journal contribution
posted on 2023-03-30, 23:53 authored by Julie Giraud, Laura M. Failla, Jean-Marc Pascussi, Ebba L. Lagerqvist, Jérémy Ollier, Pascal Finetti, François Bertucci, Chu Ya, Imène Gasmi, Jean-François Bourgaux, Michel Prudhomme, Thibault Mazard, Imade Ait-Arsa, Leila Houhou, Daniel Birnbaum, André Pélegrin, Charles Vincent, James G. Ryall, Dominique Joubert, Julie Pannequin, Frédéric Hollande Legend for Supplemental Figures S1-S6.
Funding
French National Research Agency
Association pour la Recherche contre le Cancer (ARC)
Department of Pathology, University of Melbourne
FRM
National Health and Medical Research Council (NH&MRC) of Australia
History
ARTICLE 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 ALDHhigh cells, impairing their tumor-initiating potential, and inhibited the high glycolytic activity of ALDHhigh 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.
