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Sorafenib inhibits macrophage-induced growth of hepatoma cells by interference with insulin-like growth factor-1

Martin Franz Sprinzl1, Andreas Puschnik2, Anna Melissa Schlitter3

  • 1Institute of Virology, Technische Universität/Helmholtz Zentrum München, München, Germany; I. Medical Department, Universitätsmedizin, Mainz, Germany; Clinical Registry Unit, I. Medical Department, Universitätsmedizin, Mainz, Germany.

Journal of Hepatology
|December 3, 2014
PubMed
Abstract

Insights

Sorafenib treatment reduces growth factors released by tumor-associated macrophages (TAMs), inhibiting hepatocellular carcinoma (HCC) cell proliferation. This suggests targeting macrophages could enhance HCC therapy.

Area of Science:

  • Immunology
  • Oncology
  • Pharmacology

Background:

  • Hepatocellular carcinoma (HCC) growth is accelerated by tumor-associated macrophages (TAMs) releasing growth factors.
  • TAMs and their signaling pathways represent potential therapeutic targets for HCC.
  • Understanding sorafenib's effects on macrophage function is crucial for HCC treatment.

Purpose of the Study:

  • To investigate the impact of sorafenib on macrophage function, specifically focusing on growth factor secretion.
  • To determine how sorafenib affects macrophage polarization and their contribution to HCC progression.
  • To evaluate the role of Insulin-like Growth Factor 1 (IGF-1) in macrophage-driven hepatoma cell propagation.

Main Methods:

  • Investigated macrophage markers and cytokine/growth factor release in M1 and M2 macrophages.
  • Treated macrophages with sorafenib and assessed effects on hepatoma cell growth using conditioned media.
  • Blocked IGF signaling with NVP-AEW541 and measured serum soluble mCD163 in HCC patients treated with sorafenib.

Main Results:

  • Alternative M2 macrophages, expressing higher IGF-1 and CD163, enhanced hepatoma growth.
  • Sorafenib reduced M2 macrophage release of mCD163 and IGF-1, decelerating HuH7 and HepG2 proliferation.
  • IGF-receptor blockade dose-dependently reduced M2-mediated growth induction; transient mCD163 reduction in patients indicated M2 inhibition.

Conclusions:

  • Sorafenib alters macrophage polarization, reducing IGF-1-driven HCC growth in vitro.
  • Sorafenib partially inhibits macrophage activation in vivo, potentially contributing to its anti-cancer activity.
  • Further development of macrophage-directed therapies is needed for more effective HCC treatment.
Keywords:
ImmunologyLiver cancerMacrophagesStromaTherapyTumor

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