Progastrin production transitions from Bmi1+/Prox1+ to Lgr5high cells during early intestinal tumorigenesis
| Autor: | Bénédicte Brulin, Unmesh Jadhav, Philippe Crespy, Zeinab Homayed, Jihane Boubaker-Vitre, Fanny Grillet, J. Hazerbroucq, Frédéric Hollande, Cyril Breuker, Julie Giraud, Christine Pignodel, J-F. Bourgaux, Ramesh A. Shivdasani, Philippe Jay, Julie Pannequin, Momeneh Foroutan |
|---|---|
| Přispěvatelé: | MORNET, Dominique, Institut de Génomique Fonctionnelle (IGF), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), University of Melbourne, Dana-Farber Cancer Institute [Boston], Harvard Medical School [Boston] (HMS), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Hôpital Universitaire Carémeau [Nîmes] (CHU Nîmes), Centre Hospitalier Universitaire de Nîmes (CHU Nîmes), Université de Montpellier (UM)-Université Montpellier 1 (UM1)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Montpellier 2 - Sciences et Techniques (UM2)-Centre National de la Recherche Scientifique (CNRS) |
| Jazyk: | angličtina |
| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
Cancer Research FACS Fluorescence-Activated Cell Sorting [SDV]Life Sciences [q-bio] Intestinal polyp Enteroendocrine cell Biology Tumor initiating cells lcsh:RC254-282 Lgr5 (GPR49) 03 medical and health sciences 0302 clinical medicine Intestinal mucosa Lgr5 leucine-rich repeat containing G protein-coupled receptor 5 Neoplastic transformation APC Adenomatous Polyposis Coli Original Research PG progastrin Progastrin Intestinal stem cells Wnt signaling pathway LGR5 CBC crypt base columnar cells lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens Adenomas 3. Good health SPF Specific Pathogen Free [SDV] Life Sciences [q-bio] 030104 developmental biology EGFP Enhanced Green Fluorescence Protein Oncology BMI1 030220 oncology & carcinogenesis Cancer research Stem cell DAPI 4′ 6-diamidino-2-phenylindole |
| Zdroj: | Translational Oncology Translational Oncology, 2020, 14 (2), pp.101001. ⟨10.1016/j.tranon.2020.101001⟩ Translational Oncology, Vol 14, Iss 2, Pp 101001-(2021) Translational Oncology, Elsevier, 2020, 14 (2), pp.101001. ⟨10.1016/j.tranon.2020.101001⟩ |
| ISSN: | 1944-7124 1936-5233 |
| DOI: | 10.1016/j.tranon.2020.101001⟩ |
| Popis: | Highlights • Secretion of progastrin is a signature event of early malignant transformation in the colon. • In the healthy epithelium, progastrin is produced by a subset of enteroendocrine cells expressing both Bmi1 and Prox1. • LGR5-high intestinal stem cells are a primary source of progastrin production in early mouse and human intestinal adenomas. Progastrin is an unprocessed soluble peptide precursor with a well-described tumor-promoting role in colorectal cancer. It is expressed at small levels in the healthy intestinal mucosa, and its expression is enhanced at early stages of intestinal tumor development, with high levels of this peptide in hyperplastic intestinal polyps being associated with poor neoplasm-free survival in patients. Yet, the precise type of progastrin-producing cells in the healthy intestinal mucosa and in early adenomas remains unclear. Here, we used a combination of immunostaining, RNAscope labelling and retrospective analysis of single cell RNAseq results to demonstrate that progastrin is produced within intestinal crypts by a subset of Bmi1+/Prox1+/LGR5low endocrine cells, previously shown to act as replacement stem cells in case of mucosal injury. In contrast, our findings indicate that intestinal stem cells, specified by expression of the Wnt signaling target LGR5, become the main source of progastrin production in early mouse and human intestinal adenomas. Collectively our results suggest that the previously identified feed-forward mechanisms between progastrin and Wnt signaling is a hallmark of early neoplastic transformation in mouse and human colonic adenomas. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|