Small-cell lung cancer (SCLC) is the most aggressive lung cancer subtype and lacks effective early detection methods and therapies. timing of autoantibody development relative to malignancy and the nature of the immune trigger remain to be elucidated. Here we review what is currently known about SCLC-associated autoantibodies and describe a recently developed mouse model system of SCLC that appears to lend itself well to the study of the SCLC-associated immune response. We also discuss potential clinical applications for these autoantibodies such as SCLC diagnosis early detection and therapy. Introduction Lung cancer is the leading cause of cancer-related death in the world claiming the lives of 1 1.3 million individuals worldwide in 2007 . In the United States lung cancer killed over 150 0 Americans in 2009 2009 [2 3 and caused more deaths than breast prostate pancreatic and colon cancer combined. Small-cell lung cancer (SCLC) a highly malignant tumor thought to originate from primitive neuroendocrine cells in the lung  accounts for up to 15% of all newly diagnosed lung cancers . Cigarette smoking is the major cause of SCLC where both the smoking intensity (smokes/day) and the number of years of smoking increase the risk of SCLC development . Recently it was shown that repetitive nicotine KW-2478 exposure induces many malignant features in SCLC cells including increased adhesion enhanced migration and resistance to chemotherapy . Initially SCLC patients respond well to chemotherapy. However relapses are inevitable as patients become resistant to cytotoxic treatment . Despite treatment the relative 5-year survival is only 6.4%  making SCLC the most aggressive lung cancer subtype. There are as yet no effective early detection tools for SCLC. It is most often diagnosed due to symptoms associated with disseminated disease such as bulky intrathoracic malignancy or distant metastases. Cough shortness of breath and chest pain are the most common local symptoms and distant signs of the disease include weight loss and weakness. After presentation of symptoms histological analysis of bronchoscopic biopsy samples and cytological study of fine-needle aspiration (FNA) transbronchoscopic needle aspiration (TBNA) or endoscopic ultrasound (EUS)-guided fine-needle aspiration (EUS-FNA) samples are common approaches to confirm SCLC diagnosis [9-12]. The cancer is defined as a malignant epithelial tumor consisting of small cells with altered cytoplasm ill-defined KW-2478 cell borders granular nuclear chromatin and absent or inconspicuous nucleoli. The cells can be round oval or spindle-shaped . KW-2478 It can be difficult to pathologically distinguish SCLC from other lung malignancies including neuroblastoma embryonal rhabdomyosarcoma desmoplastic small round cell tumor primitive peripheral neuroectodermal tumors  poorly differentiated squamous cell carcinomas and large cell carcinomas . Epithelial markers such as cytokeratins and neuroendocrine markers can be employed to differentiate SCLC tumors KW-2478 from the aforementioned lung malignancies. Sampling error is the most commonly reported cause of false negatives in lung FNA cytology [10 15 SCLCs are centrally located and accessing them by FNA is usually Sirt6 more difficult in comparison to peripherally located adenocarcinomas and metastatic neoplasms . In addition the small size of the cells increases the chances KW-2478 of crushing the sample by biopsy forceps or distorting the sample during needle aspiration . Given that accurately diagnosing SCLC can be difficult the development of additional methods such as detection of molecular markers associated with this disease may increase the efficacy of diagnosis. Molecules that might be suitable for this purpose are SCLC-associated autoantibodies. Examples of such KW-2478 antibodies are those found in paraneoplastic neurologic syndromes associated with SCLC. Paraneoplastic neurologic syndromes (PNS) are defined as cancer-associated neurological diseases that damage neuronal tissues in a site remote from the tumor (unrelated to metastasis) . PNS patients typically harbor antibodies directed against neuronal antigens that are abnormally expressed in.