title: CD133+ cancer stem-like cells in small cell lung cancer are highly tumorigenic and chemoresistant but sensitive to a novel neuropeptide antagonist.
abstract: Small cell lung cancer (SCLC) is a highly aggressive malignancy with poor survival rates, with initial responses nearly invariably followed by rapid recurrence of therapy-resistant disease. Drug resistance in SCLC may be attributable to the persistence of a subpopulation of cancer stem-like cells (CSC) that exhibit multiple drug resistance. In this study, we characterized the expression of CD133, one important marker of CSC in other cancers, in SCLC cancer cells. CD133 expression correlated with chemoresistance and increased tumorigenicity in vitro and in vivo accompanied by increased expression of Akt/PKB and Bcl-2. CD133 expression was increased in mouse and human SCLC after chemotherapy, an observation confirmed in clinical specimens isolated longitudinally from a patient receiving chemotherapy. We discovered in CD133(+) SCLC cells, an increased expression of the mitogenic neuropeptide receptors for gastrin-releasing peptide and arginine vasopressin. Notably, these cells exhibited increased sensitivity to the growth inhibitory and proapoptotic effects of a novel broad spectrum neuropeptide antagonist (related to SP-G), which has completed a phase I clinical trial for SCLC. Our results offer evidence that this agent can preferentially target chemoresistant CD133(+) cells with CSC character in SCLC, emphasizing its potential utility for improving therapy in this setting.
authors.affiliation: Authors' Affiliations: MRC Centre for Inflammation Research, The Queen's Medical Research Institute; MRC Centre for Regenerative Medicine; School of Chemistry, Joseph Black Building, University of Edinburgh, Edinburgh; Department of Thoracic Oncology, Papworth Hospital NHS Foundation Trust, Cambridge; and Department of Respiratory Medicine and Allergy, Kings College Denmark Hill Campus, London, United Kingdom.
authors.forename: Sana
authors.initials: S
authors.lastname: Sarvi
authors.forename: Alison C
authors.initials: AC
authors.lastname: Mackinnon
authors.forename: Nicolaos
authors.initials: N
authors.lastname: Avlonitis
authors.forename: Mark
authors.initials: M
authors.lastname: Bradley
authors.forename: Robert C
authors.initials: RC
authors.lastname: Rintoul
authors.forename: Doris M
authors.initials: DM
authors.lastname: Rassl
authors.forename: Wei
authors.initials: W
authors.lastname: Wang
authors.forename: Stuart J
authors.initials: SJ
authors.lastname: Forbes
authors.forename: Christopher D
authors.initials: CD
authors.lastname: Gregory
authors.forename: Tariq
authors.initials: T
authors.lastname: Sethi
mesh_terms: D000071916:AC133 Antigen; D000818:Animals; D015703:Antigens, CD / Q000235:genetics* / Q000378:metabolism*; D063646:Carcinogenesis / Q000235:genetics; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D005260:Female; D006023:Glycoproteins / Q000235:genetics* / Q000378:metabolism*; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D014411:Neoplastic Stem Cells / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D009479:Neuropeptides / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D010455:Peptides / Q000235:genetics* / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism; D018013:Receptors, Neuropeptide / Q000235:genetics / Q000378:metabolism; D055752:Small Cell Lung Carcinoma / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology
chemical_list: D000071916:AC133 Antigen; D015703:Antigens, CD; D006023:Glycoproteins; D009479:Neuropeptides; C000606023:PROM1 protein, human; D010455:Peptides; C000606024:Prom1 protein, mouse; D018013:Receptors, Neuropeptide; D051057:Proto-Oncogene Proteins c-akt