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Transforming Growth Factor- and Axl Induce CXCL5 and Neutrophil Recruitment in Hepatocellular Carcinoma
AuthorSchreiner, Wolfgang ; Haider, Christine ; Hnat, Julia ; Wagner, Roland ; Huber, Heidemarie ; Timelthaler, Gerald ; Grubinger, Markus ; Coulouarn, Cédric ; Schlangen, Karin ; Sieghart, Wolfgang ; Peck-Radosavljevic, Markus ; Mikulits, Wolfgang
Published in
Hepatology, 2019, Vol. 69, Issue 1, page 222-236
PublishedWiley-Blackwell, 2019
Document typeJournal Article
URNurn:nbn:at:at-ubmuw:3-607 Persistent Identifier (URN)
 The work is publicly available
Transforming Growth Factor- and Axl Induce CXCL5 and Neutrophil Recruitment in Hepatocellular Carcinoma [1.13 mb]
Abstract (English)

Transforming growth factor (TGF) suppresses early hepatocellular carcinoma (HCC) development but triggers prooncogenic abilities at later stages. Recent data suggest that the receptor tyrosine kinase Axl causes a TGF switch toward dedifferentiation and invasion of HCC cells. Here, we analyzed two human cellular HCC models with opposing phenotypes in response to TGF. Both HCC models showed reduced proliferation and clonogenic growth behavior following TGF stimulation, although they exhibited differences in chemosensitivity and migratory abilities, suggesting that HCC cells evade traits of antioncogenic TGF. Transcriptome profiling revealed differential regulation of the chemokine CXCL5, which positively correlated with TGF expression in HCC patients. The expression and secretion of CXCL5 was dependent on Axl expression, suggesting that CXCL5 is a TGF target gene collaborating with Axl signaling. Loss of either TGF or Axl signaling abrogated CXCL5dependent 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. Conclusion: The synergy of TGF and Axl induces CXCL5 secretion, causing the infiltration of neutrophils into HCC tissue. Intervention with TGF/Axl/CXCL5 signaling may be an effective therapeutic strategy to combat HCC progression in TGFpositive patients.

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