TY - JOUR
T1 - Sorafenib inhibits macrophage-induced growth of hepatoma cells by interference with insulin-like growth factor-1 secretion
AU - Sprinzl, Martin Franz
AU - Puschnik, Andreas
AU - Schlitter, Anna Melissa
AU - Schad, Arno
AU - Ackermann, Kerstin
AU - Esposito, Irene
AU - Lang, Hauke
AU - Galle, Peter Robert
AU - Weinmann, Arndt
AU - Heikenwälder, Mathias
AU - Protzer, Ulrike
N1 - Funding Information:
The study was funded by the Helmholtz Alliance for Cancer Immunotherapy (HAIT, HA-202 ) offered to U.P. and the preclinical comprehensive cancer center (PCCC) and ERC grant (LiverCancerMechanisms; ERC-2010-StG_20091118 ) offered to M.H. M.F.S. was supported by a clinical leave stipend from HAIT. M.H. was supported by the Peter-Hans Hofschneider foundation and the Helmholtz foundation.
PY - 2015/4/1
Y1 - 2015/4/1
N2 - Background & Aims 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.
AB - Background & Aims 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.
KW - Immunology
KW - Liver cancer
KW - Macrophages
KW - Stroma
KW - Therapy
KW - Tumor
UR - http://www.scopus.com/inward/record.url?scp=84926408870&partnerID=8YFLogxK
U2 - 10.1016/j.jhep.2014.11.011
DO - 10.1016/j.jhep.2014.11.011
M3 - Article
C2 - 25463538
AN - SCOPUS:84926408870
SN - 0168-8278
VL - 62
SP - 863
EP - 870
JO - Journal of Hepatology
JF - Journal of Hepatology
IS - 4
ER -
