{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,12]],"date-time":"2026-09-12T01:44:01Z","timestamp":1789177441912,"version":"build-2803163510"},"reference-count":38,"publisher":"Elsevier BV","issue":"1","license":[{"start":{"date-parts":[[2021,1,1]],"date-time":"2021-01-01T00:00:00Z","timestamp":1609459200000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/www.elsevier.com\/tdm\/userlicense\/1.0\/"},{"start":{"date-parts":[[2021,1,1]],"date-time":"2021-01-01T00:00:00Z","timestamp":1609459200000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/www.elsevier.com\/legal\/tdmrep-license"}],"funder":[{"DOI":"10.13039\/100000054","name":"National Cancer Institute","doi-asserted-by":"publisher","award":["R00CA187317"],"award-info":[{"award-number":["R00CA187317"]}],"id":[{"id":"10.13039\/100000054","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100007797","name":"Helsingin Yliopisto","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100007797","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100008723","name":"Suomen L\u00e4\u00e4ketieteen S\u00e4\u00e4ti\u00f6","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100008723","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100015735","name":"Helsinki Institute of Life Science, Helsingin Yliopisto","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100015735","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100013840","name":"Biocenter Finland","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100013840","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000043","name":"American Association for Cancer Research","doi-asserted-by":"publisher","award":["18-20-01-TAMM"],"award-info":[{"award-number":["18-20-01-TAMM"]}],"id":[{"id":"10.13039\/100000043","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003756","name":"Biomedicum Helsinki-s\u00e4\u00e4ti\u00f6","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100003756","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100006306","name":"Sigrid Jus\u00e9liuksen S\u00e4\u00e4ti\u00f6","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100006306","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100010711","name":"Sy\u00f6p\u00e4s\u00e4\u00e4ti\u00f6","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100010711","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000289","name":"Cancer Research UK","doi-asserted-by":"publisher","award":["A17196"],"award-info":[{"award-number":["A17196"]}],"id":[{"id":"10.13039\/501100000289","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100002341","name":"Academy of Finland","doi-asserted-by":"publisher","award":["2019-2022"],"award-info":[{"award-number":["2019-2022"]}],"id":[{"id":"10.13039\/501100002341","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100002341","name":"Academy of Finland","doi-asserted-by":"publisher","award":["273817"],"award-info":[{"award-number":["273817"]}],"id":[{"id":"10.13039\/501100002341","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100002341","name":"Academy of Finland","doi-asserted-by":"publisher","award":["320185"],"award-info":[{"award-number":["320185"]}],"id":[{"id":"10.13039\/501100002341","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["clinicalkey.com","clinicalkey.com.au","clinicalkey.es","clinicalkey.fr","clinicalkey.jp","gastrojournal.org","elsevier.com","sciencedirect.com"],"crossmark-restriction":true},"short-container-title":["Gastroenterology"],"published-print":{"date-parts":[[2021,1]]},"DOI":"10.1053\/j.gastro.2020.09.011","type":"journal-article","created":{"date-parts":[[2020,9,14]],"date-time":"2020-09-14T11:05:04Z","timestamp":1600081504000},"page":"245-259","update-policy":"https:\/\/doi.org\/10.1016\/elsevier_cm_policy","source":"Crossref","is-referenced-by-count":38,"title":["Expression of R-Spondin 1 in Apc Mice Suppresses Growth of Intestinal Adenomas by Altering Wnt and Transforming Growth Factor Beta Signaling"],"prefix":"10.1053","volume":"160","author":[{"given":"Marianne","family":"L\u00e4hde","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sarika","family":"Heino","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jenny","family":"H\u00f6gstr\u00f6m","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Seppo","family":"Kaijalainen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0259-1273","authenticated-orcid":false,"given":"Andrey","family":"Anisimov","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dustin","family":"Flanagan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6374-6203","authenticated-orcid":false,"given":"Pauliina","family":"Kallio","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Veli-Matti","family":"Lepp\u00e4nen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ari","family":"Ristim\u00e4ki","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7017-6931","authenticated-orcid":false,"given":"Olli","family":"Ritvos","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katherine","family":"Wu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tuomas","family":"Tammela","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael","family":"Hodder","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Owen J.","family":"Sansom","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kari","family":"Alitalo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"78","reference":[{"key":"10.1053\/j.gastro.2020.09.011_bib1","first-page":"7","article-title":"Cancer statistics, 2018","volume":"68","author":"Siegel","year":"2018","journal-title":"CA Cancer J Clin"},{"key":"10.1053\/j.gastro.2020.09.011_bib2","doi-asserted-by":"crossref","first-page":"589","DOI":"10.1016\/0092-8674(81)90021-0","article-title":"Identification and characterization of the familial adenomatous polyposis coli gene","volume":"66","author":"Groden","year":"1991","journal-title":"Cell"},{"key":"10.1053\/j.gastro.2020.09.011_bib3","doi-asserted-by":"crossref","first-page":"704","DOI":"10.1136\/gut.2007.136127","article-title":"Guidelines for the clinical management of familial adenomatous polyposis (FAP)","volume":"57","author":"Vasen","year":"2008","journal-title":"Gut"},{"key":"10.1053\/j.gastro.2020.09.011_bib4","doi-asserted-by":"crossref","first-page":"877","DOI":"10.1101\/gad.1295405","article-title":"Wnt signaling in the intestinal epithelium: from endoderm to cancer","volume":"19","author":"Gregorieff","year":"2005","journal-title":"Genes Dev"},{"key":"10.1053\/j.gastro.2020.09.011_bib5","doi-asserted-by":"crossref","first-page":"407","DOI":"10.1016\/j.ccr.2008.02.020","article-title":"Transcription factor PROX1 induces colon cancer progression by promoting the transition from benign to highly dysplastic phenotype","volume":"13","author":"Petrova","year":"2008","journal-title":"Cancer Cell"},{"key":"10.1053\/j.gastro.2020.09.011_bib6","doi-asserted-by":"crossref","first-page":"1943","DOI":"10.1016\/j.celrep.2014.08.034","article-title":"Prox1 promotes expansion of the colorectal cancer stem cell population to fuel tumor growth and ischemia resistance","volume":"8","author":"Wiener","year":"2014","journal-title":"Cell Rep"},{"issue":"7165","key":"10.1053\/j.gastro.2020.09.011_bib7","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"},{"issue":"5738","key":"10.1053\/j.gastro.2020.09.011_bib8","doi-asserted-by":"crossref","first-page":"1256","DOI":"10.1126\/science.1112521","article-title":"Medicine: mitogenic influence of human R-spondin1 on the intestinal epithelium","volume":"309","author":"Kim","year":"2005","journal-title":"Science"},{"issue":"37","key":"10.1053\/j.gastro.2020.09.011_bib9","doi-asserted-by":"crossref","first-page":"14700","DOI":"10.1073\/pnas.0702305104","article-title":"R-Spondin1 regulates Wnt signaling by inhibiting internalization of LRP6","volume":"104","author":"Binnerts","year":"2007","journal-title":"Proc Natl Acad Sci U S A"},{"key":"10.1053\/j.gastro.2020.09.011_bib10","doi-asserted-by":"crossref","first-page":"2588","DOI":"10.1091\/mbc.e08-02-0187","article-title":"R-spondin family members regulate the Wnt pathway by a common mechanism","volume":"19","author":"Kim","year":"2008","journal-title":"Mol Biol Cell"},{"issue":"7360","key":"10.1053\/j.gastro.2020.09.011_bib11","doi-asserted-by":"crossref","first-page":"293","DOI":"10.1038\/nature10337","article-title":"Lgr5 homologues associate with Wnt receptors and mediate R-spondin signalling","volume":"476","author":"de Lau","year":"2011","journal-title":"Nature"},{"issue":"7584","key":"10.1053\/j.gastro.2020.09.011_bib12","doi-asserted-by":"crossref","first-page":"97","DOI":"10.1038\/nature16466","article-title":"Targeting PTPRK-RSPO3 colon tumours promotes differentiation and loss of stem-cell function","volume":"529","author":"Storm","year":"2016","journal-title":"Nature"},{"key":"10.1053\/j.gastro.2020.09.011_bib13","doi-asserted-by":"crossref","first-page":"3149","DOI":"10.1038\/ncomms4149","article-title":"RSPO2\u2013LGR5 signaling has tumour-suppressive activity in colorectal cancer","volume":"5","author":"Wu","year":"2014","journal-title":"Nat Commun"},{"key":"10.1053\/j.gastro.2020.09.011_bib14","doi-asserted-by":"crossref","first-page":"6589","DOI":"10.1158\/0008-5472.CAN-17-0219","article-title":"R-Spondin1\/LGR5 activates TGF\u03b2 signaling and suppresses colon cancer\u00a0metastasis","volume":"77","author":"Zhou","year":"2017","journal-title":"Cancer Res"},{"issue":"7229","key":"10.1053\/j.gastro.2020.09.011_bib15","doi-asserted-by":"crossref","first-page":"608","DOI":"10.1038\/nature07602","article-title":"Crypt stem cells as the cells-of-origin of intestinal cancer","volume":"457","author":"Barker","year":"2009","journal-title":"Nature"},{"key":"10.1053\/j.gastro.2020.09.011_bib16","doi-asserted-by":"crossref","first-page":"3150","DOI":"10.1038\/ncomms4150","article-title":"The miR-363-GATA6-Lgr5 pathway is critical for colorectal tumourigenesis","volume":"5","author":"Tsuji","year":"2014","journal-title":"Nat Commun"},{"key":"10.1053\/j.gastro.2020.09.011_bib17","doi-asserted-by":"crossref","first-page":"8654","DOI":"10.1038\/srep08654","article-title":"Characterization of LGR5 stem cells in colorectal adenomas and carcinomas","volume":"5","author":"Baker","year":"2015","journal-title":"Sci Rep"},{"issue":"7413","key":"10.1053\/j.gastro.2020.09.011_bib18","doi-asserted-by":"crossref","first-page":"660","DOI":"10.1038\/nature11282","article-title":"Recurrent R-spondin fusions in colon cancer","volume":"488","author":"Seshagiri","year":"2012","journal-title":"Nature"},{"key":"10.1053\/j.gastro.2020.09.011_bib19","doi-asserted-by":"crossref","first-page":"15945","DOI":"10.1038\/ncomms15945","article-title":"R-spondin chromosome rearrangements drive Wnt-dependent tumour initiation and maintenance in the intestine","volume":"8","author":"Han","year":"2017","journal-title":"Nat Commun"},{"key":"10.1053\/j.gastro.2020.09.011_bib20","doi-asserted-by":"crossref","first-page":"924","DOI":"10.1016\/j.immuni.2019.03.024","article-title":"Transforming growth factor-\u03b2 signaling in immunity and cancer","volume":"50","author":"Batlle","year":"2019","journal-title":"Immunity"},{"key":"10.1053\/j.gastro.2020.09.011_bib21","doi-asserted-by":"crossref","first-page":"2783","DOI":"10.1101\/gad.1350705","article-title":"Smad transcription factors","volume":"19","author":"Massagu\u00e9","year":"2005","journal-title":"Genes Dev"},{"key":"10.1053\/j.gastro.2020.09.011_bib22","doi-asserted-by":"crossref","first-page":"3152","DOI":"10.1158\/0008-5472.CAN-07-5348","article-title":"Transforming growth factor \u03b2 induces apoptosis through repressing the phosphoinositide 3-kinase\/AKT\/survivin pathway in colon cancer cells","volume":"68","author":"Wang","year":"2008","journal-title":"Cancer Res"},{"key":"10.1053\/j.gastro.2020.09.011_bib23","doi-asserted-by":"crossref","first-page":"E2229","DOI":"10.1073\/pnas.1406444111","article-title":"Oncogenic mutations in intestinal adenomas regulate BIM-mediated apoptosis induced by TGF-\u03b2","volume":"111","author":"Wiener","year":"2014","journal-title":"Proc Natl Acad Sci U S A"},{"issue":"10","key":"10.1053\/j.gastro.2020.09.011_bib24","doi-asserted-by":"crossref","first-page":"1681","DOI":"10.1038\/cdd.2017.92","article-title":"TGF\u03b2 pathway limits dedifferentiation following WNT and MAPK pathway activation to suppress intestinal tumourigenesis","volume":"24","author":"Cammareri","year":"2017","journal-title":"Cell Death Differ"},{"key":"10.1053\/j.gastro.2020.09.011_bib25","first-page":"320","article-title":"Mutational inactivation of transforming growth factor \u03b2 receptor type II in microsatellite stable colon cancers","volume":"59","author":"Grady","year":"1999","journal-title":"Cancer Res"},{"key":"10.1053\/j.gastro.2020.09.011_bib26","doi-asserted-by":"crossref","first-page":"1072","DOI":"10.1038\/ng1642","article-title":"Lymphatic vascular defects promoted by Prox1 haploinsufficiency cause adult-onset obesity","volume":"37","author":"Harvey","year":"2005","journal-title":"Nat Genet"},{"key":"10.1053\/j.gastro.2020.09.011_bib27","doi-asserted-by":"crossref","first-page":"759","DOI":"10.1016\/j.devcel.2006.03.015","article-title":"Apc tumor suppressor gene is the \u201czonation-keeper\u201d of mouse liver","volume":"10","author":"Benhamouche","year":"2006","journal-title":"Dev Cell"},{"key":"10.1053\/j.gastro.2020.09.011_bib28","doi-asserted-by":"crossref","first-page":"491","DOI":"10.1083\/jcb.152.3.491","article-title":"Apical membrane localization of the adenomatous polyposis coli tumor suppressor protein and subcellular distribution of the \u03b2-catenin destruction complex in polarized epithelial cells","volume":"152","author":"Reinacher-Schick","year":"2001","journal-title":"J\u00a0Cell Biol"},{"key":"10.1053\/j.gastro.2020.09.011_bib29","doi-asserted-by":"crossref","first-page":"141","DOI":"10.1002\/path.4645","article-title":"Mouse models of intestinal cancer","volume":"238","author":"Jackstadt","year":"2016","journal-title":"J\u00a0Pathol"},{"key":"10.1053\/j.gastro.2020.09.011_bib30","doi-asserted-by":"crossref","first-page":"239","DOI":"10.1002\/path.2718","article-title":"Nuclear \u03b2-catenin expression and Wnt signalling: in defence of the dogma","volume":"221","author":"Fodde","year":"2010","journal-title":"J\u00a0Pathol"},{"key":"10.1053\/j.gastro.2020.09.011_bib31","doi-asserted-by":"crossref","first-page":"1590","DOI":"10.1158\/2159-8290.CD-19-1536","article-title":"Lineage reversion drives WNT independence in intestinal cancer","volume":"10","author":"Han","year":"2020","journal-title":"Cancer Discov"},{"key":"10.1053\/j.gastro.2020.09.011_bib32","doi-asserted-by":"crossref","first-page":"305","DOI":"10.1101\/gad.235473.113","article-title":"The R-spondin\/Lgr5\/Rnf43 module: regulator of wnt signal strength","volume":"28","author":"de Lau","year":"2014","journal-title":"Genes Dev"},{"key":"10.1053\/j.gastro.2020.09.011_bib33","doi-asserted-by":"crossref","first-page":"1132","DOI":"10.1038\/s41467-018-03426-2","article-title":"Wnt ligands influence tumour initiation by controlling the number of intestinal stem cells","volume":"9","author":"Huels","year":"2018","journal-title":"Nat Commun"},{"key":"10.1053\/j.gastro.2020.09.011_bib34","doi-asserted-by":"crossref","first-page":"124","DOI":"10.1016\/j.ydbio.2007.08.023","article-title":"Mouse R-spondin2 is required for apical ectodermal ridge maintenance in the hindlimb","volume":"311","author":"Nam","year":"2007","journal-title":"Dev Biol"},{"key":"10.1053\/j.gastro.2020.09.011_bib35","doi-asserted-by":"crossref","first-page":"1291","DOI":"10.1038\/ng.239","article-title":"Lgr5 marks cycling, yet long-lived, hair follicle stem cells","volume":"40","author":"Jaks","year":"2008","journal-title":"Nat Genet"},{"key":"10.1053\/j.gastro.2020.09.011_bib36","doi-asserted-by":"crossref","first-page":"25","DOI":"10.1016\/j.stem.2009.11.013","article-title":"Lgr5+ve stem cells drive self-renewal in the stomach and build long-lived gastric units in\u00a0vitro","volume":"6","author":"Barker","year":"2010","journal-title":"Cell Stem Cell"},{"issue":"6103","key":"10.1053\/j.gastro.2020.09.011_bib37","doi-asserted-by":"crossref","first-page":"108","DOI":"10.1126\/science.1223821","article-title":"Wnt5a potentiates TGF-\u03b2 signaling to promote colonic crypt regeneration after tissue injury","volume":"338","author":"Miyoshi","year":"2012","journal-title":"Science"},{"issue":"7653","key":"10.1053\/j.gastro.2020.09.011_bib38","doi-asserted-by":"crossref","first-page":"238","DOI":"10.1038\/nature22313","article-title":"Non-equivalence of Wnt and R-spondin ligands during Lgr5+ intestinal stem-cell self-renewal","volume":"545","author":"Yan","year":"2017","journal-title":"Nature"}],"container-title":["Gastroenterology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.elsevier.com\/content\/article\/PII:S0016508520351489?httpAccept=text\/xml","content-type":"text\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/api.elsevier.com\/content\/article\/PII:S0016508520351489?httpAccept=text\/plain","content-type":"text\/plain","content-version":"vor","intended-application":"text-mining"}],"deposited":{"date-parts":[[2025,11,3]],"date-time":"2025-11-03T09:48:34Z","timestamp":1762163314000},"score":1,"resource":{"primary":{"URL":"https:\/\/linkinghub.elsevier.com\/retrieve\/pii\/S0016508520351489"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,1]]},"references-count":38,"journal-issue":{"issue":"1","published-print":{"date-parts":[[2021,1]]}},"alternative-id":["S0016508520351489"],"URL":"https:\/\/doi.org\/10.1053\/j.gastro.2020.09.011","relation":{},"ISSN":["0016-5085"],"issn-type":[{"value":"0016-5085","type":"print"}],"subject":[],"published":{"date-parts":[[2021,1]]},"assertion":[{"value":"Elsevier","name":"publisher","label":"This article is maintained by"},{"value":"Expression of R-Spondin 1 in ApcMin\/+ Mice Suppresses Growth of Intestinal Adenomas by Altering Wnt and Transforming Growth Factor Beta Signaling","name":"articletitle","label":"Article Title"},{"value":"Gastroenterology","name":"journaltitle","label":"Journal Title"},{"value":"https:\/\/doi.org\/10.1053\/j.gastro.2020.09.011","name":"articlelink","label":"CrossRef DOI link to publisher maintained version"},{"value":"article","name":"content_type","label":"Content Type"},{"value":"\u00a9 2021 by the AGA Institute","name":"copyright","label":"Copyright"}]}}