title: Intracellular autofluorescence: a biomarker for epithelial cancer stem cells.
abstract: Cancer stem cells (CSCs) are thought to drive tumor growth, metastasis and chemoresistance. Although surface markers such as CD133 and CD44 have been successfully used to isolate CSCs, their expression is not exclusively linked to the CSC phenotype and is prone to environmental alteration. We identified cells with an autofluorescent subcellular compartment that exclusively showed CSC features across different human tumor types. Primary tumor-derived autofluorescent cells did not overlap with side-population (SP) cells, were enriched in sphere culture and during chemotherapy, strongly expressed pluripotency-associated genes, were highly metastatic and showed long-term in vivo tumorigenicity, even at the single-cell level. Autofluorescence was due to riboflavin accumulation in membrane-bounded cytoplasmic structures bearing ATP-dependent ABCG2 transporters. In summary, we identified and characterized an intrinsic autofluorescent phenotype in CSCs of diverse epithelial cancers and used this marker to isolate and characterize these cells.
authors.affiliation: Stem Cells and Cancer Group, Molecular Pathology Programme, Spanish National Cancer Research Centre (CNIO), Madrid, Spain.
authors.forename: Irene
authors.initials: I
authors.lastname: Miranda-Lorenzo
authors.affiliation: Stem Cells and Cancer Group, Molecular Pathology Programme, Spanish National Cancer Research Centre (CNIO), Madrid, Spain.
authors.forename: Jorge
authors.initials: J
authors.lastname: Dorado
authors.affiliation: Stem Cells and Cancer Group, Molecular Pathology Programme, Spanish National Cancer Research Centre (CNIO), Madrid, Spain.
authors.forename: Enza
authors.initials: E
authors.lastname: Lonardo
authors.affiliation: Stem Cells and Cancer Group, Molecular Pathology Programme, Spanish National Cancer Research Centre (CNIO), Madrid, Spain.
authors.forename: Sonia
authors.initials: S
authors.lastname: Alcala
authors.affiliation: Melanoma Group, Molecular Pathology Programme, CNIO, Madrid, Spain.
authors.forename: Alicia G
authors.initials: AG
authors.lastname: Serrano
authors.affiliation: Stem Cells and Cancer Group, Molecular Pathology Programme, Spanish National Cancer Research Centre (CNIO), Madrid, Spain.
authors.forename: Jenifer
authors.initials: J
authors.lastname: Clausell-Tormos
authors.affiliation: Stem Cells and Cancer Group, Molecular Pathology Programme, Spanish National Cancer Research Centre (CNIO), Madrid, Spain.
authors.forename: Michele
authors.initials: M
authors.lastname: Cioffi
authors.affiliation: Confocal Microscopy Unit, Biotechnology Programme, CNIO, Madrid, Spain.
authors.forename: Diego
authors.initials: D
authors.lastname: Megias
authors.affiliation: Stem Cells and Cancer Group, Molecular Pathology Programme, Spanish National Cancer Research Centre (CNIO), Madrid, Spain.
authors.forename: Sladjana
authors.initials: S
authors.lastname: Zagorac
authors.affiliation: Stem Cells and Cancer Group, Molecular Pathology Programme, Spanish National Cancer Research Centre (CNIO), Madrid, Spain.
authors.forename: Anamaria
authors.initials: A
authors.lastname: Balic
authors.affiliation: Gastrointestinal Cancer Clinical Research Unit, Clinical Research Programme, CNIO, Madrid, Spain.
authors.forename: Manuel
authors.initials: M
authors.lastname: Hidalgo
authors.affiliation: Chirurgische Klinik, Technische Universität München, Munich, Germany.
authors.forename: Mert
authors.initials: M
authors.lastname: Erkan
authors.affiliation: Chirurgische Klinik, Technische Universität München, Munich, Germany.
authors.forename: Joerg
authors.initials: J
authors.lastname: Kleeff
authors.affiliation: Università degli Studi di Verona, Centro Ricerca Applicata ARC-NET, Verona, Italy.
authors.forename: Aldo
authors.initials: A
authors.lastname: Scarpa
authors.affiliation: Stem Cells and Cancer Group, Molecular Pathology Programme, Spanish National Cancer Research Centre (CNIO), Madrid, Spain.
authors.forename: Bruno
authors.initials: B
authors.lastname: Sainz
authors.affiliation: 1] Stem Cells and Cancer Group, Molecular Pathology Programme, Spanish National Cancer Research Centre (CNIO), Madrid, Spain. [2] Centre for Stem Cells in Cancer &Ageing, Barts Cancer Institute, Queen Mary University of London, London, UK.
authors.forename: Christopher
authors.initials: C
authors.lastname: Heeschen
mesh_terms: D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000378:metabolism; D000818:Animals; D001343:Autophagy; D000071192:Autophagy-Related Protein 12; D014408:Biomarkers, Tumor / Q000378:metabolism*; D006528:Carcinoma, Hepatocellular / Q000473:pathology; D002289:Carcinoma, Non-Small-Cell Lung / Q000473:pathology; D021441:Carcinoma, Pancreatic Ductal / Q000473:pathology; D002469:Cell Separation / Q000379:methods*; D015179:Colorectal Neoplasms / Q000473:pathology; D005260:Female; D006801:Humans; D008113:Liver Neoplasms / Q000473:pathology; D008175:Lung Neoplasms / Q000473:pathology; D051379:Mice; D008819:Mice, Nude; D008869:Microtubule-Associated Proteins / Q000096:biosynthesis; D009363:Neoplasm Proteins / Q000378:metabolism; D014411:Neoplastic Stem Cells / Q000378:metabolism* / Q000473:pathology*; D061848:Optical Imaging / Q000379:methods*; D010190:Pancreatic Neoplasms / Q000473:pathology; D012256:Riboflavin / Q000378:metabolism*; D025841:Small Ubiquitin-Related Modifier Proteins / Q000096:biosynthesis; D014407:Tumor Cells, Cultured
chemical_list: C116614:ABCG2 protein, human; C466624:ATG12 protein, human; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; D000071192:Autophagy-Related Protein 12; D014408:Biomarkers, Tumor; C477012:MAP1LC3A protein, human; D008869:Microtubule-Associated Proteins; D009363:Neoplasm Proteins; D025841:Small Ubiquitin-Related Modifier Proteins; D012256:Riboflavin