Transforming Growth Factor-β and Axl Induce CXCL5 and Neutrophil Recruitment in Hepatocellular Carcinoma

Christine Haider (1) , Julia Hnat (1) , Roland Wagner (1) , Heidemarie Huber (1) , Gerald Timelthaler (1) , Markus Grubinger (1) , Cédric Coulouarn (2) , Wolfgang Schreiner (1) , Karin Schlangen (1) , Wolfgang Sieghart (1) , Markus Peck-Radosavljevic (1) , Wolfgang Mikulits (1)

1 Medizinische Universität Wien = Medical University of Vienna
2 NuMeCan - Nutrition, Métabolismes et Cancer

Transforming growth factor (TGF)-β suppresses early hepatocellular carcinoma (HCC) development but triggers pro-oncogenic abilities at later stages. Recent data suggest that the receptor tyrosine kinase Axl causes a TGF-β switch towards dedifferentiation and invasion of HCC cells. Here, we analyzed two human cellular HCC models with opposing phenotypes in response to TGF-β. Both HCC models showed reduced proliferation and clonogenic growth behavior upon TGF-β stimulation, however, exhibited differences in chemosensitivity and migratory abilities, suggesting that HCC cells evade traits of anti-oncogenic TGF-β. Transcriptome profiling revealed differential regulation of the chemokine CXCL5, which positively correlated with TGF-β expression in HCC patients. The expression and secretion of CXCL5 was dependent on Axl expression suggesting that CXCL5 is a TGF-β target gene collaborating with Axl signaling. Loss of either TGF-β or Axl signaling abrogated CXCL5-dependent attraction of neutrophils. In mice, tumor formation of transplanted HCC cells relied on CXCL5 expression. In HCC patients, high levels of Axl and CXCL5 correlated with advanced tumor stages, recruitment of neutrophils into HCC tissue and reduced survival.

Mots clés: TGF-β; hepatocellular carcinoma; neutrophil; CXCL5; patient survival

Domaines: Cancer; Hépatologie et Gastroentérologie; Génomique, Transcriptomique et Protéomique [q-bio.GN]

Christine Haider, Julia Hnat, Roland Wagner, Heidemarie Huber, Gerald Timelthaler, et al.. Transforming Growth Factor-β and Axl Induce CXCL5 and Neutrophil Recruitment in Hepatocellular Carcinoma. Hepatology, 2019, 69 (1), pp.222-236. ⟨10.1002/hep.30166⟩. ⟨hal-01862575⟩