Dynamics of Axl Receptor Shedding in Hepatocellular Carcinoma and Its Implication for Theranostics

Abstract

Signaling of the receptor tyrosine kinase Axl and its ligand Gas6 is crucially involved in the development of liver fibrosis and hepatocellular carcinoma (HCC) by activation of hepatic stellate cells and modulation of hepatocyte differentiation. Shedding of Axl’s ectodomain leads to the release of soluble Axl (sAxl), which is increased in advanced fibrosis and in early-to-late stage HCC in the presence and absence of cirrhosis. Here, we focus on the dynamics of Axl receptor shedding and delineate possible scenarios how Axl signaling might act as driver of fibrosis progression and HCC development. Based on experimental and clinical data, we discuss the consequences of modifying Axl signaling by sAxl cleavage, as well as cellular strategies to escape from antagonizing effects of Axl shedding by the involvement of the hepatic microenvironment. We emphasize a correlation between free Gas6 and free sAxl levels favoring abundant Gas6/Axl signaling in advanced fibrosis and HCC. The raised scenario provides a solid basis for theranostics allowing the use of sAxl as an accurate diagnostic biomarker of liver cirrhosis and HCC, as well as Axl receptor signaling for therapeutic intervention in stratified HCC patients.

Gas6/TAM Signaling Components as Novel Biomarkers of Liver Fibrosis

“…In the background of fibrosis, sinusoidal endothelial cells, activated HSCs, and Axl-positive myofibroblasts as well as Kupffer cells release Gas6 into the tumor microenvironment of HCC, causing a Gas6-enriched HCC stroma. These data suggest that Axl signaling drives HCC progression in the presence of large amounts of bioactive Gas6 and is of even more particular interest as tyrosine kinase inhibition is one of the most exploited antitumoral approaches of targeted therapies (e.g., bosutinib) [114, 117, 118]. However, since very complex mechanisms are involved that go extensively beyond the simple induction of hepatic fibrosis, the precise analysis of the possible oncogenic roles of the Gas6/TAM system in HCC signaling (in many cases still lacking solid evidence) remains outside the purpose of the present review.…”

AXL as a Target in Breast Cancer Therapy

“…sAXL, the cleaved extracellular domain of AXL, is being explored as a potential biomarker in certain cancers and other inflammatory conditions, such as in hepatocellular carcinoma, neurofibromatosis type 1, and in NSCLC Journal of Oncology [30][31][32]77]. sAXL was overexpressed in effusions from patients with breast carcinoma; however, this was not informative of chemoresponse or survival [78].…”

High Risk of Hepatocellular Carcinoma Development in Fibrotic Liver: Role of the Hippo-YAP/TAZ Signaling Pathway

“…Growth arrest-specific gene 6 (Gas6) product is a vitamin K-dependent protein [134] that activates a family of TAM (Tyro3, Axl, MERTK) receptors with tyrosine kinase activity [135]. TAM signaling plays a role in tissue development and homeostasis, and disposes of apoptotic cells [136].…”

“…In normal liver, Gas6 is mainly expressed in Kupffer cells while Axl, which is related to cell differentiation and carcinogenesis among TAM receptors, is expressed in macrophages and quiescent HSC [135]. MERTK is expressed in Kupffer cells and sinusoidal endothelial cells, but not in hepatocytes, while Tyro3 is only found in resident macrophages [137].…”