Neuroendocrine and epithelial phenotypes in small-cell lung cancer: implications for metastasis and survival in patients

Abstract

Background:Small-cell lung cancer (SCLC) has a very aggressive clinical course with early metastasis. This study investigated how the distinctive neuroendocrine characteristics contribute to disease progression and invasion in human SCLC.Methods:The neuroendocrine phenotype (pro-opiomelanocortin (POMC)) was quantified by ELISA in blood samples from 43 SCLC patients. The neuroendocrine (POMC, chromogranin A, neuron-specific enolase, NCAM) and epithelial (cytokeratin and E-cadherin) phenotypes were investigated, using ELISA and immunocytochemistry/immunohistochemistry.Results:In SCLC patients, 16% had elevated circulating POMC, which was associated with significantly worse survival (P=0.02) and liver metastases (P=0.004). In addition, POMC correlated with epithelial-positive circulating tumour cells (P=0.0002). In a panel of SCLC cell lines, all POMC-secreting cell lines expressed cytokeratin (40% of total). Even after cloning, DMS 79 cells expressed both neuroendocrine and epithelial markers. DMS 79 xenografts secreted POMC into the blood, which mirrored the tumour volume. These xenografts expressed both neuroendocrine and epithelial phenotypes in all tumours, with both phenotypes prevalent in cells invading the surrounding tissue.Conclusion:Both neuroendocrine and epithelial phenotypes coexist in human SCLC tumours in vitro and in vivo and this persists in invading tumour cells. In patients, POMC secretion predicts poor survival and liver metastases, suggesting a crucial role of the neuroendocrine phenotype.

Cancer Stem Cells, Epithelial to Mesenchymal Markers, and Circulating Tumor Cells in Small Cell Lung Cancer

“…Although epithelial markers can be detected in SCLC, SCLC has a neuroendocrine origin. In a recent report the presence of both neuroendocrine and epithelial markers were detected in SCLC, and a neuroendocrine phenotype correlated with liver metastases and poor survival of patients (Stovold et al, 2013). Thus, in addition to EMT-like events in this tumor M A N U S C R I P T A C C E P T E D ACCEPTED MANUSCRIPT 10 type, also neuroendocrine properties correlate with prognoses and may be relevant to explain the role of the changes in ECad and c-MET in SCLC.…”

11-Dehydrocorticosterone Causes Metabolic Syndrome, Which Is Prevented when 11β-HSD1 Is Knocked Out in Livers of Male Mice

“…Pro-opiomelanocortin (POMC) levels were measured in terminal plasma samples using a specific two-site ELISA as previously described (18). ACTH was measured in terminal plasma samples using a commercially available ELISA (Biomerica, Irvine, California) as previously described (19).…”

Biomarkers for small cell lung cancer: Neuroendocrine, epithelial and circulating tumour cells

“…Recently we have detected elevated levels of circulating POMC in 30% of patients with SCLC [63]. We have also observed, using a mouse xenograft model of a POMC positive human SCLC cell line (DMS 79), that circulating POMC levels mirror tumour growth [64], suggesting a useful role Fig. 3.…”