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

• Published in: British journal of cancer Vol. 108; no. 8; pp. 1704 - 1711
• Main Authors: Stovold, R, Meredith, S L, Bryant, J L, Babur, M, Williams, K J, Dean, E J, Dive, C, Blackhall, F H, White, A
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 30.04.2013; Nature Publishing Group
• Subjects: 631/67/322; 692/53/2423; 692/699/67/1612/1350; Animals; Biological and medical sciences; Biomedical and Life Sciences; Biomedicine; Cadherins - biosynthesis; Cancer Research; Carcinoma, Small Cell - blood; Carcinoma, Small Cell - pathology; Drug Resistance; Enzyme-Linked Immunosorbent Assay; Epidemiology; Epithelial Cells - metabolism; Epithelial Cells - pathology; Humans; Keratins - biosynthesis; Liver Neoplasms - blood; Liver Neoplasms - secondary; Lung cancer; Lung Neoplasms - blood; Lung Neoplasms - pathology; Medical sciences; Mice; Mice, Nude; Molecular Diagnostics; Molecular Medicine; Multiple tumors. Solid tumors. Tumors in childhood (general aspects); Neoplasm Metastasis; Neoplastic Cells, Circulating - pathology; Neuroendocrine Cells - metabolism; Neuroendocrine Cells - pathology; Oncology; Phenotype; Pneumology; Pro-Opiomelanocortin - blood; Survival Rate; Transplantation, Heterologous; Tumors; Tumors of the respiratory system and mediastinum; cytokeratin; xenografts; pro-opiomelanocortin; metastasis; Cytokeratin; Lung cancer; Bonchopulmonary small cell carcinoma; Transplantation; Metastasis; Heterograft; Heterotransplantation; Cancerology; Surgery; Graft; Bronchus disease; Human; Lung disease; Respiratory disease; Patient; Malignant tumor; Survival; Phenotype; Treatment; Animal; Epithelial cell; Endocrinology; Cancer
• DOI: 10.1038/bjc.2013.112
• ISSN: 0007-0920

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.