title: Autocrine Secretion of Progastrin Promotes the Survival and Self-Renewal of Colon Cancer Stem-like Cells.
abstract: Subpopulations of cancer stem-like cells (CSC) are thought to drive tumor progression and posttreatment recurrence in multiple solid tumors. However, the mechanisms that maintain stable proportions of self-renewing CSC within heterogeneous tumors under homeostatic conditions remain poorly understood. Progastrin is a secreted peptide that exhibits tumor-forming potential in colorectal cancer, where it regulates pathways known to modulate colon CSC behaviors. In this study, we investigated the role of progastrin in regulating CSC phenotype in advanced colorectal cancer. Progastrin expression and secretion were highly enriched in colon CSC isolated from human colorectal cancer cell lines and colon tumor biopsies. Progastrin expression promoted CSC self-renewal and survival, whereas its depletion by RNA interference-mediated or antibody-mediated strategies altered the homeostatic proportions of CSC cells within heterogeneous colorectal cancer tumors. Progastrin downregulation also decreased the frequency of ALDH(high) cells, impairing their tumor-initiating potential, and inhibited the high glycolytic activity of ALDH(high) CSC to limit their self-renewal capability. Taken together, our results show how colorectal CSC maintain their tumor-initiating and self-renewal capabilities by secreting progastrin, thereby contributing to the tumor microenvironment to support malignancy. Cancer Res; 76(12); 3618-28. ©2016 AACR.
authors.affiliation: CNRS, UMR-5203, Institut de Génomique Fonctionnelle, Montpellier, France. INSERM, U661, Montpellier, France. Universités de Montpellier 1 & 2, UMR-5203, Montpellier, France.
authors.forename: Julie
authors.initials: J
authors.lastname: Giraud
authors.affiliation: Department of Pathology, The University of Melbourne, Parkville, Victoria, Australia.
authors.forename: Laura M
authors.initials: LM
authors.lastname: Failla
authors.affiliation: CNRS, UMR-5203, Institut de Génomique Fonctionnelle, Montpellier, France. INSERM, U661, Montpellier, France. Universités de Montpellier 1 & 2, UMR-5203, Montpellier, France.
authors.forename: Jean-Marc
authors.initials: JM
authors.lastname: Pascussi
authors.affiliation: CNRS, UMR-5203, Institut de Génomique Fonctionnelle, Montpellier, France. INSERM, U661, Montpellier, France. Universités de Montpellier 1 & 2, UMR-5203, Montpellier, France.
authors.forename: Ebba L
authors.initials: EL
authors.lastname: Lagerqvist
authors.affiliation: CNRS, UMR-5203, Institut de Génomique Fonctionnelle, Montpellier, France. INSERM, U661, Montpellier, France. Universités de Montpellier 1 & 2, UMR-5203, Montpellier, France.
authors.forename: Jérémy
authors.initials: J
authors.lastname: Ollier
authors.affiliation: Centre de Recherche en Cancérologie de Marseille, Institut Paoli-Calmettes, INSERM UMR1068, CNRS UMR725, Marseille, France.
authors.forename: Pascal
authors.initials: P
authors.lastname: Finetti
authors.affiliation: Centre de Recherche en Cancérologie de Marseille, Institut Paoli-Calmettes, INSERM UMR1068, CNRS UMR725, Marseille, France.
authors.forename: François
authors.initials: F
authors.lastname: Bertucci
authors.affiliation: CNRS, UMR-5203, Institut de Génomique Fonctionnelle, Montpellier, France. INSERM, U661, Montpellier, France. Universités de Montpellier 1 & 2, UMR-5203, Montpellier, France.
authors.forename: Chu
authors.initials: C
authors.lastname: Ya
authors.affiliation: CNRS, UMR-5203, Institut de Génomique Fonctionnelle, Montpellier, France. INSERM, U661, Montpellier, France. Universités de Montpellier 1 & 2, UMR-5203, Montpellier, France.
authors.forename: Imène
authors.initials: I
authors.lastname: Gasmi
authors.affiliation: Centre Hospitalier Universitaire (CHU) Carémeau, Nîmes, France.
authors.forename: Jean-François
authors.initials: JF
authors.lastname: Bourgaux
authors.affiliation: Centre Hospitalier Universitaire (CHU) Carémeau, Nîmes, France.
authors.forename: Michel
authors.initials: M
authors.lastname: Prudhomme
authors.affiliation: Institut de Recherche en Cancérologie de Montpellier (ICM), Montpellier, France.
authors.forename: Thibault
authors.initials: T
authors.lastname: Mazard
authors.affiliation: Institut de Recherche en Cancérologie de Montpellier (ICM), Montpellier, France.
authors.forename: Imade
authors.initials: I
authors.lastname: Ait-Arsa
authors.affiliation: BioRéalités s.a.s, Montpellier, France.
authors.forename: Leila
authors.initials: L
authors.lastname: Houhou
authors.affiliation: Centre de Recherche en Cancérologie de Marseille, Institut Paoli-Calmettes, INSERM UMR1068, CNRS UMR725, Marseille, France.
authors.forename: Daniel
authors.initials: D
authors.lastname: Birnbaum
authors.affiliation: Institut de Recherche en Cancérologie de Montpellier (ICM), Montpellier, France.
authors.forename: André
authors.initials: A
authors.lastname: Pélegrin
authors.affiliation: Institut de Recherche en Cancérologie de Montpellier (ICM), Montpellier, France.
authors.forename: Charles
authors.initials: C
authors.lastname: Vincent
authors.affiliation: Stem Cell Metabolism & Regenerative Medicine Group, Department of Physiology, The University of Melbourne, Parkville, Victoria, Australia.
authors.forename: James G
authors.initials: JG
authors.lastname: Ryall
authors.affiliation: CNRS, UMR-5203, Institut de Génomique Fonctionnelle, Montpellier, France. INSERM, U661, Montpellier, France. Universités de Montpellier 1 & 2, UMR-5203, Montpellier, France.
authors.forename: Dominique
authors.initials: D
authors.lastname: Joubert
authors.affiliation: CNRS, UMR-5203, Institut de Génomique Fonctionnelle, Montpellier, France. INSERM, U661, Montpellier, France. Universités de Montpellier 1 & 2, UMR-5203, Montpellier, France. frederic.hollande@unimelb.edu.au julie.pannequin@igf.cnrs.fr.
authors.forename: Julie
authors.initials: J
authors.lastname: Pannequin
authors.affiliation: CNRS, UMR-5203, Institut de Génomique Fonctionnelle, Montpellier, France. INSERM, U661, Montpellier, France. Universités de Montpellier 1 & 2, UMR-5203, Montpellier, France. Department of Pathology, The University of Melbourne, Parkville, Victoria, Australia. frederic.hollande@unimelb.edu.au julie.pannequin@igf.cnrs.fr.
authors.forename: Frédéric
authors.initials: F
authors.lastname: Hollande
mesh_terms: D000444:Aldehyde Dehydrogenase / Q000378:metabolism; D000818:Animals; D045744:Cell Line, Tumor; D002470:Cell Survival; D003110:Colonic Neoplasms / Q000473:pathology*; D005755:Gastrins / Q000502:physiology*; D006801:Humans; D051379:Mice; D014411:Neoplastic Stem Cells / Q000502:physiology*; D011498:Protein Precursors / Q000502:physiology*; D059016:Tumor Microenvironment
chemical_list: D005755:Gastrins; D011498:Protein Precursors; C013706:big gastrin; D000444:Aldehyde Dehydrogenase