{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,12]],"date-time":"2026-01-12T23:30:48Z","timestamp":1768260648836,"version":"3.49.0"},"reference-count":34,"publisher":"MDPI AG","issue":"11","license":[{"start":{"date-parts":[[2021,10,28]],"date-time":"2021-10-28T00:00:00Z","timestamp":1635379200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100004587","name":"Instituto de Salud Carlos III","doi-asserted-by":"publisher","award":["PI19\/00013"],"award-info":[{"award-number":["PI19\/00013"]}],"id":[{"id":"10.13039\/501100004587","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>Background: Previous studies in mice indicated that Paneth cells and c-Kit-positive goblet cells represent the stem cell niche of the small intestine and colon, respectively, partly by supporting Wnt and Notch activation. Whether these cell populations play a similar role in human intestinal cancer remains unexplored. Methods: We performed histopathological evaluation and immunohistochemical analysis of early colorectal adenomas and carcinoma adenoma from patients at the Hospital del Mar in Barcelona. We then determined the possible correlation between the different parameters analyzed and with patient outcomes. Results: Paneth cells accumulate in a subset of human colorectal adenomas directly associated with Notch and Wnt\/\u03b2-catenin activation. Adenoma areas containing Paneth cells display increased vessel density in the lamina propria and higher levels of the stem cell marker EphB2. In an in-house cohort of 200 colorectal adenoma samples, we also observed a significant correlation between the presence of Paneth cells and Wnt activation. Kaplan\u2013Meier analysis indicated that early adenoma patients carrying Paneth cell-positive tumors display reduced disease-free survival compared with patients with Paneth cell-free lesions. Conclusions: Our results indicate that Paneth cells contribute to the initial steps of cancer progression by providing the stem cell niche to adenoma cells, which could be therapeutically exploited.<\/jats:p>","DOI":"10.3390\/cells10112928","type":"journal-article","created":{"date-parts":[[2021,10,28]],"date-time":"2021-10-28T23:50:28Z","timestamp":1635465028000},"page":"2928","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":15,"title":["Accumulation of Paneth Cells in Early Colorectal Adenomas Is Associated with Beta-Catenin Signaling and Poor Patient Prognosis"],"prefix":"10.3390","volume":"10","author":[{"given":"Erika","family":"L\u00f3pez-Arribillaga","sequence":"first","affiliation":[{"name":"Stem Cells and Cancer Research Laboratory, Institut Hospital del Mar d\u2019Investigacions M\u00e8diques (IMIM), CIBERONC, 08003 Barcelona, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Bing","family":"Yan","sequence":"additional","affiliation":[{"name":"Stem Cells and Cancer Research Laboratory, Institut Hospital del Mar d\u2019Investigacions M\u00e8diques (IMIM), CIBERONC, 08003 Barcelona, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Teresa","family":"Lobo-Jarne","sequence":"additional","affiliation":[{"name":"Stem Cells and Cancer Research Laboratory, Institut Hospital del Mar d\u2019Investigacions M\u00e8diques (IMIM), CIBERONC, 08003 Barcelona, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8673-6470","authenticated-orcid":false,"given":"Yolanda","family":"Guill\u00e9n","sequence":"additional","affiliation":[{"name":"Stem Cells and Cancer Research Laboratory, Institut Hospital del Mar d\u2019Investigacions M\u00e8diques (IMIM), CIBERONC, 08003 Barcelona, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9116-8743","authenticated-orcid":false,"given":"Silvia","family":"Men\u00e9ndez","sequence":"additional","affiliation":[{"name":"Departament of Oncology, Hospital del Mar, 08003 Barcelona, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Montserrat","family":"Andreu","sequence":"additional","affiliation":[{"name":"Gastroenterology Department, Hospital del Mar, IMIM (Hospital del Mar Medical Research Institute), 08003 Barcelona, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4801-6899","authenticated-orcid":false,"given":"Anna","family":"Bigas","sequence":"additional","affiliation":[{"name":"Stem Cells and Cancer Research Laboratory, Institut Hospital del Mar d\u2019Investigacions M\u00e8diques (IMIM), CIBERONC, 08003 Barcelona, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mar","family":"Iglesias","sequence":"additional","affiliation":[{"name":"Departament of Pathology, Hospital del Mar, CIBERONC, 08003 Barcelona, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2897-4099","authenticated-orcid":false,"given":"Llu\u00eds","family":"Espinosa","sequence":"additional","affiliation":[{"name":"Stem Cells and Cancer Research Laboratory, Institut Hospital del Mar d\u2019Investigacions M\u00e8diques (IMIM), CIBERONC, 08003 Barcelona, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2021,10,28]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"511","DOI":"10.1016\/j.stem.2011.02.020","article-title":"The Intestinal Stem Cell Signature Identifies Colorectal Cancer Stem Cells and Predicts Disease Relapse","volume":"8","author":"Barriga","year":"2011","journal-title":"Cell Stem Cell"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1762","DOI":"10.1053\/j.gastro.2011.07.050","article-title":"Long-term Expansion of Epithelial Organoids From Human Colon, Adenoma, Adenocarcinoma, and Barrett\u2019s Epithelium","volume":"141","author":"Sato","year":"2011","journal-title":"Gastroenterology"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1003","DOI":"10.1038\/nature06196","article-title":"Identification of stem cells in small intestine and colon by marker gene Lgr5","volume":"449","author":"Barker","year":"2007","journal-title":"Nature"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"179","DOI":"10.1073\/pnas.1013004108","article-title":"Mouse telomerase reverse transcriptase (mTert) expression marks slowly cycling intestinal stem cells","volume":"108","author":"Montgomery","year":"2011","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"915","DOI":"10.1038\/ng.165","article-title":"Bmi1 is expressed in vivo in intestinal stem cells","volume":"40","author":"Sangiorgi","year":"2008","journal-title":"Nat. Genet."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1420","DOI":"10.1126\/science.1213214","article-title":"Interconversion Between Intestinal Stem Cell Populations in Distinct Niches","volume":"334","author":"Takeda","year":"2011","journal-title":"Science"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"401","DOI":"10.1038\/ncb2464","article-title":"Lrig1 controls intestinal stem-cell homeostasis by negative regulation of ErbB signalling","volume":"14","author":"Wong","year":"2012","journal-title":"Nat. Cell Biol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"26599","DOI":"10.1073\/pnas.1801888117","article-title":"Enteroendocrine and tuft cells support Lgr5 stem cells on Paneth cell depletion","volume":"116","author":"Wiebrands","year":"2019","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1195","DOI":"10.1053\/j.gastro.2012.02.006","article-title":"Identification of a cKit+ Colonic Crypt Base Secretory Cell That Supports Lgr5+ Stem Cells in Mice","volume":"142","author":"Rothenberg","year":"2012","journal-title":"Gastroenterology"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"2312","DOI":"10.1016\/j.celrep.2018.07.085","article-title":"Paneth Cells Respond to Inflammation and Contribute to Tissue Regeneration by Acquiring Stem-like Features through SCF\/c-Kit Signaling","volume":"24","author":"Schmitt","year":"2018","journal-title":"Cell Rep."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"46","DOI":"10.1016\/j.stem.2018.05.002","article-title":"Paneth Cell Multipotency Induced by Notch Activation following Injury","volume":"23","author":"Yu","year":"2018","journal-title":"Cell Stem Cell"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"125","DOI":"10.1016\/j.ccr.2010.11.008","article-title":"Suppression of Colon Cancer Metastasis by Aes through Inhibition of Notch Signaling","volume":"19","author":"Sonoshita","year":"2011","journal-title":"Cancer Cell"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"93","DOI":"10.1038\/onc.2011.212","article-title":"Gamma-secretase inhibitors target tumor-initiating cells in a mouse model of ERBB2 breast cancer","volume":"31","author":"Kondratyev","year":"2012","journal-title":"Oncogene"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"964","DOI":"10.1038\/nature03589","article-title":"Notch signals control the fate of immature progenitor cells in the intestine","volume":"435","author":"Fre","year":"2005","journal-title":"Nature"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"3141","DOI":"10.1158\/1078-0432.CCR-09-2823","article-title":"Targeting Notch to Target Cancer Stem Cells","volume":"16","author":"Pannuti","year":"2010","journal-title":"Clin. Cancer Res."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"41","DOI":"10.1242\/dev.107714","article-title":"Bmi1 regulates murine intestinal stem cell proliferation and self-renewal downstream of Notch","volume":"142","author":"Rodilla","year":"2015","journal-title":"Development"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1230","DOI":"10.1053\/j.gastro.2011.01.005","article-title":"Dll1- and Dll4-Mediated Notch Signaling Are Required for Homeostasis of Intestinal Stem Cells","volume":"140","author":"Pellegrinet","year":"2011","journal-title":"Gastroenterology"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"2992","DOI":"10.1038\/s41467-018-05385-0","article-title":"Manic Fringe deficiency imposes Jagged1 addiction to intestinal tumor cells","volume":"9","author":"Rodilla","year":"2018","journal-title":"Nat. Commun."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"468","DOI":"10.1038\/ncb2048","article-title":"Wnt activity defines colon cancer stem cells and is regulated by the microenvironment","volume":"12","author":"Vermeulen","year":"2010","journal-title":"Nat. Cell Biol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"241","DOI":"10.1016\/S0092-8674(02)01014-0","article-title":"The \u03b2-Catenin\/TCF-4 Complex Imposes a Crypt Progenitor Phenotype on Colorectal Cancer Cells","volume":"111","author":"Sancho","year":"2002","journal-title":"Cell"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"571","DOI":"10.1016\/j.ccr.2012.08.013","article-title":"Dependency of Colorectal Cancer on a TGF-\u03b2-Driven Program in Stromal Cells for Metastasis Initiation","volume":"22","author":"Calon","year":"2012","journal-title":"Cancer Cell"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"6315","DOI":"10.1073\/pnas.0813221106","article-title":"Jagged1 is the pathological link between Wnt and Notch pathways in colorectal cancer","volume":"106","author":"Rodilla","year":"2009","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"872","DOI":"10.1016\/j.humpath.2008.12.003","article-title":"Paneth cell differentiation in colonic epithelial neoplasms: Evidence for the role of the Apc\/\u03b2-catenin\/Tcf pathway","volume":"40","author":"Joo","year":"2009","journal-title":"Hum. Pathol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"252","DOI":"10.1038\/s42003-020-0989-y","article-title":"IDO1+ Paneth cells promote immune escape of colorectal cancer","volume":"3","author":"Svinka","year":"2020","journal-title":"Commun. Biol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"26129","DOI":"10.1038\/srep26129","article-title":"Paneth Cell in Adenomas of the Distal Colorectum Is Inversely Associated with Synchronous Advanced Adenoma and Carcinoma","volume":"6","author":"Mahon","year":"2016","journal-title":"Sci. Rep."},{"key":"ref_26","first-page":"38","article-title":"Paneth cell metaplasia in colonic adenocarcinoms","volume":"35","author":"Pai","year":"1998","journal-title":"Indian J. Cancer"},{"key":"ref_27","first-page":"67","article-title":"A simple method to demonstrate normal and metaplastic Paneth cells in tissue sections","volume":"17","author":"Rubio","year":"2003","journal-title":"In Vivo"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"e202000934","DOI":"10.26508\/lsa.202000934","article-title":"Paneth cell\u2013derived growth factors support tumorigenesis in the small intestine","volume":"4","author":"Chen","year":"2021","journal-title":"Life Sci. Alliance"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"804","DOI":"10.1136\/gut.10.10.804","article-title":"The Paneth cell in disease","volume":"10","author":"Lewin","year":"1969","journal-title":"Gut"},{"key":"ref_30","first-page":"135","article-title":"Paneth cells and goblet cells express the neuroendocrine peptide synaptophysin. I. Normal duodenal mucosa","volume":"26","author":"Rubio","year":"2012","journal-title":"In Vivo"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"415","DOI":"10.1038\/nature09637","article-title":"Paneth cells constitute the niche for Lgr5 stem cells in intestinal crypts","volume":"469","author":"Sato","year":"2011","journal-title":"Nature"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"6309","DOI":"10.1073\/pnas.0900427106","article-title":"Notch and Wnt signals cooperatively control cell proliferation and tumorigenesis in the intestine","volume":"106","author":"Fre","year":"2009","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"66","DOI":"10.1242\/dev.084103","article-title":"Dose-dependent roles for canonical Wnt signalling in de novo crypt formation and cell cycle properties of the colonic epithelium","volume":"140","author":"Hirata","year":"2013","journal-title":"Development"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"3132","DOI":"10.1158\/1078-0432.CCR-11-3066","article-title":"Mutations in the Ras\u2013Raf Axis Underlie the Prognostic Value of CD133 in Colorectal Cancer","volume":"18","author":"Kemper","year":"2012","journal-title":"Clin. Cancer Res."}],"container-title":["Cells"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4409\/10\/11\/2928\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T07:22:02Z","timestamp":1760167322000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4409\/10\/11\/2928"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,10,28]]},"references-count":34,"journal-issue":{"issue":"11","published-online":{"date-parts":[[2021,11]]}},"alternative-id":["cells10112928"],"URL":"https:\/\/doi.org\/10.3390\/cells10112928","relation":{},"ISSN":["2073-4409"],"issn-type":[{"value":"2073-4409","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,10,28]]}}}