title: Achaete-scute complex homologue 1 regulates tumor-initiating capacity in human small cell lung cancer.
abstract: The basic helix-loop-helix transcription factor achaete-scute complex homologue 1 (ASCL1) is essential for the development of normal lung neuroendocrine cells as well as other endocrine and neural tissues. Small cell lung cancer (SCLC) and non-SCLC with neuroendocrine features express ASCL1, where the factor may play a role in the virulence and primitive neuroendocrine phenotype of these tumors. In this study, RNA interference knockdown of ASCL1 in cultured SCLC resulted in inhibition of soft agar clonogenic capacity and induction of apoptosis. cDNA microarray analyses bolstered by expression studies, flow cytometry, and chromatin immunoprecipitation identified two candidate stem cell marker genes, CD133 and aldehyde dehydrogenase 1A1 (ALDH1A1), to be directly regulated by ASCL1 in SCLC. In SCLC direct xenograft tumors, we detected a relatively abundant CD133(high)-ASCL1(high)-ALDH1(high) subpopulation with markedly enhanced tumorigenicity compared with cells with weak CD133 expression. Tumorigenicity in the CD133(high) subpopulation depended on continued ASCL1 expression. Whereas CD133(high) cells readily reconstituted the range of CD133 expression seen in the original xenograft tumor, CD133(low) cells could not. Our findings suggest that a broad range of SCLC cells has tumorigenic capacity rather than a small discrete population. Intrinsic tumor cell heterogeneity, including variation in key regulatory factors such as ASCL1, can modulate tumorigenicity in SCLC.
authors.affiliation: Departments of Oncology, Johns Hopkins University School of Medicine, Baltimore, Maryland 21231, USA.
authors.forename: Tianyun
authors.initials: T
authors.lastname: Jiang
authors.forename: Brendan J
authors.initials: BJ
authors.lastname: Collins
authors.forename: Ning
authors.initials: N
authors.lastname: Jin
authors.forename: David N
authors.initials: DN
authors.lastname: Watkins
authors.forename: Malcolm V
authors.initials: MV
authors.lastname: Brock
authors.forename: William
authors.initials: W
authors.lastname: Matsui
authors.forename: Barry D
authors.initials: BD
authors.lastname: Nelkin
authors.forename: Douglas W
authors.initials: DW
authors.lastname: Ball
mesh_terms: D000071916:AC133 Antigen; D000444:Aldehyde Dehydrogenase / Q000096:biosynthesis / Q000235:genetics; D000080924:Aldehyde Dehydrogenase 1 Family; D000818:Animals; D015703:Antigens, CD / Q000096:biosynthesis / Q000235:genetics; D017209:Apoptosis / Q000502:physiology; D051792:Basic Helix-Loop-Helix Proteins / Q000096:biosynthesis* / Q000235:genetics; D018288:Carcinoma, Small Cell / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D048708:Cell Growth Processes / Q000502:physiology; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006023:Glycoproteins / Q000096:biosynthesis / Q000235:genetics; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008819:Mice, Nude; D010455:Peptides / Q000235:genetics; D050697:Retinal Dehydrogenase; D014183:Transplantation, Heterologous
chemical_list: D000071916:AC133 Antigen; D000444:Aldehyde Dehydrogenase; D000080924:Aldehyde Dehydrogenase 1 Family; D015703:Antigens, CD; D051792:Basic Helix-Loop-Helix Proteins; D006023:Glycoproteins; D010455:Peptides; D050697:Retinal Dehydrogenase; C065500:ASCL1 protein, human; C000606023:PROM1 protein, human; C000606024:Prom1 protein, mouse; C510223:ALDH1A1 protein, human