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Human and mouse VEGFA-amplified hepatocellular carcinomas are highly sensitive to sorafenib treatment.

  • Horwitz E Authors' Affiliations:The Lautenberg Center for Immunology; Department of Developmental Biology and Cancer Research, IMRIC, Hadassah Medical School, Hebrew University;Department of Pathology, Hadassah-Hebrew University Medical Center, Jerusalem; Liver Unit, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel; Institute of Pathology, University Hospital Basel, Basel, Switzerland; Division of Signal Transduction and Growth Control (A100), Division of Molecular Genetics (B060), and Junior Group Molecular Mechanisms of Head and Neck Tumors (A102), German Cancer Research Center (DKFZ), DKFZ-ZMBH Alliance; Institute of Pathology, University Hospital Heidelberg; Departments of Otolaryngology, Head and Neck Surgery and Internal Medicine, University Hospital Heidelberg, Heidelberg; and Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany.
  • Stein I Authors' Affiliations:The Lautenberg Center for Immunology; Department of Developmental Biology and Cancer Research, IMRIC, Hadassah Medical School, Hebrew University;Department of Pathology, Hadassah-Hebrew University Medical Center, Jerusalem; Liver Unit, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel; Institute of Pathology, University Hospital Basel, Basel, Switzerland; Division of Signal Transduction and Growth Control (A100), Division of Molecular Genetics (B060), and Junior Group Molecular Mechanisms of Head and Neck Tumors (A102), German Cancer Research Center (DKFZ), DKFZ-ZMBH Alliance; Institute of Pathology, University Hospital Heidelberg; Departments of Otolaryngology, Head and Neck Surgery and Internal Medicine, University Hospital Heidelberg, Heidelberg; and Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, GermanyAuthors' Affiliations:The Lautenberg Center for Immunology; Department of Developmental Biology and Cancer Research, IMRIC, Hadassah Medical School, Hebrew University;Department of Pathology, Hadassah-Hebrew University Medical Center, Jerusalem; Liver Unit, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel; Institute of Pathology, University Hospital Basel, Basel, Switzerland; Division of Signal Transduction and Growth Control (A100), Division of Molecular Genetics (B060), and Junior Group Molecular Mechanisms of Head and Neck Tumors (A102), German Cancer Research Center (DKFZ), DKFZ-ZMBH Alliance; Institute of Pathology, University Hospital Heidelberg; Departments of Otolaryngology, Head and Neck Surgery and Internal Medicine, University Hospital Heidelberg, Heidelberg; and Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany.
  • Andreozzi M Authors' Affiliations:The Lautenberg Center for Immunology; Department of Developmental Biology and Cancer Research, IMRIC, Hadassah Medical School, Hebrew University;Department of Pathology, Hadassah-Hebrew University Medical Center, Jerusalem; Liver Unit, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel; Institute of Pathology, University Hospital Basel, Basel, Switzerland; Division of Signal Transduction and Growth Control (A100), Division of Molecular Genetics (B060), and Junior Group Molecular Mechanisms of Head and Neck Tumors (A102), German Cancer Research Center (DKFZ), DKFZ-ZMBH Alliance; Institute of Pathology, University Hospital Heidelberg; Departments of Otolaryngology, Head and Neck Surgery and Internal Medicine, University Hospital Heidelberg, Heidelberg; and Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany.
  • Nemeth J Authors' Affiliations:The Lautenberg Center for Immunology; Department of Developmental Biology and Cancer Research, IMRIC, Hadassah Medical School, Hebrew University;Department of Pathology, Hadassah-Hebrew University Medical Center, Jerusalem; Liver Unit, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel; Institute of Pathology, University Hospital Basel, Basel, Switzerland; Division of Signal Transduction and Growth Control (A100), Division of Molecular Genetics (B060), and Junior Group Molecular Mechanisms of Head and Neck Tumors (A102), German Cancer Research Center (DKFZ), DKFZ-ZMBH Alliance; Institute of Pathology, University Hospital Heidelberg; Departments of Otolaryngology, Head and Neck Surgery and Internal Medicine, University Hospital Heidelberg, Heidelberg; and Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany.
  • Shoham A Authors' Affiliations:The Lautenberg Center for Immunology; Department of Developmental Biology and Cancer Research, IMRIC, Hadassah Medical School, Hebrew University;Department of Pathology, Hadassah-Hebrew University Medical Center, Jerusalem; Liver Unit, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel; Institute of Pathology, University Hospital Basel, Basel, Switzerland; Division of Signal Transduction and Growth Control (A100), Division of Molecular Genetics (B060), and Junior Group Molecular Mechanisms of Head and Neck Tumors (A102), German Cancer Research Center (DKFZ), DKFZ-ZMBH Alliance; Institute of Pathology, University Hospital Heidelberg; Departments of Otolaryngology, Head and Neck Surgery and Internal Medicine, University Hospital Heidelberg, Heidelberg; and Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany.
  • Pappo O Authors' Affiliations:The Lautenberg Center for Immunology; Department of Developmental Biology and Cancer Research, IMRIC, Hadassah Medical School, Hebrew University;Department of Pathology, Hadassah-Hebrew University Medical Center, Jerusalem; Liver Unit, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel; Institute of Pathology, University Hospital Basel, Basel, Switzerland; Division of Signal Transduction and Growth Control (A100), Division of Molecular Genetics (B060), and Junior Group Molecular Mechanisms of Head and Neck Tumors (A102), German Cancer Research Center (DKFZ), DKFZ-ZMBH Alliance; Institute of Pathology, University Hospital Heidelberg; Departments of Otolaryngology, Head and Neck Surgery and Internal Medicine, University Hospital Heidelberg, Heidelberg; and Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany.
  • Schweitzer N Authors' Affiliations:The Lautenberg Center for Immunology; Department of Developmental Biology and Cancer Research, IMRIC, Hadassah Medical School, Hebrew University;Department of Pathology, Hadassah-Hebrew University Medical Center, Jerusalem; Liver Unit, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel; Institute of Pathology, University Hospital Basel, Basel, Switzerland; Division of Signal Transduction and Growth Control (A100), Division of Molecular Genetics (B060), and Junior Group Molecular Mechanisms of Head and Neck Tumors (A102), German Cancer Research Center (DKFZ), DKFZ-ZMBH Alliance; Institute of Pathology, University Hospital Heidelberg; Departments of Otolaryngology, Head and Neck Surgery and Internal Medicine, University Hospital Heidelberg, Heidelberg; and Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany.
  • Tornillo L Authors' Affiliations:The Lautenberg Center for Immunology; Department of Developmental Biology and Cancer Research, IMRIC, Hadassah Medical School, Hebrew University;Department of Pathology, Hadassah-Hebrew University Medical Center, Jerusalem; Liver Unit, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel; Institute of Pathology, University Hospital Basel, Basel, Switzerland; Division of Signal Transduction and Growth Control (A100), Division of Molecular Genetics (B060), and Junior Group Molecular Mechanisms of Head and Neck Tumors (A102), German Cancer Research Center (DKFZ), DKFZ-ZMBH Alliance; Institute of Pathology, University Hospital Heidelberg; Departments of Otolaryngology, Head and Neck Surgery and Internal Medicine, University Hospital Heidelberg, Heidelberg; and Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany.
  • Kanarek N Authors' Affiliations:The Lautenberg Center for Immunology; Department of Developmental Biology and Cancer Research, IMRIC, Hadassah Medical School, Hebrew University;Department of Pathology, Hadassah-Hebrew University Medical Center, Jerusalem; Liver Unit, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel; Institute of Pathology, University Hospital Basel, Basel, Switzerland; Division of Signal Transduction and Growth Control (A100), Division of Molecular Genetics (B060), and Junior Group Molecular Mechanisms of Head and Neck Tumors (A102), German Cancer Research Center (DKFZ), DKFZ-ZMBH Alliance; Institute of Pathology, University Hospital Heidelberg; Departments of Otolaryngology, Head and Neck Surgery and Internal Medicine, University Hospital Heidelberg, Heidelberg; and Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany.
  • Quagliata L Authors' Affiliations:The Lautenberg Center for Immunology; Department of Developmental Biology and Cancer Research, IMRIC, Hadassah Medical School, Hebrew University;Department of Pathology, Hadassah-Hebrew University Medical Center, Jerusalem; Liver Unit, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel; Institute of Pathology, University Hospital Basel, Basel, Switzerland; Division of Signal Transduction and Growth Control (A100), Division of Molecular Genetics (B060), and Junior Group Molecular Mechanisms of Head and Neck Tumors (A102), German Cancer Research Center (DKFZ), DKFZ-ZMBH Alliance; Institute of Pathology, University Hospital Heidelberg; Departments of Otolaryngology, Head and Neck Surgery and Internal Medicine, University Hospital Heidelberg, Heidelberg; and Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany.
  • Zreik F Authors' Affiliations:The Lautenberg Center for Immunology; Department of Developmental Biology and Cancer Research, IMRIC, Hadassah Medical School, Hebrew University;Department of Pathology, Hadassah-Hebrew University Medical Center, Jerusalem; Liver Unit, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel; Institute of Pathology, University Hospital Basel, Basel, Switzerland; Division of Signal Transduction and Growth Control (A100), Division of Molecular Genetics (B060), and Junior Group Molecular Mechanisms of Head and Neck Tumors (A102), German Cancer Research Center (DKFZ), DKFZ-ZMBH Alliance; Institute of Pathology, University Hospital Heidelberg; Departments of Otolaryngology, Head and Neck Surgery and Internal Medicine, University Hospital Heidelberg, Heidelberg; and Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany.
  • Porat RM Authors' Affiliations:The Lautenberg Center for Immunology; Department of Developmental Biology and Cancer Research, IMRIC, Hadassah Medical School, Hebrew University;Department of Pathology, Hadassah-Hebrew University Medical Center, Jerusalem; Liver Unit, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel; Institute of Pathology, University Hospital Basel, Basel, Switzerland; Division of Signal Transduction and Growth Control (A100), Division of Molecular Genetics (B060), and Junior Group Molecular Mechanisms of Head and Neck Tumors (A102), German Cancer Research Center (DKFZ), DKFZ-ZMBH Alliance; Institute of Pathology, University Hospital Heidelberg; Departments of Otolaryngology, Head and Neck Surgery and Internal Medicine, University Hospital Heidelberg, Heidelberg; and Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany.
  • Finkelstein R Authors' Affiliations:The Lautenberg Center for Immunology; Department of Developmental Biology and Cancer Research, IMRIC, Hadassah Medical School, Hebrew University;Department of Pathology, Hadassah-Hebrew University Medical Center, Jerusalem; Liver Unit, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel; Institute of Pathology, University Hospital Basel, Basel, Switzerland; Division of Signal Transduction and Growth Control (A100), Division of Molecular Genetics (B060), and Junior Group Molecular Mechanisms of Head and Neck Tumors (A102), German Cancer Research Center (DKFZ), DKFZ-ZMBH Alliance; Institute of Pathology, University Hospital Heidelberg; Departments of Otolaryngology, Head and Neck Surgery and Internal Medicine, University Hospital Heidelberg, Heidelberg; and Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany.
  • Reuter H Authors' Affiliations:The Lautenberg Center for Immunology; Department of Developmental Biology and Cancer Research, IMRIC, Hadassah Medical School, Hebrew University;Department of Pathology, Hadassah-Hebrew University Medical Center, Jerusalem; Liver Unit, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel; Institute of Pathology, University Hospital Basel, Basel, Switzerland; Division of Signal Transduction and Growth Control (A100), Division of Molecular Genetics (B060), and Junior Group Molecular Mechanisms of Head and Neck Tumors (A102), German Cancer Research Center (DKFZ), DKFZ-ZMBH Alliance; Institute of Pathology, University Hospital Heidelberg; Departments of Otolaryngology, Head and Neck Surgery and Internal Medicine, University Hospital Heidelberg, Heidelberg; and Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany.
  • Koschny R Authors' Affiliations:The Lautenberg Center for Immunology; Department of Developmental Biology and Cancer Research, IMRIC, Hadassah Medical School, Hebrew University;Department of Pathology, Hadassah-Hebrew University Medical Center, Jerusalem; Liver Unit, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel; Institute of Pathology, University Hospital Basel, Basel, Switzerland; Division of Signal Transduction and Growth Control (A100), Division of Molecular Genetics (B060), and Junior Group Molecular Mechanisms of Head and Neck Tumors (A102), German Cancer Research Center (DKFZ), DKFZ-ZMBH Alliance; Institute of Pathology, University Hospital Heidelberg; Departments of Otolaryngology, Head and Neck Surgery and Internal Medicine, University Hospital Heidelberg, Heidelberg; and Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany.
  • Ganten T Authors' Affiliations:The Lautenberg Center for Immunology; Department of Developmental Biology and Cancer Research, IMRIC, Hadassah Medical School, Hebrew University;Department of Pathology, Hadassah-Hebrew University Medical Center, Jerusalem; Liver Unit, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel; Institute of Pathology, University Hospital Basel, Basel, Switzerland; Division of Signal Transduction and Growth Control (A100), Division of Molecular Genetics (B060), and Junior Group Molecular Mechanisms of Head and Neck Tumors (A102), German Cancer Research Center (DKFZ), DKFZ-ZMBH Alliance; Institute of Pathology, University Hospital Heidelberg; Departments of Otolaryngology, Head and Neck Surgery and Internal Medicine, University Hospital Heidelberg, Heidelberg; and Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany.
  • Mogler C Authors' Affiliations:The Lautenberg Center for Immunology; Department of Developmental Biology and Cancer Research, IMRIC, Hadassah Medical School, Hebrew University;Department of Pathology, Hadassah-Hebrew University Medical Center, Jerusalem; Liver Unit, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel; Institute of Pathology, University Hospital Basel, Basel, Switzerland; Division of Signal Transduction and Growth Control (A100), Division of Molecular Genetics (B060), and Junior Group Molecular Mechanisms of Head and Neck Tumors (A102), German Cancer Research Center (DKFZ), DKFZ-ZMBH Alliance; Institute of Pathology, University Hospital Heidelberg; Departments of Otolaryngology, Head and Neck Surgery and Internal Medicine, University Hospital Heidelberg, Heidelberg; and Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany.
  • Shibolet O Authors' Affiliations:The Lautenberg Center for Immunology; Department of Developmental Biology and Cancer Research, IMRIC, Hadassah Medical School, Hebrew University;Department of Pathology, Hadassah-Hebrew University Medical Center, Jerusalem; Liver Unit, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel; Institute of Pathology, University Hospital Basel, Basel, Switzerland; Division of Signal Transduction and Growth Control (A100), Division of Molecular Genetics (B060), and Junior Group Molecular Mechanisms of Head and Neck Tumors (A102), German Cancer Research Center (DKFZ), DKFZ-ZMBH Alliance; Institute of Pathology, University Hospital Heidelberg; Departments of Otolaryngology, Head and Neck Surgery and Internal Medicine, University Hospital Heidelberg, Heidelberg; and Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany.
  • Hess J Authors' Affiliations:The Lautenberg Center for Immunology; Department of Developmental Biology and Cancer Research, IMRIC, Hadassah Medical School, Hebrew University;Department of Pathology, Hadassah-Hebrew University Medical Center, Jerusalem; Liver Unit, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel; Institute of Pathology, University Hospital Basel, Basel, Switzerland; Division of Signal Transduction and Growth Control (A100), Division of Molecular Genetics (B060), and Junior Group Molecular Mechanisms of Head and Neck Tumors (A102), German Cancer Research Center (DKFZ), DKFZ-ZMBH Alliance; Institute of Pathology, University Hospital Heidelberg; Departments of Otolaryngology, Head and Neck Surgery and Internal Medicine, University Hospital Heidelberg, Heidelberg; and Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, GermanyAuthors' Affiliations:The Lautenberg Center for Immunology; Department of Developmental Biology and Cancer Research, IMRIC, Hadassah Medical School, Hebrew University;Department of Pathology, Hadassah-Hebrew University Medical Center, Jerusalem; Liver Unit, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel; Institute of Pathology, University Hospital Basel, Basel, Switzerland; Division of Signal Transduction and Growth Control (A100), Division of Molecular Genetics (B060), and Junior Group Molecular Mechanisms of Head and Neck Tumors (A102), German Cancer Research Center (DKFZ), DKFZ-ZMBH Alliance; Institute of Pathology, University Hospital Heidelberg; Departments of Otolaryngology, Head and Neck Surgery and Internal Medicine, University Hospital Heidelberg, Heidelberg; and Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, GermanyAuthors' Affiliations:The Lautenberg Center for Immunology; Department of Developmental Biology and Cancer Research, IMRIC, Hadassah Medical School, Hebrew University;Department of Pathology, Hadassah-Hebrew University
  • Breuhahn K Authors' Affiliations:The Lautenberg Center for Immunology; Department of Developmental Biology and Cancer Research, IMRIC, Hadassah Medical School, Hebrew University;Department of Pathology, Hadassah-Hebrew University Medical Center, Jerusalem; Liver Unit, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel; Institute of Pathology, University Hospital Basel, Basel, Switzerland; Division of Signal Transduction and Growth Control (A100), Division of Molecular Genetics (B060), and Junior Group Molecular Mechanisms of Head and Neck Tumors (A102), German Cancer Research Center (DKFZ), DKFZ-ZMBH Alliance; Institute of Pathology, University Hospital Heidelberg; Departments of Otolaryngology, Head and Neck Surgery and Internal Medicine, University Hospital Heidelberg, Heidelberg; and Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany.
  • Grunewald M Authors' Affiliations:The Lautenberg Center for Immunology; Department of Developmental Biology and Cancer Research, IMRIC, Hadassah Medical School, Hebrew University;Department of Pathology, Hadassah-Hebrew University Medical Center, Jerusalem; Liver Unit, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel; Institute of Pathology, University Hospital Basel, Basel, Switzerland; Division of Signal Transduction and Growth Control (A100), Division of Molecular Genetics (B060), and Junior Group Molecular Mechanisms of Head and Neck Tumors (A102), German Cancer Research Center (DKFZ), DKFZ-ZMBH Alliance; Institute of Pathology, University Hospital Heidelberg; Departments of Otolaryngology, Head and Neck Surgery and Internal Medicine, University Hospital Heidelberg, Heidelberg; and Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany.
  • Schirmacher P Authors' Affiliations:The Lautenberg Center for Immunology; Department of Developmental Biology and Cancer Research, IMRIC, Hadassah Medical School, Hebrew University;Department of Pathology, Hadassah-Hebrew University Medical Center, Jerusalem; Liver Unit, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel; Institute of Pathology, University Hospital Basel, Basel, Switzerland; Division of Signal Transduction and Growth Control (A100), Division of Molecular Genetics (B060), and Junior Group Molecular Mechanisms of Head and Neck Tumors (A102), German Cancer Research Center (DKFZ), DKFZ-ZMBH Alliance; Institute of Pathology, University Hospital Heidelberg; Departments of Otolaryngology, Head and Neck Surgery and Internal Medicine, University Hospital Heidelberg, Heidelberg; and Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany.
  • Vogel A Authors' Affiliations:The Lautenberg Center for Immunology; Department of Developmental Biology and Cancer Research, IMRIC, Hadassah Medical School, Hebrew University;Department of Pathology, Hadassah-Hebrew University Medical Center, Jerusalem; Liver Unit, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel; Institute of Pathology, University Hospital Basel, Basel, Switzerland; Division of Signal Transduction and Growth Control (A100), Division of Molecular Genetics (B060), and Junior Group Molecular Mechanisms of Head and Neck Tumors (A102), German Cancer Research Center (DKFZ), DKFZ-ZMBH Alliance; Institute of Pathology, University Hospital Heidelberg; Departments of Otolaryngology, Head and Neck Surgery and Internal Medicine, University Hospital Heidelberg, Heidelberg; and Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany.
  • Terracciano L Authors' Affiliations:The Lautenberg Center for Immunology; Department of Developmental Biology and Cancer Research, IMRIC, Hadassah Medical School, Hebrew University;Department of Pathology, Hadassah-Hebrew University Medical Center, Jerusalem; Liver Unit, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel; Institute of Pathology, University Hospital Basel, Basel, Switzerland; Division of Signal Transduction and Growth Control (A100), Division of Molecular Genetics (B060), and Junior Group Molecular Mechanisms of Head and Neck Tumors (A102), German Cancer Research Center (DKFZ), DKFZ-ZMBH Alliance; Institute of Pathology, University Hospital Heidelberg; Departments of Otolaryngology, Head and Neck Surgery and Internal Medicine, University Hospital Heidelberg, Heidelberg; and Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany.
  • Angel P Authors' Affiliations:The Lautenberg Center for Immunology; Department of Developmental Biology and Cancer Research, IMRIC, Hadassah Medical School, Hebrew University;Department of Pathology, Hadassah-Hebrew University Medical Center, Jerusalem; Liver Unit, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel; Institute of Pathology, University Hospital Basel, Basel, Switzerland; Division of Signal Transduction and Growth Control (A100), Division of Molecular Genetics (B060), and Junior Group Molecular Mechanisms of Head and Neck Tumors (A102), German Cancer Research Center (DKFZ), DKFZ-ZMBH Alliance; Institute of Pathology, University Hospital Heidelberg; Departments of Otolaryngology, Head and Neck Surgery and Internal Medicine, University Hospital Heidelberg, Heidelberg; and Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany.
  • Ben-Neriah Y Authors' Affiliations:The Lautenberg Center for Immunology; Department of Developmental Biology and Cancer Research, IMRIC, Hadassah Medical School, Hebrew University;Department of Pathology, Hadassah-Hebrew University Medical Center, Jerusalem; Liver Unit, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel; Institute of Pathology, University Hospital Basel, Basel, Switzerland; Division of Signal Transduction and Growth Control (A100), Division of Molecular Genetics (B060), and Junior Group Molecular Mechanisms of Head and Neck Tumors (A102), German Cancer Research Center (DKFZ), DKFZ-ZMBH Alliance; Institute of Pathology, University Hospital Heidelberg; Departments of Otolaryngology, Head and Neck Surgery and Internal Medicine, University Hospital Heidelberg, Heidelberg; and Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany peli@hadassah.org.il yinonb@ekmd.huji.ac.il.
  • Pikarsky E Authors' Affiliations:The Lautenberg Center for Immunology; Department of Developmental Biology and Cancer Research, IMRIC, Hadassah Medical School, Hebrew University;Department of Pathology, Hadassah-Hebrew University Medical Center, Jerusalem; Liver Unit, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel; Institute of Pathology, University Hospital Basel, Basel, Switzerland; Division of Signal Transduction and Growth Control (A100), Division of Molecular Genetics (B060), and Junior Group Molecular Mechanisms of Head and Neck Tumors (A102), German Cancer Research Center (DKFZ), DKFZ-ZMBH Alliance; Institute of Pathology, University Hospital Heidelberg; Departments of Otolaryngology, Head and Neck Surgery and Internal Medicine, University Hospital Heidelberg, Heidelberg; and Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, GermanyAuthors' Affiliations:The Lautenberg Center for Immunology; Department of Developmental Biology and Cancer Research, IMRIC, Hadassah Medical School, Hebrew University;Department of Pathology, Hadassah-Hebrew University Medical Center, Jerusalem; Liver Unit, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel; Institute of Pathology, University Hospital Basel, Basel, Switzerland; Division of Signal Transduction and Growth Control (A100), Division of Molecular Genetics (B060), and Junior Group Molecular Mechanisms of Head and Neck Tumors (A102), German Cancer Research Center (DKFZ), DKFZ-ZMBH Alliance; Institute of Pathology, University Hospital Heidelberg; Departments of Otolaryngology, Head and Neck Surgery and Internal Medicine, University Hospital Heidelberg, Heidelberg; and Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany peli@hadassah.org.il yinonb@ekmd.huji.ac.il.
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  • 2014-04-02
Published in:
  • Cancer discovery. - 2014
ATP Binding Cassette Transporter, Subfamily B
Animals
Antineoplastic Agents
Carcinoma, Hepatocellular
Cell Line, Tumor
Cell Proliferation
Female
Hepatocytes
Humans
Liver Neoplasms
Macrophages
Male
Mice, Knockout
Niacinamide
Phenylurea Compounds
Protein Kinase Inhibitors
Sorafenib
Tumor Burden
Vascular Endothelial Growth Factor A
English UNLABELLED
Death rates from hepatocellular carcinoma (HCC) are steadily increasing, yet therapeutic options for advanced HCC are limited. We identify a subset of mouse and human HCCs harboring VEGFA genomic amplification, displaying distinct biologic characteristics. Unlike common tumor amplifications, this one seems to work via heterotypic paracrine interactions; stromal VEGF receptors (VEGFR), responding to tumor VEGF-A, produce hepatocyte growth factor (HGF) that reciprocally affects tumor cells. VEGF-A inhibition results in HGF downregulation and reduced proliferation, specifically in amplicon-positive mouse HCCs. Sorafenib-the first-line drug in advanced HCC-targets multiple kinases, including VEGFRs, but has only an overall mild beneficial effect. We found that VEGFA amplification specifies mouse and human HCCs that are distinctly sensitive to sorafenib. FISH analysis of a retrospective patient cohort showed markedly improved survival of sorafenib-treated patients with VEGFA-amplified HCCs, suggesting that VEGFA amplification is a potential biomarker for HCC response to VEGF-A-blocking drugs.


SIGNIFICANCE
Using a mouse model of inflammation-driven cancer, we identified a subclass of HCC carrying VEGFA amplification, which is particularly sensitive to VEGF-A inhibition. We found that a similar amplification in human HCC identifies patients who favorably responded to sorafenib-the first-line treatment of advanced HCC-which has an overall moderate therapeutic efficacy.
Language
  • English
Open access status
bronze
Identifiers
Persistent URL
https://folia.unifr.ch/global/documents/83944
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