title: Anaplastic large cell lymphoma-propagating cells are detectable by side population analysis and possess an expression profile reflective of a primitive origin.
abstract: Cancer stem cells or tumour-propagating cells (TPCs) have been identified for a number of cancers, but data pertaining to their existence in lymphoma so far remain elusive. We show for the first time that a small subset of cells purified from human anaplastic lymphoma kinase (ALK)-positive and -negative, anaplastic large cell lymphoma cell lines and primary patient tumours using the side population (SP) technique have serial tumour-propagating capacity both in vitro and in vivo; they give rise to both themselves and the bulk tumour population as well as supporting growth of the latter through the production of soluble factors. In vivo serial dilution assays utilising a variety of model systems inclusive of human cell lines, primary human tumours and nucleophosmin (NPM)-ALK-induced murine tumours demonstrate the TPC frequency to vary from as many as 1/54 to 1/1336 tumour cells. In addition, the SP cells express higher levels of pluripotency-associated transcription factors and are enriched for a gene expression profile consistent with early thymic progenitors. Finally, our data show that the SP cells express higher levels of the NPM-ALK oncogene and are sensitive to an ALK inhibitor.
authors.affiliation: Division of Molecular Histopathology, Department of Pathology, University of Cambridge, Cambridge, UK.
authors.forename: N
authors.initials: N
authors.lastname: Moti
authors.affiliation: Division of Molecular Histopathology, Department of Pathology, University of Cambridge, Cambridge, UK.
authors.forename: T
authors.initials: T
authors.lastname: Malcolm
authors.affiliation: Division of Molecular Histopathology, Department of Pathology, University of Cambridge, Cambridge, UK.
authors.forename: R
authors.initials: R
authors.lastname: Hamoudi
authors.affiliation: Molecular Diagnostics and Personalised Therapeutics Unit, College of Applied Medical Sciences, University of Ha'il, Ha'il, Kingdom of Saudi Arabia.
authors.forename: S
authors.initials: S
authors.lastname: Mian
authors.affiliation: Division of Molecular Histopathology, Department of Pathology, University of Cambridge, Cambridge, UK.
authors.forename: G
authors.initials: G
authors.lastname: Garland
authors.affiliation: Department of Histopathology and Cytology, Addenbrooke's Hospital, Cambridge, UK.
authors.forename: C E
authors.initials: CE
authors.lastname: Hook
authors.affiliation: Department of Paediatric Oncology, Addenbrooke's Hospital, Cambridge, UK.
authors.forename: G A A
authors.initials: GA
authors.lastname: Burke
authors.affiliation: Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: M A
authors.initials: MA
authors.lastname: Wasik
authors.affiliation: 1] Department for Translational Oncology, National Center for Tumor Diseases (NCT), German Cancer Research Center (DKFZ), Im Neuenheimer Feld, Heidelberg, Germany [2] European Research Initiative on ALK related malignancies (ERIA).
authors.forename: O
authors.initials: O
authors.lastname: Merkel
authors.affiliation: 1] European Research Initiative on ALK related malignancies (ERIA) [2] Clinical Institute of Pathology, Medical University of Vienna, Vienna, Austria [3] Ludwig Boltzmann Institute for Cancer Research (LBI-CR), Vienna, Austria.
authors.forename: L
authors.initials: L
authors.lastname: Kenner
authors.affiliation: 1] Campbell Family Institute, Ontario Cancer Institute, Princess Margaret Hospital, University Health Network, Toronto, ON, Canada [2] Department of Molecular Genetics, University of Toronto, Toronto, ON, Canada.
authors.forename: E
authors.initials: E
authors.lastname: Laurenti
authors.affiliation: 1] Campbell Family Institute, Ontario Cancer Institute, Princess Margaret Hospital, University Health Network, Toronto, ON, Canada [2] Department of Molecular Genetics, University of Toronto, Toronto, ON, Canada.
authors.forename: J E
authors.initials: JE
authors.lastname: Dick
authors.affiliation: 1] Division of Molecular Histopathology, Department of Pathology, University of Cambridge, Cambridge, UK [2] European Research Initiative on ALK related malignancies (ERIA).
authors.forename: S D
authors.initials: SD
authors.lastname: Turner
mesh_terms: D000328:Adult; D000369:Aged, 80 and over; D000077548:Anaplastic Lymphoma Kinase; D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology; D017209:Apoptosis; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002470:Cell Survival; D002648:Child; D002675:Child, Preschool; D000077547:Crizotinib; D005047:Etoposide / Q000494:pharmacology; D005260:Female; D020869:Gene Expression Profiling; D006801:Humans; D017728:Lymphoma, Large-Cell, Anaplastic / Q000235:genetics / Q000473:pathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008875:Middle Aged; D014411:Neoplastic Stem Cells / Q000166:cytology; D009687:Nuclear Proteins / Q000378:metabolism*; D000090243:Nucleophosmin; D039904:Pluripotent Stem Cells / Q000166:cytology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D019009:Proto-Oncogene Proteins c-kit / Q000096:biosynthesis; D011720:Pyrazoles / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology; D020794:Receptor Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D058985:Side-Population Cells / Q000166:cytology* / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D000972:Antineoplastic Agents, Phytogenic; C000716967:NPM1 protein, human; D009687:Nuclear Proteins; D047428:Protein Kinase Inhibitors; D011720:Pyrazoles; D011725:Pyridines; D000090243:Nucleophosmin; D000077547:Crizotinib; D005047:Etoposide; C000626173:ALK protein, human; C000626174:Alk protein, mouse; D000077548:Anaplastic Lymphoma Kinase; D019009:Proto-Oncogene Proteins c-kit; D020794:Receptor Protein-Tyrosine Kinases