title: 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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Faculty of Life Sciences, Manchester Academic Health Sciences Centre, University of Manchester, 3.016 AV Hill Building, Manchester M13 9PT, UK.
authors.forename: R
authors.initials: R
authors.lastname: Stovold
authors.forename: S L
authors.initials: SL
authors.lastname: Meredith
authors.forename: J L
authors.initials: JL
authors.lastname: Bryant
authors.forename: M
authors.initials: M
authors.lastname: Babur
authors.forename: K J
authors.initials: KJ
authors.lastname: Williams
authors.forename: E J
authors.initials: EJ
authors.lastname: Dean
authors.forename: C
authors.initials: C
authors.lastname: Dive
authors.forename: F H
authors.initials: FH
authors.lastname: Blackhall
authors.forename: A
authors.initials: A
authors.lastname: White
mesh_terms: D000818:Animals; D015820:Cadherins / Q000096:biosynthesis; D018288:Carcinoma, Small Cell / Q000097:blood* / Q000473:pathology*; D004797:Enzyme-Linked Immunosorbent Assay; D004847:Epithelial Cells / Q000378:metabolism / Q000473:pathology*; D006801:Humans; D007633:Keratins / Q000096:biosynthesis; D008113:Liver Neoplasms / Q000097:blood / Q000556:secondary; D008175:Lung Neoplasms / Q000097:blood* / Q000473:pathology*; D051379:Mice; D008819:Mice, Nude; D009362:Neoplasm Metastasis; D009360:Neoplastic Cells, Circulating / Q000473:pathology; D055099:Neuroendocrine Cells / Q000378:metabolism / Q000473:pathology*; D010641:Phenotype; D011333:Pro-Opiomelanocortin / Q000097:blood*; D015996:Survival Rate; D014183:Transplantation, Heterologous
chemical_list: D015820:Cadherins; D011333:Pro-Opiomelanocortin; D007633:Keratins