Martin Franz Sprinzl1, Andreas Puschnik2, Anna Melissa Schlitter3, Arno Schad4, Kerstin Ackermann2, Irene Esposito3, Hauke Lang5, Peter Robert Galle6, Arndt Weinmann7, Mathias Heikenwälder2, Ulrike Protzer8. 1. 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. 2. Institute of Virology, Technische Universität/Helmholtz Zentrum München, München, Germany. 3. Institute of Pathology, Technische Universität, München, Germany. 4. Institute of Pathology, Universitätsmedizin, Mainz, Germany. 5. Department of Surgery, Universitätsmedizin, Mainz, Germany. 6. I. Medical Department, Universitätsmedizin, Mainz, Germany. 7. I. Medical Department, Universitätsmedizin, Mainz, Germany; Clinical Registry Unit, I. Medical Department, Universitätsmedizin, Mainz, Germany. 8. Institute of Virology, Technische Universität/Helmholtz Zentrum München, München, Germany. Electronic address: ulrike.protzer@virologie.med.tum.de.
Abstract
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.
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.
Authors: Josep M Llovet; Florian Castet; Mathias Heikenwalder; Mala K Maini; Vincenzo Mazzaferro; David J Pinato; Eli Pikarsky; Andrew X Zhu; Richard S Finn Journal: Nat Rev Clin Oncol Date: 2021-11-11 Impact factor: 65.011