Soluble Axl is an accurate biomarker of cirrhosis and hepatocellular carcinoma development: results from a large scale multicenter analysis

Abstract

Patients with chronic liver disease (CLD) and cirrhosis are at high risk for hepatocellular carcinoma (HCC). Current diagnostic tools for HCC detection include imaging techniques and serum biomarkers such as α-fetoprotein (AFP). Yet, these methods are limited in sensitivity and specificity to accurately detect early HCC. Here we focused on the potential of soluble Axl (sAxl) as a biomarker in CLD patients by analyzing serum samples of 1067 patients and healthy controls from centers in Europe and Asia. We show that serum concentrations of sAxl were significantly increased at early (82.57 ng/mL) and later stages of HCC (114.50 ng/mL) as compared to healthy controls (40.15 ng/mL). Notably, no elevated sAxl levels were detected in patients with CLD including chronic viral hepatitis, autoimmune hepatitis, cholestatic liver disease, or non-alcoholic fatty liver disease versus healthy controls. Furthermore, sAxl did not rise in liver adenomas or cholangiocarcinoma (CCA). Yet, patients with advanced fibrosis (F3) or cirrhosis (F4) showed enhanced sAxl concentrations (F3: 54.67 ng/mL; F4: 94.74 ng/mL). Hepatic myofibroblasts exhibited an increased release of sAxl, suggesting that elevated sAxl levels arise from these cells during fibrosis. Receiver operating characteristic curve analysis of sAxl displayed a strongly increased sensitivity and specificity to detect both cirrhosis (80.8%/92.0%) and HCC (83.3%/86.7%) with an area under the curve of 0.935/0.903 as compared to AFP. In conclusion, sAxl shows high diagnostic accuracy at early stage HCC as well as cirrhosis, thereby outperforming AFP. Importantly, sAxl remains normal in most common CLDs, liver adenomas and CCA.

Differential TAM receptor regulation of hepatic physiology and injury

“…Soluble Axl ectodomain (sAxl) has been reported to be an accurate biomarker of cirrhosis and the development of hepatocellular carcinoma (58). Our results provide a mechanistic explanation for sAxl release subsequent to Axl activation in the presence of ACs.…”

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].…”

“…e extracellular domain contains intact ligand-binding capabilities, and therefore sAXL can inhibit ligand-mediated AXL signaling [29]. sAXL levels are elevated in some cancer types, including hepatocellular carcinoma, and sAXL is being investigated as a biomarker in certain cancers and other inflammatory diseases [30][31][32].…”

Soluble Axl Is a Novel Diagnostic Biomarker of Hepatocellular Carcinoma in Chinese Patients with Chronic Hepatitis B Virus Infection

“…It is greatly needed to identify a novel serum marker for HCC. sAxl levels have been used as a potential marker of HCC in current reports [17][18][19]. Therefore, we examined levels of sAxl to test and verify the diagnosis power in HCC.…”

“…Furthermore, Axl can be proteolytically processed, resulting in the release of an 80-kDa soluble protein (sAxl) that can be observed in serum [15,16]. Recently, studies investigated that serum sAxl had better accuracy than AFP for diagnosis of early-stage HCC [17][18][19].…”