title: Cell surface marker profiling of human tracheal basal cells reveals distinct subpopulations, identifies MST1/MSP as a mitogenic signal, and identifies new biomarkers for lung squamous cell carcinomas.
abstract: BACKGROUND
  The large airways of the lungs (trachea and bronchi) are lined with a pseudostratified mucociliary epithelium, which is maintained by stem cells/progenitors within the basal cell compartment. Alterations in basal cell behavior can contribute to large airway diseases including squamous cell carcinomas (SQCCs). Basal cells have traditionally been thought of as a uniform population defined by basolateral position, cuboidal cell shape, and expression of pan-basal cell lineage markers like KRT5 and TP63. While some evidence suggests that basal cells are not all functionally equivalent, few heterogeneously expressed markers have been identified to purify and study subpopulations. In addition, few signaling pathways have been identified that regulate their cell behavior. The goals of this work were to investigate tracheal basal cell diversity and to identify new signaling pathways that regulate basal cell behavior.
  
  
  METHODS
  We used flow cytometry (FACS) to profile cell surface marker expression at a single cell level in primary human tracheal basal cell cultures that maintain stem cell/progenitor activity. FACS results were validated with tissue staining, in silico comparisons with normal basal cell and lung cancer datasets, and an in vitro proliferation assay.
  
  
  RESULTS
  We identified 105 surface markers, with 47 markers identifying potential subpopulations. These subpopulations generally fell into more (~ > 13%) or less abundant (~ < 6%) groups. Microarray gene expression profiling supported the heterogeneous expression of these markers in the total population, and immunostaining of large airway tissue suggested that some of these markers are relevant in vivo. 24 markers were enriched in lung SQCCs relative to adenocarcinomas, with four markers having prognostic significance in SQCCs. We also identified 33 signaling receptors, including the MST1R/RON growth factor receptor, whose ligand MST1/MSP was mitogenic for basal cells.
  
  
  CONCLUSIONS
  This work provides the largest description to date of molecular diversity among human large airway basal cells. Furthermore, these markers can be used to further study basal cell function in repair and disease, and may aid in the classification and study of SQCCs.
authors.forename: Emily
authors.initials: E
authors.lastname: Van de Laar
authors.forename: Monica
authors.initials: M
authors.lastname: Clifford
authors.forename: Stefan
authors.initials: S
authors.lastname: Hasenoeder
authors.forename: Bo Ram
authors.initials: BR
authors.lastname: Kim
authors.forename: Dennis
authors.initials: D
authors.lastname: Wang
authors.forename: Sharon
authors.initials: S
authors.lastname: Lee
authors.forename: Josh
authors.initials: J
authors.lastname: Paterson
authors.forename: Nancy M
authors.initials: NM
authors.lastname: Vu
authors.forename: Thomas K
authors.initials: TK
authors.lastname: Waddell
authors.forename: Shaf
authors.initials: S
authors.lastname: Keshavjee
authors.forename: Ming-Sound
authors.initials: MS
authors.lastname: Tsao
authors.forename: Laurie
authors.initials: L
authors.lastname: Ailles
authors.forename: Nadeem
authors.initials: N
authors.lastname: Moghal
mesh_terms: D000368:Aged; D000818:Animals; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism*; D002294:Carcinoma, Squamous Cell / Q000235:genetics / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D045744:Cell Line, Tumor; D019070:Cell Lineage; D049109:Cell Proliferation; D004847:Epithelial Cells / Q000378:metabolism* / Q000637:transplantation; D005434:Flow Cytometry / Q000379:methods*; D020869:Gene Expression Profiling; D017228:Hepatocyte Growth Factor / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007150:Immunohistochemistry; D053208:Kaplan-Meier Estimate; D008175:Lung Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D008297:Male; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D008875:Middle Aged; D011379:Prognosis; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D051381:Rats; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism; D015203:Reproducibility of Results; D015398:Signal Transduction; D033581:Stem Cell Transplantation; D013234:Stem Cells / Q000378:metabolism*; D013997:Time Factors; D014132:Trachea / Q000378:metabolism* / Q000637:transplantation
chemical_list: D014408:Biomarkers, Tumor; D011518:Proto-Oncogene Proteins; C082332:macrophage stimulating protein; D017228:Hepatocyte Growth Factor; C080835:RON protein; D020794:Receptor Protein-Tyrosine Kinases