Abstract
Lung neuroendocrine (NE) tumors are a heterogeneous group of tumors arising from neuroendocrine cells that includes typical carcinoid, atypical carcinoid, small cell lung cancer (SCLC), and large cell NE cancer. The subtyping of NE tumors is based on the number of mitoses per high powered field and the presences of necrosis. However, the best diagnostic criteria to differentiate various subtypes of lung NE tumors remains controversial and few diagnostic markers distinguish typical and atypical carcinoid. In this study, we show that FAIM2, an inhibitory molecule in the Fas-apoptosis pathway, is significantly overexpressed in SCLC compared to non-small cell lung cancer. In addition, FAIM2 expression is significantly higher in atypical carcinoid than typical carcinoid. As atypical carcinoid has been shown to have worse clinical outcomes than typical carcinoid, our data suggests that FAIM2 may be a useful diagnostic marker for atypical carcinoid. Knockdown of FAIM2 expression increases Fas-induced apoptotic cell death in SCLC cells. Etoposide treatment combined with FAIM2 inhibition also shows modest but significant reduction of viable SCLC cells. Taken together, our results suggest that FAIM2 is a potential NE tumor marker with higher expression in atypical carcinoid and SCLC, and could be a new therapeutic target for SCLC.
Highlights
Molecular markers for atypical carcinoid are evaluated based on their correlation to worse clinical outcomes
These cell lines were categorized into non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC) based on the available histology subtype information
FAIM2 is known as an anti-apoptosis gene that directly interacts with Fas receptor and inhibits apoptosis by interfering with caspase 8 activation[23]
Summary
Molecular markers for atypical carcinoid are evaluated based on their correlation to worse clinical outcomes. It has been suggested that some NSCLC cells with EGFR mutations can be converted into SCLC cells after treatment with tyrosine kinase inhibitors (TKIs) or even synchronously without any treatment[13]. While circulating tumor cells (CTC) have recently been suggested as potential diagnostic markers for SCLC17, none are close to approval for clinical use. In order to develop an efficient early diagnostic method for SCLC it is important to identify SCLC–specific or dominant molecular markers. Several markers such as synaptophysin, chromogranin, or CD56 (NCAM) have been used to diagnose SCLC and other NE tumors in the lung[2]. Almost nothing is known about the role of FAIM2 in the development of SCLC or other NE tumors in lung
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