The expression of Axl receptor tyrosine kinase influences the tumour phenotype and clinical outcome of patients with malignant pleural mesothelioma.
BACKGROUND
Recent preclinical studies identified Axl, a tyrosine kinase receptor implicated in tumour progression and epithelial-to-mesenchymal transition, as a putative therapeutic target in malignant pleural mesothelioma (MPM), an invariably fatal malignancy with limited treatment options. Here, we studied the expression of Axl and its ligand Gas-6 (growth arrest signal-6) in primary specimens of MPM, correlating their expression levels with tumour phenotype and clinical outcomes.


METHODS
Two independent cohorts of consecutive patients diagnosed with MPM were studied: a derivation cohort composed of 63 cases and a validation set of 35 cases. Clinical variables including patients' demographics, tumour stage, histotype, performance status (PS), Axl and Gas-6 staining were tested for predicting overall survival (OS) using univariate and multivariate analyses.


RESULTS
In the derivation cohort, Axl (P=0.001) but not Gas-6 overexpression (P=0.35) emerged as a univariate prognostic factor for OS, together with stage (P=0.05), PS (P<0.001) hypoalbuminaemia (P<0.001) and anaemia (P<0.001). Multivariate analyses confirmed Axl overexpression (P=0.01), PS (P=0.01), hypoalbuminaemia (P<0.001) and anaemia (P=0.04) as independent predictors of OS. The prognostic role of Axl overexpression was externally validated in an independent cohort (P=0.03).


CONCLUSIONS
Overexpression of Axl is found in the majority of MPM specimens and influences patient's survival independently from other established prognostic factors. Such information may support patient selection for future trials.
Department of Experimental Medicine, Imperial Center for Translational and Experimental Medicine, Imperial College London, Du Cane Road, W12 0HS London, UK.
D J
DJ
Pinato
F A
FA
Mauri
T
T
Lloyd
V
V
Vaira
C
C
Casadio
R L
RL
Boldorini
R
R
Sharma
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D007124:Immunoenzyme Techniques; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism*; D008297:Male; D008654:Mesothelioma / Q000378:metabolism / Q000401:mortality / Q000473:pathology*; D008875:Middle Aged; D009367:Neoplasm Staging; D010641:Phenotype; D010997:Pleural Neoplasms / Q000378:metabolism / Q000401:mortality / Q000473:pathology*; D011379:Prognosis; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D020794:Receptor Protein-Tyrosine Kinases / Q000378:metabolism*; D012189:Retrospective Studies; D015996:Survival Rate; D000094963:Axl Receptor Tyrosine Kinase; D000099255:Growth Arrest-Specific Protein 6
D036341:Intercellular Signaling Peptides and Proteins; D011518:Proto-Oncogene Proteins; D020794:Receptor Protein-Tyrosine Kinases; D000094963:Axl Receptor Tyrosine Kinase; D000099255:Growth Arrest-Specific Protein 6; C000722289:AXL protein, human