title: Sorafenib inhibits macrophage-induced growth of hepatoma cells by interference with insulin-like growth factor-1 secretion.
abstract: OBJECTIVE
  Hepatocellular carcinoma (HCC) associated macrophages accelerate tumor progression by growth factor release. Therefore, tumor-associated macrophages (TAM) and their initiated signaling cascades are potential therapeutic targets. Aiming at understanding anticancer effects of systemic HCC therapy, we investigated the impact of sorafenib on macrophage function, focusing on macrophage-related growth factor secretion.
  
  
  METHODS
  Macrophage markers, cytokine and growth factor release were investigated in CSF-1 (M1) or GMCSF (M2) maturated monocyte-derived macrophages. Macrophages were treated with sorafenib (1.2-5.0 μg/ml) and culture supernatants were transferred to hepatoma cell cultures to assess growth propagation. Insulin-like growth factor (IGF) signaling was blocked with NVP-AEW541 to confirm the role of IGF-1 in macrophage-driven hepatoma cell propagation. Macrophage activation was followed by ELISA of serum soluble mCD163 in sorafenib-treated patients with HCC.
  
  
  RESULTS
  Alternative macrophages (M2), which showed higher IGF-1 (p=0.022) and CD163 mRNA (p=0.032) expression compared to classical macrophages (M1), increased hepatoma growth. This effect was mediated by M2-conditioned culture media. In turn, sorafenib lowered mCD163 and IGF-1 release by M2 macrophages, which decelerated M2 macrophage driven HuH7 and HepG2 proliferation by 47% and 64%, respectively. IGF-receptor blockage with NVP-AEW541 reduced growth induction by M2-conditioned culture media in a dose dependent manner. A transient mCD163 reduction during sorafenib treatment indicated a coherent M2 macrophage inhibition in patients with HCC.
  
  
  CONCLUSIONS
  Sorafenib alters macrophage polarization, reduces IGF-1-driven cancer growth in vitro and partially inhibits macrophage activation in vivo. Thus macrophage modulation might contribute to the anti-cancer activity of sorafenib. However, more efficient macrophage-directed therapies are required.
authors.affiliation: Institute of Virology, Technische Universität/Helmholtz Zentrum München, München, Germany; I. Medical Department, Universitätsmedizin, Mainz, Germany; Clinical Registry Unit, I. Medical Department, Universitätsmedizin, Mainz, Germany. Electronic address: martin.sprinzl@unimedizin-mainz.de.
authors.forename: Martin Franz
authors.initials: MF
authors.lastname: Sprinzl
authors.affiliation: Institute of Virology, Technische Universität/Helmholtz Zentrum München, München, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Puschnik
authors.affiliation: Institute of Pathology, Technische Universität, München, Germany.
authors.forename: Anna Melissa
authors.initials: AM
authors.lastname: Schlitter
authors.affiliation: Institute of Pathology, Universitätsmedizin, Mainz, Germany.
authors.forename: Arno
authors.initials: A
authors.lastname: Schad
authors.affiliation: Institute of Virology, Technische Universität/Helmholtz Zentrum München, München, Germany.
authors.forename: Kerstin
authors.initials: K
authors.lastname: Ackermann
authors.affiliation: Institute of Pathology, Technische Universität, München, Germany.
authors.forename: Irene
authors.initials: I
authors.lastname: Esposito
authors.affiliation: Department of Surgery, Universitätsmedizin, Mainz, Germany.
authors.forename: Hauke
authors.initials: H
authors.lastname: Lang
authors.affiliation: I. Medical Department, Universitätsmedizin, Mainz, Germany.
authors.forename: Peter Robert
authors.initials: PR
authors.lastname: Galle
authors.affiliation: I. Medical Department, Universitätsmedizin, Mainz, Germany; Clinical Registry Unit, I. Medical Department, Universitätsmedizin, Mainz, Germany.
authors.forename: Arndt
authors.initials: A
authors.lastname: Weinmann
authors.affiliation: Institute of Virology, Technische Universität/Helmholtz Zentrum München, München, Germany.
authors.forename: Mathias
authors.initials: M
authors.lastname: Heikenwälder
authors.affiliation: Institute of Virology, Technische Universität/Helmholtz Zentrum München, München, Germany. Electronic address: ulrike.protzer@virologie.med.tum.de.
authors.forename: Ulrike
authors.initials: U
authors.lastname: Protzer
mesh_terms: D015703:Antigens, CD / Q000378:metabolism; D015214:Antigens, Differentiation, Myelomonocytic / Q000378:metabolism; D000970:Antineoplastic Agents / Q000494:pharmacology; D006528:Carcinoma, Hepatocellular / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000378:metabolism*; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000378:metabolism; D008113:Liver Neoplasms / Q000378:metabolism / Q000473:pathology; D008262:Macrophage Activation / Q000187:drug effects; D016173:Macrophage Colony-Stimulating Factor / Q000378:metabolism*; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism; D009536:Niacinamide / Q000031:analogs & derivatives* / Q000494:pharmacology; D010671:Phenylurea Compounds / Q000494:pharmacology*; D011956:Receptors, Cell Surface / Q000378:metabolism; D040262:Receptors, Vascular Endothelial Growth Factor / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D000077157:Sorafenib; D048490:raf Kinases / Q000378:metabolism; D000098902:CD163 Antigen
chemical_list: D015703:Antigens, CD; D015214:Antigens, Differentiation, Myelomonocytic; D000970:Antineoplastic Agents; D000098902:CD163 Antigen; D010671:Phenylurea Compounds; D011956:Receptors, Cell Surface; D009536:Niacinamide; D007334:Insulin-Like Growth Factor I; D016173:Macrophage Colony-Stimulating Factor; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D000077157:Sorafenib; D040262:Receptors, Vascular Endothelial Growth Factor; D048490:raf Kinases
keywords: Immunology; Liver cancer; Macrophages; Stroma; Therapy; Tumor