title: Squamous cell cancers contain a side population of stem-like cells that are made chemosensitive by ABC transporter blockade.
abstract: Cancers are a heterogeneous mix of cells, some of which exhibit cancer stem cell-like characteristics including ATP-dependent drug efflux and elevated tumorigenic potential. To determine whether aerodigestive squamous cell carcinomas (SCCs) contain a subpopulation of cancer stem cell-like cells, we performed Hoechst dye efflux assays using four independent cell lines. Results revealed the presence of a rare, drug effluxing stem cell-like side population (SP) of cells within all cell lines tested (SCC-SP cells). These cells resembled previously characterised epithelial stem cells, and SCC-SP cell abundance was positively correlated with overall cellular density and individual cell quiescence. Serial SCC-SP fractionation and passaging increased their relative abundance within the total cell population. Purified SCC-SP cells also exhibited increased clonogenic potential in secondary cultures and enhanced tumorigenicity in vivo. Despite this, SCC-SP cells remained chemotherapeutically sensitive upon ATP-dependent transporter inhibition. Overall, these findings suggest that the existence of ATP transporter-dependent cancer stem-like cells may be relatively common, particularly within established tumours. Future chemotherapeutic strategies should therefore consider coupling identification and targeting of this potential stem cell-like population with standard treatment methodologies.
authors.affiliation: Centre For Respiratory Research, Rayne Institute, University College London, 5 University Street, London WC1E 6JJ, UK.
authors.forename: M R
authors.initials: MR
authors.lastname: Loebinger
authors.forename: A
authors.initials: A
authors.lastname: Giangreco
authors.forename: K R
authors.initials: KR
authors.lastname: Groot
authors.forename: L
authors.initials: L
authors.lastname: Prichard
authors.forename: K
authors.initials: K
authors.lastname: Allen
authors.forename: C
authors.initials: C
authors.lastname: Simpson
authors.forename: L
authors.initials: L
authors.lastname: Bazley
authors.forename: N
authors.initials: N
authors.lastname: Navani
authors.forename: S
authors.initials: S
authors.lastname: Tibrewal
authors.forename: D
authors.initials: D
authors.lastname: Davies
authors.forename: S M
authors.initials: SM
authors.lastname: Janes
mesh_terms: D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D014408:Biomarkers, Tumor / Q000378:metabolism; D002294:Carcinoma, Squamous Cell / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D002452:Cell Count; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002469:Cell Separation; D019008:Drug Resistance, Neoplasm / Q000187:drug effects* / Q000235:genetics; D006801:Humans; D008297:Male; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000235:genetics / Q000378:metabolism; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism; D014411:Neoplastic Stem Cells / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D014700:Verapamil / Q000494:pharmacology; D023041:Xenograft Model Antitumor Assays
chemical_list: D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D009363:Neoplasm Proteins; D014700:Verapamil; C116614:ABCG2 protein, human; C421109:multidrug resistance-associated protein 1