title: Irradiation Decreases the Neuroendocrine Biomarker Pro-Opiomelanocortin in Small Cell Lung Cancer Cells In Vitro and In Vivo.
abstract: BACKGROUND
  Small cell lung cancer (SCLC) is an extremely aggressive disease, commonly displaying therapy-resistant relapse. We have previously identified neuroendocrine and epithelial phenotypes in SCLC tumours and the neuroendocrine marker, pro-opiomelanocortin (POMC), correlated with worse overall survival in patients. However, the effect of treatment on these phenotypes is not understood. The current study aimed to determine the effect of repeated irradiation treatment on SCLC cell phenotype, focussing on the neuroendocrine marker, POMC.
  
  
  RESULTS
  Human SCLC cells (DMS 79) were established as subcutaneous xenograft tumours in CBA nude mice and then exposed to repeated 2Gy irradiation. In untreated animals, POMC in the blood closely mirrored tumour growth; an ideal characteristic for a circulating biomarker. Following repeated localised irradiation in vivo, circulating POMC decreased (p< 0.01), in parallel with a decrease in tumour size, but remained low even when the tumours re-established. The excised tumours displayed reduced and distinctly heterogeneous expression of POMC compared to untreated tumours. There was no difference in the epithelial marker, cytokeratin. However, there were significantly more N-cadherin positive cells in the irradiated tumours. To investigate the tumour response to irradiation, DMS79 cells were repeatedly irradiated in vitro and the surviving cells selected. POMC expression was reduced, while mesenchymal markers N-cadherin, β1-integrin, fibroblast-specific protein 1, β-catenin and Zeb1 expression were amplified in the more irradiation-primed cells. There were no consistent changes in epithelial marker expression. Cell morphology changed dramatically with repeatedly irradiated cells displaying a more elongated shape, suggesting a switch to a more mesenchymal phenotype.
  
  
  CONCLUSIONS
  In summary, POMC biomarker expression and secretion were reduced in SCLC tumours which regrew after irradiation and in repeatedly irradiation (irradiation-primed) cells. Therefore, POMC was no longer predictive of tumour burden. This highlights the importance of fully evaluating biomarkers during and after therapy to assess clinical utility. Furthermore, the gain in mesenchymal characteristics in irradiated cells could be indicative of a more invasive phenotype.
authors: Faculty of Medical and Human Sciences, University of Manchester, Manchester, M13 9PT, United Kingdom.
authors: Suzanne L
authors: SL
authors: Meredith
authors: Faculty of Medical and Human Sciences, University of Manchester, Manchester, M13 9PT, United Kingdom.|Faculty of Life Sciences, University of Manchester, Manchester, M13 9PT, United Kingdom.
authors: Jennifer L
authors: JL
authors: Bryant
authors: Faculty of Medical and Human Sciences, University of Manchester, Manchester, M13 9PT, United Kingdom.
authors: Muhammad
authors: M
authors: Babur
authors: Faculty of Life Sciences, University of Manchester, Manchester, M13 9PT, United Kingdom.
authors: Philip W
authors: PW
authors: Riddell
authors: Faculty of Medical and Human Sciences, University of Manchester, Manchester, M13 9PT, United Kingdom.
authors: Roya
authors: R
authors: Behrouzi
authors: Faculty of Medical and Human Sciences, University of Manchester, Manchester, M13 9PT, United Kingdom.
authors: Kaye J
authors: KJ
authors: Williams
authors: Faculty of Medical and Human Sciences, University of Manchester, Manchester, M13 9PT, United Kingdom.|Faculty of Life Sciences, University of Manchester, Manchester, M13 9PT, United Kingdom.
authors: Anne
authors: A
authors: White
mesh_terms: D000818:Animals; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000528:radiation effects; D002471:Cell Transformation, Neoplastic; D004307:Dose-Response Relationship, Radiation; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000528:radiation effects; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology* / Q000532:radiotherapy; D008648:Mesoderm / Q000473:pathology / Q000528:radiation effects; D051379:Mice; D055099:Neuroendocrine Cells / Q000378:metabolism* / Q000473:pathology / Q000528:radiation effects*; D010641:Phenotype; D011333:Pro-Opiomelanocortin / Q000235:genetics / Q000378:metabolism*; D055752:Small Cell Lung Carcinoma / Q000235:genetics / Q000378:metabolism / Q000473:pathology* / Q000532:radiotherapy
chemical_list: D014408:Biomarkers, Tumor; D011333:Pro-Opiomelanocortin