Therapy (N.R., E.G.) and Division of Image-guided Therapy and Interventional Oncology, Department of Radiology (S.N.G.), Hadassah Hebrew University Hospital, Jerusalem, Israel.
authors.forename: Yuanguo
authors.initials: Y
authors.lastname: Wang
authors.affiliation: From the Laboratory for Minimally Invasive Tumor Therapies, Department of Radiology, Beth Israel Deaconess Medical Center/Harvard Medical School, 1 Deaconess Rd, WCC 308-B, Boston, MA 02215 (M.A., G.K., M.M., Y.W., S.N.G.); and Goldyne Savad Institute of Gene Therapy (N.R., E.G.) and Division of Image-guided Therapy and Interventional Oncology, Department of Radiology (S.N.G.), Hadassah Hebrew University Hospital, Jerusalem, Israel.
authors.forename: Nir
authors.initials: N
authors.lastname: Rozenblum
authors.affiliation: From the Laboratory for Minimally Invasive Tumor Therapies, Department of Radiology, Beth Israel Deaconess Medical Center/Harvard Medical School, 1 Deaconess Rd, WCC 308-B, Boston, MA 02215 (M.A., G.K., M.M., Y.W., S.N.G.); and Goldyne Savad Institute of Gene Therapy (N.R., E.G.) and Division of Image-guided Therapy and Interventional Oncology, Department of Radiology (S.N.G.), Hadassah Hebrew University Hospital, Jerusalem, Israel.
authors.forename: Eithan
authors.initials: E
authors.lastname: Galun
authors.affiliation: From the Laboratory for Minimally Invasive Tumor Therapies, Department of Radiology, Beth Israel Deaconess Medical Center/Harvard Medical School, 1 Deaconess Rd, WCC 308-B, Boston, MA 02215 (M.A., G.K., M.M., Y.W., S.N.G.); and Goldyne Savad Institute of Gene Therapy (N.R., E.G.) and Division of Image-guided Therapy and Interventional Oncology, Department of Radiology (S.N.G.), Hadassah Hebrew University Hospital, Jerusalem, Israel.
authors.forename: S Nahum
authors.initials: SN
authors.lastname: Goldberg
mesh_terms: D000230:Adenocarcinoma / Q000378:metabolism* / Q000473:pathology; D000818:Animals; D017115:Catheter Ablation; D005260:Female; D017228:Hepatocyte Growth Factor / Q000378:metabolism; D007150:Immunohistochemistry; D007211:Indoles / Q000494:pharmacology*; D008099:Liver / Q000601:surgery*; D008325:Mammary Neoplasms, Experimental / Q000378:metabolism* / Q000473:pathology; D011846:Radio Waves; D051381:Rats; D011916:Rats, Inbred F344; D013450:Sulfones / Q000494:pharmacology*; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
chemical_list: C480541:5-((2,6-dichlorobenzyl)sulfonyl)-3-((3,5-dimethyl-4-((2-(pyrrolidin-1-ylmethyl)pyrrolidin-1-yl)carbonyl)-1H-pyrrol-2-yl)methylene)-1,3-dihydro-2H-indol-2-one; D007211:Indoles; D013450:Sulfones; D042461:Vascular Endothelial Growth Factor A; D017228:Hepatocyte Growth Factor