Crypt stem cells as the cells-of-origin of intestinal cancer

Barker, Nick; Ridgway, Rachel A.; Es, Johan H. van; Wetering, Marc van de; Begthel, Harry; Born, Marise Ph.; Danenberg, Esther; Clarke, Alan R.; Sansom, Owen J.; Clevers, Hans

doi:10.1038/nature07602

Cited by 1,942 publications

(1,818 citation statements)

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“…4). Lgr5þ crypt base cells are the likely cells of origin of intestinal neoplasia (5). Whether CBCCs and position þ4 cells in the small intestine represent different, overlapping, or identical populations of ISCs remains unresolved.…”

Section: Introductionmentioning

confidence: 99%

PHLDA1 Expression Marks the Putative Epithelial Stem Cells and Contributes to Intestinal Tumorigenesis

et al. 2011

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Studies employing mouse models have identified crypt base and position þ4 cells as strong candidates for intestinal epithelial stem cells. Equivalent cell populations are thought to exist in the human intestine; however robust and specific protein markers are lacking. Here, we show that in the human small and large intestine, PHLDA1 is expressed in discrete crypt base and some position þ4 cells. In small adenomas, PHLDA1 was expressed in a subset of undifferentiated and predominantly Ki-67-negative neoplastic cells, suggesting that a basic hierarchy of differentiation is retained in early tumorigenesis. In large adenomas, carcinomas, and metastases PHLDA1 expression became widespread, with increased expression and nuclear localization at invasive margins. siRNA-mediated suppression of PHLDA1 in colon cancer cells inhibited migration and anchorage-independent growth in vitro and tumor growth in vivo. The integrins ITGA2 and ITGA6 were downregulated in response to PHLDA1 suppression, and accordingly cell adhesion to laminin and collagen was significantly reduced. We conclude that PHLDA1 is a putative epithelial stem cell marker in the human small and large intestine and contributes to migration and proliferation in colon cancer cells. Cancer Res; 71(10);

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Section: Introductionmentioning

confidence: 99%

PHLDA1 Expression Marks the Putative Epithelial Stem Cells and Contributes to Intestinal Tumorigenesis

et al. 2011

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“…Deletion of Apc has to occur in ISCs; otherwise, the transformed cells fail to progress to malignancy (Barker et al ., 2009). To test the ability of EGFP‐dnTCF4 to suppress tumor growth, the Apc gene was inactivated in Rosa26 +/tdTomato /Apc CKO/CKO /Lgr5‐EGFP‐IRES‐CreERT2 + and Apc CKO/CKO /Lgr5‐EGFP‐IRES‐CreERT2 + mice.…”

Section: Resultsmentioning

confidence: 99%

“…The animals were injected by a single dose of tamoxifen to induce Cre nuclear activity and their small intestine was analyzed 16 days later. Histological analysis of Apc CKO/CKO /Lgr5‐EGFP‐IRES‐CreERT2 + mice revealed a continuous “zone” of transformed small intestinal epithelium as described previously (Barker et al ., 2009). The intestinal tumors in Rosa26 +/tdTomato /ApcCKO /CKO /Lgr5‐EGFP‐IRES‐CreERT2 + animals were substantially smaller.…”

Section: Resultsmentioning

confidence: 99%

Wnt Signaling Inhibition Deprives Small Intestinal Stem Cells of Clonogenic Capacity

Janečková

Fafílek

Krausová

et al. 2016

Genesis

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SummaryThe Wnt pathway plays a crucial role in self‐renewal and differentiation of cells in the adult gut. In the present study, we revealed the functional consequences of inhibition of canonical Wnt signaling in the intestinal epithelium. The study was based on generation of a novel transgenic mouse strain enabling inducible expression of an N‐terminally truncated variant of nuclear Wnt effector T cell factor 4 (TCF4). The TCF4 variant acting as a dominant negative (dn) version of wild‐type (wt) TCF4 protein decreased transcription of β‐catenin‐TCF4‐responsive genes. Interestingly, suppression of Wnt/β‐catenin signaling affected asymmetric division of intestinal stem cells (ISCs) rather than proliferation. ISCs expressing the transgene underwent several rounds of division but lost their clonogenic potential and migrated out of the crypt. Expression profiling of crypt cells revealed that besides ISC‐specific markers, the dnTCF4 production downregulated expression levels of epithelial genes produced in other crypt cells including markers of Paneth cells. Additionally, in Apc conditional knockout mice, dnTCF activation efficiently suppressed growth of Apc‐deficient tumors. In summary, the generated mouse strain represents a convenient tool to study cell‐autonomous inhibition of β‐catenin‐Tcf‐mediated transcription. genesis 54:101–114, 2016. © 2016 The Authors genesis Published by Wiley Periodicals, Inc.

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“…Le cas des CS tumorales intestinales : une démonstration directe La génération d'une nouvelle tumeur à partir de cellules ayant des caractéristiques de cellule souche était un argument fort pour impliquer les cellules souches dans l'émer-gence du processus tumoral, mais ce n'était pas une démonstration expérimentale en bonne et due forme. La réelle démonstration expérimentale, en ce qui concerne l'intestin, est venue à nouveau du groupe de Hans Clevers [21]. L'expérience suivante a été réali-sée : la tumorigenèse de l'intestin est associée très tôt à la présence d'une mutation dans le gène APC (adenomatous polyposis coli) au point que cet événement mutationnel est dit initiateur de la tumeur de l'intestin.…”

Section: Le Cancer Intestinal a Pour Origine La Cellule Soucheunclassified