title: TMPRSS4 induces cancer stem cell-like properties in lung cancer cells and correlates with ALDH expression in NSCLC patients.
abstract: Metastasis involves a series of changes in cancer cells that promote their escape from the primary tumor and colonization to a new organ. This process is related to the transition from an epithelial to a mesenchymal phenotype (EMT). Recently, some authors have shown that migratory cells with an EMT phenotype share properties of cancer stem cells (CSCs), which allow them to form a new tumor mass. The type II transmembrane serine protease TMPRSS4 is highly expressed in some solid tumors, promotes metastasis and confers EMT features to cancer cells. We hypothesized that TMPRSS4 could also provide CSC properties. Overexpression of TMPRSS4 reduces E-cadherin and induces N-cadherin and vimentin in A549 lung cancer cells, supporting an EMT phenotype. These changes are accompanied by enhanced migration, invasion and tumorigenicity in vivo. TMPRSS4 expression was highly increased in a panel of lung cancer cells cultured as tumorspheres (a typical assay to enrich for CSCs). H358 and H441 cells with knocked-down TMPRSS4 levels were significantly less able to form primary and secondary tumorspheres than control cells. Moreover, they showed a lower proportion of ALDH+ cells (examined by FACS analysis) and lower expression of some CSC markers than controls. A549 cells overexpressing TMPRSS4 conferred the opposite phenotype and were also more sensitive to the CSC-targeted drug salinomycin than control cells, but were more resistant to regular chemotherapeutic drugs (cisplatin, gemcitabine and 5-fluorouracil). Analysis of 70 NSCLC samples from patients revealed a very significant correlation between TMPRSS4 expression and CSC markers ALDH (p = 0.0018) and OCT4 (p = 0.0004), suggesting that TMPRSS4 is associated with a CSC phenotype in patients' tumors. These results show that TMPRSS4, in addition to inducing EMT, can also promote CSC features in lung cancer; therefore, CSC-targeting drugs could be an appropriate treatment for TMPRSS4+ tumors.
authors.affiliation: Department of Histology and Pathology, School of Medicine, University of Navarra, C/Irunlarrea 1, 31008 Pamplona, Spain; Program of Solid Tumors and Biomarkers, Center for Applied Medical Research (CIMA), University of Navarra, Pamplona, Spain.
authors.forename: Arrate L
authors.initials: AL
authors.lastname: de Aberasturi
authors.affiliation: Program of Solid Tumors and Biomarkers, Center for Applied Medical Research (CIMA), University of Navarra, Pamplona, Spain.
authors.forename: Miriam
authors.initials: M
authors.lastname: Redrado
authors.affiliation: Department of Histology and Pathology, School of Medicine, University of Navarra, C/Irunlarrea 1, 31008 Pamplona, Spain; Program of Solid Tumors and Biomarkers, Center for Applied Medical Research (CIMA), University of Navarra, Pamplona, Spain.
authors.forename: Maria
authors.initials: M
authors.lastname: Villalba
authors.affiliation: Program of Solid Tumors and Biomarkers, Center for Applied Medical Research (CIMA), University of Navarra, Pamplona, Spain.
authors.forename: Leyre
authors.initials: L
authors.lastname: Larzabal
authors.affiliation: Department of Histology and Pathology, School of Medicine, University of Navarra, C/Irunlarrea 1, 31008 Pamplona, Spain; Program of Solid Tumors and Biomarkers, Center for Applied Medical Research (CIMA), University of Navarra, Pamplona, Spain.
authors.forename: Maria J
authors.initials: MJ
authors.lastname: Pajares
authors.affiliation: Department of Histology and Pathology, School of Medicine, University of Navarra, C/Irunlarrea 1, 31008 Pamplona, Spain.
authors.forename: Javier
authors.initials: J
authors.lastname: Garcia
authors.affiliation: Program of Solid Tumors and Biomarkers, Center for Applied Medical Research (CIMA), University of Navarra, Pamplona, Spain.
authors.forename: Stephanie R
authors.initials: SR
authors.lastname: Evans
authors.affiliation: Department of Histology and Pathology, School of Medicine, University of Navarra, C/Irunlarrea 1, 31008 Pamplona, Spain.
authors.forename: David
authors.initials: D
authors.lastname: Garcia-Ros
authors.affiliation: Department of Histology and Pathology, School of Medicine, University of Navarra, C/Irunlarrea 1, 31008 Pamplona, Spain.
authors.forename: Maria Elena
authors.initials: ME
authors.lastname: Bodegas
authors.affiliation: Ingenasa Inc., Madrid, Spain.
authors.forename: Lissett
authors.initials: L
authors.lastname: Lopez
authors.affiliation: Department of Histology and Pathology, School of Medicine, University of Navarra, C/Irunlarrea 1, 31008 Pamplona, Spain; Program of Solid Tumors and Biomarkers, Center for Applied Medical Research (CIMA), University of Navarra, Pamplona, Spain.
authors.forename: Luis
authors.initials: L
authors.lastname: Montuenga
authors.affiliation: Department of Histology and Pathology, School of Medicine, University of Navarra, C/Irunlarrea 1, 31008 Pamplona, Spain; Program of Solid Tumors and Biomarkers, Center for Applied Medical Research (CIMA), University of Navarra, Pamplona, Spain. Electronic address: acalvo@unav.es.
authors.forename: Alfonso
authors.initials: A
authors.lastname: Calvo
mesh_terms: D000444:Aldehyde Dehydrogenase / Q000032:analysis*; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy / Q000473:pathology*; D045744:Cell Line, Tumor; D002465:Cell Movement; D049109:Cell Proliferation; D058750:Epithelial-Mesenchymal Transition; D005260:Female; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy / Q000473:pathology*; D008297:Male; D008565:Membrane Proteins / Q000032:analysis / Q000037:antagonists & inhibitors / Q000502:physiology*; D009361:Neoplasm Invasiveness; D014411:Neoplastic Stem Cells / Q000187:drug effects* / Q000502:physiology; D050814:Octamer Transcription Factor-3 / Q000032:analysis; D051057:Proto-Oncogene Proteins c-akt / Q000502:physiology; D012697:Serine Endopeptidases / Q000032:analysis / Q000502:physiology*
chemical_list: D008565:Membrane Proteins; D050814:Octamer Transcription Factor-3; C494173:POU5F1 protein, human; D000444:Aldehyde Dehydrogenase; D051057:Proto-Oncogene Proteins c-akt; D012697:Serine Endopeptidases; C528837:TMPRSS4 protein, human
keywords: ALDH; Cancer stem cells; Lung cancer; TMPRSS4; Tumorspheres