title: Self-renewal as a therapeutic target in human colorectal cancer.
abstract: Tumor recurrence following treatment remains a major clinical challenge. Evidence from xenograft models and human trials indicates selective enrichment of cancer-initiating cells (CICs) in tumors that survive therapy. Together with recent reports showing that CIC gene signatures influence patient survival, these studies predict that targeting self-renewal, the key 'stemness' property unique to CICs, may represent a new paradigm in cancer therapy. Here we demonstrate that tumor formation and, more specifically, human colorectal CIC function are dependent on the canonical self-renewal regulator BMI-1. Downregulation of BMI-1 inhibits the ability of colorectal CICs to self-renew, resulting in the abrogation of their tumorigenic potential. Treatment of primary colorectal cancer xenografts with a small-molecule BMI-1 inhibitor resulted in colorectal CIC loss with long-term and irreversible impairment of tumor growth. Targeting the BMI-1-related self-renewal machinery provides the basis for a new therapeutic approach in the treatment of colorectal cancer.
authors.affiliation: 1] Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada. [2] Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Antonija
authors.initials: A
authors.lastname: Kreso
authors.affiliation: Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada.
authors.forename: Peter
authors.initials: P
authors.lastname: van Galen
authors.affiliation: 1] Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada. [2] Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Nicholas M
authors.initials: NM
authors.lastname: Pedley
authors.affiliation: Structural Genomics Consortium, Toronto, Ontario, Canada.
authors.forename: Evelyne
authors.initials: E
authors.lastname: Lima-Fernandes
authors.affiliation: 1] Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada. [2] Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Catherine
authors.initials: C
authors.lastname: Frelin
authors.affiliation: PTC Therapeutics, South Plainfield, New Jersey, USA.
authors.forename: Thomas
authors.initials: T
authors.lastname: Davis
authors.affiliation: PTC Therapeutics, South Plainfield, New Jersey, USA.
authors.forename: Liangxian
authors.initials: L
authors.lastname: Cao
authors.affiliation: PTC Therapeutics, South Plainfield, New Jersey, USA.
authors.forename: Ramil
authors.initials: R
authors.lastname: Baiazitov
authors.affiliation: PTC Therapeutics, South Plainfield, New Jersey, USA.
authors.forename: Wu
authors.initials: W
authors.lastname: Du
authors.affiliation: PTC Therapeutics, South Plainfield, New Jersey, USA.
authors.forename: Nadiya
authors.initials: N
authors.lastname: Sydorenko
authors.affiliation: PTC Therapeutics, South Plainfield, New Jersey, USA.
authors.forename: Young-Choon
authors.initials: YC
authors.lastname: Moon
authors.affiliation: 1] Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada. [2] Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Lianne
authors.initials: L
authors.lastname: Gibson
authors.affiliation: 1] Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada. [2] Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Yadong
authors.initials: Y
authors.lastname: Wang
authors.affiliation: 1] Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada. [2] Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Cherry
authors.initials: C
authors.lastname: Leung
authors.affiliation: 1] Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada. [2] Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada. [3] Department of Immunology, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Norman N
authors.initials: NN
authors.lastname: Iscove
authors.affiliation: 1] Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada. [2] Structural Genomics Consortium, Toronto, Ontario, Canada. [3] Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Cheryl H
authors.initials: CH
authors.lastname: Arrowsmith
authors.affiliation: Department of Pathology, Toronto General Hospital, Toronto, Ontario, Canada.
authors.forename: Eva
authors.initials: E
authors.lastname: Szentgyorgyi
authors.affiliation: 1] Department of Surgery, Toronto General Hospital, Toronto, Ontario, Canada. [2] Fred Litwin Centre for Cancer Genetics, Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada.
authors.forename: Steven
authors.initials: S
authors.lastname: Gallinger
authors.affiliation: 1] Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada. [2] Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada. [3].
authors.forename: John E
authors.initials: JE
authors.lastname: Dick
authors.affiliation: 1] Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada. [2] Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada. [3] Department of Surgery, Toronto General Hospital, Toronto, Ontario, Canada. [4].
authors.forename: Catherine A
authors.initials: CA
authors.lastname: O'Brien
mesh_terms: D000818:Animals; D015153:Blotting, Western; D001973:Bromodeoxyuridine; D045744:Cell Line, Tumor; D015179:Colorectal Neoplasms / Q000188:drug therapy*; D005434:Flow Cytometry; D005822:Genetic Vectors / Q000235:genetics; D006574:Heterocyclic Compounds, 2-Ring / Q000494:pharmacology* / Q000627:therapeutic use; D006801:Humans; D008156:Luciferases; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D009364:Neoplasm Recurrence, Local / Q000378:metabolism*; D014411:Neoplastic Stem Cells / Q000378:metabolism*; D063150:Polycomb Repressive Complex 1 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000235:genetics; D013844:Thiazoles / Q000494:pharmacology* / Q000627:therapeutic use
chemical_list: C069077:BMI1 protein, human; D006574:Heterocyclic Compounds, 2-Ring; C586999:PTC-209; D034741:RNA, Small Interfering; D013844:Thiazoles; D008156:Luciferases; D063150:Polycomb Repressive Complex 1; D001973:Bromodeoxyuridine