Identification of the soluble form of tyrosine kinase receptor Axl as a potential biomarker for intracranial aneurysm rupture

Abstract

BackgroundSubarachnoid hemorrhage caused by a ruptured intracranial aneurysm (RIA) is a devastating condition with significant morbidity and mortality. Despite the fact that RIAs can be prevented by microsurgical clipping or endovascular coiling, there are no reliable means of effectively predicting IA patients at risk for rupture. The purpose of our study was to discover differentially-expressed glycoproteins in IAs with or without rupture as potential biomarkers to predict rupture.MethodsForty age/gender-matched patients with RIA, unruptured IA (UIA), healthy controls (HCs) and disease controls (DCs) (discovery cohort, n = 10 per group) were recruited and a multiplex quantitative proteomic method, iTRAQ (isobaric Tagging for Relative and Absolute protein Quantification), was used to quantify relative changes in the lectin-purified glycoproteins in CSF from RIAs and UIAs compared to HCs and DCs. Then we verified the proteomic results in an independent set of samples (validation cohort, n = 20 per group) by enzyme-linked immunosorbent assay. Finally, we evaluated the specificity and sensitivity of the candidate marker with receiver operating characteristic (ROC) curve methods.ResultsThe proteomic findings identified 294 proteins, 40 of which displayed quantitative changes unique to RIA, 13 to UIA, and 20 to IA. One of these proteins, receptor tyrosine kinase Axl, was significantly increased in RIA, as confirmed in CSF from the discovery cohort as well as in CSF and plasma from the validation cohort (p <0.05). Spearman’s correlation analysis revealed that the CSF and plasma Axl levels were strongly correlated (r = 0.93, p <0.0001). The ROC curve indicated an optimal CSF Axl threshold of 0.12 nM for discriminating RIA from UIA with corresponding sensitivity/specificity of 73.33%/90% and an area under the curve (AUC) of 0.89 (95% CI: 0.80-0.97, p < 0.0001). The optimal threshold for plasma Axl was 1.7 nM with corresponding sensitivity/specificity of 50%/80% and an AUC of 0.71 (95% CI: 0.54-0.87, p = 0.027).ConclusionsBoth CSF and plasma Axl levels are significantly elevated in RIA patients. Axl might serve as a promising biomarker to predict the rupture of IA.Electronic supplementary materialThe online version of this article (doi:10.1186/s12883-015-0282-8) contains supplementary material, which is available to authorized users.

Does Axl have potential as a therapeutic target in pancreatic cancer?

“…Axl can be cleaved at the proteolytic cleavage site (VKEPSTPAFSWPWW) in exon 11, resulting in an 80 kDa soluble protein containing only the extracellular domain [4]. The level of soluble Axl in serum has potential as a diagnostic marker for different diseases such as hepatocellular carcinoma [5], intracranial aneurysm rupture [6], acute coronary syndrome [7], abdominal aortic aneurysms [8], liver fibrosis and cirrhosis [9], sepsis, systemic inflammatory response syndrome [10], and systemic lupus erythematosus [11].…”

Treatment of Unruptured Intracranial Aneurysms in Autosomal Dominant Polycystic Kidney Disease: Primum Non Nocere

“…There is effort to improve the assessment of risk for IA progression and rupture with clinical and radiographic features 12 and a molecular biology approach. 13,14 However, these new risk factors have to be tested in the ADPKD population to verify their utility in this particular group.…”

Axl receptor tyrosine kinase is a regulator of apolipoprotein E

“…It is overexpressed in various cancers including breast, pancreatic and lung and is associated with low survival rates [51,52]. The role of Axl in the CNS has gained recent attention as Axl levels may be a potential biomarker for brain damage [53][54][55]. In addition to the identification of AZ7235 as a novel apoE modulator, our study demonstrates that Axl also plays a pivotal role in apoE homeostasis in CCF-STTG1 cells.…”