Abstract
We have previously shown that Met activation through the hepatocyte growth factor (HGF) increases tumorogenesis, induces epithelial-to-mesenchymal transition (EMT) and chemoresistance in SCLC. We sought to evaluate circulating HGF levels in SCLC patients and assess correlation with outcome and EMT features in the tumor. Serum samples from patients with SCLC were prospectively obtained at diagnosis, response evaluation and progression. HGF serum (sHGF) was quantified by ELISA. EMT markers and p-Met/Met were assayed by immunohistochemistry in tumor samples. Clinical data were prospectively recorder. One-hundred twelve patients were included. High baseline levels of sHGF were associated with shorter overall survival (p=0.006) and remained independently associated with survival in the multivariate analysis (p=0.016). For stage IV patients, an increase of sHGF levels at response evaluation (p=0.042) and at progression (p=0.003) were associated with poor outcome. sHGF levels were associated (p<0.05) with a mesenchymal phenotype in the tumor. In conclusion, high sHGF at diagnosis and increases during the course of the disease predict for poor outcome in SCLC patients and associate with EMT in the tumor. These data provide novel evidence on a role of sHGF in the adverse clinical behavior of SCLC and supports testing Met inhibitors in patients with high sHGF.
Highlights
Small cell lung carcinoma (SCLC) is a highly lethal disease and accounts for approximately 15% of patients with lung cancers[1]
We have previously reported that Met activation as assayed by phosphorylated Met (p-Met) expression is associated with decreased survival in SCLC[10]
We have shown in preclinical SCLC models that Hepatocyte growth factor (HGF) induces epithelial to mesenchymal transition (EMT) that results in increased tumorogenesis, invasiveness and chemoresistance
Summary
Small cell lung carcinoma (SCLC) is a highly lethal disease and accounts for approximately 15% of patients with lung cancers[1]. No targeted treatment has been successful to date in improving the outcome of patients. Outcome in advance stage remains poor with a median overall survival that does not exceed one year with available treatments www.impactjournals.com/oncotarget [5]. The research of novel targets for selected patient populations in this disease is urgently needed. Met is a transmembrane receptor tyrosine kinase that is overexpressed in many solid tumors and has been associated with poor outcome. Aberrant Met activation through HGF (autocrine or paracrine effects) or genetic mechanisms (mutation, amplification) is associated with increased motility, migration, invasion and angiogenesis in several tumor models[6,7,8]. A number of Met inhibitors are in development at the moment with promising results in solid tumors[9]
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