Intestinal Tumorigenesis Initiated by Dedifferentiation and Acquisition of Stem-Cell-like Properties

Schwitalla, Sarah; Fingerle, Alexander A.; Cammareri, Patrizia; Nebelsiek, Tim; Göktuna, Serkan Ismail; Ziegler, Paul; Canli, Özge; Heijmans, Jarom; Huels, David J.; Moreaux, Guenièvre; Rupec, Rudolf A.; Gerhard, Markus; Schmid, Roland M.; Barker, Nick; Clevers, Hans; Lang, Roland; Neumann, Jens; Kirchner, Thomas; Taketo, Makoto Mark; Brink, Gijs R. van den; Sansom, Owen J.; Arkan, Melek C.; Greten, Florian R.

doi:10.1016/j.cell.2012.12.012

Cited by 926 publications

(855 citation statements)

References 48 publications

Supporting

Mentioning

786

Contrasting

Unclassified

Order By: Relevance

“…3 Similar to BRAF, oncogenic KRAS can also initiate serrated lesions in the mouse, 45 but in contrast to BRAF, tumor progression in KRAS-transgenic mice crucially depends on loss of the tumor-suppressor Ink4a/ARF, but not on Wnt/β-catenin activation. The KRAS and BRAF oncogenes may also have contrasting effects on cellular hierarchies in the intestine, as oncogenic KRAS in combination with loss of APC can induce ectopic stem cells in the mouse intestine, 46 and KRAS mutations produced cells that favor ISC over TA cell fate and thus spread within individual crypts. 47 In contrast, our results suggest that oncogenic activation of BRAF would support the adoption of TA over ISC cell fate, which would result in preferential exclusion from the stem cell pool and clonal elimination.…”

Section: Discussionmentioning

confidence: 99%

Transgenic expression of oncogenic BRAF induces loss of stem cells in the mouse intestine, which is antagonized by β-catenin activity

et al. 2014

View full text Add to dashboard Cite

Colon cancer cells frequently carry mutations that activate the β-catenin and mitogen-activated protein kinase (MAPK) signaling cascades. Yet how oncogenic alterations interact to control cellular hierarchies during tumor initiation and progression is largely unknown. We found that oncogenic BRAF modulates gene expression associated with cell differentiation in colon cancer cells. We therefore engineered a mouse with an inducible oncogenic BRAF transgene, and analyzed BRAF effects on cellular hierarchies in the intestinal epithelium in vivo and in primary organotypic culture. We demonstrate that transgenic expression of oncogenic BRAF in the mouse strongly activated MAPK signal transduction, resulted in the rapid development of generalized serrated dysplasia, but unexpectedly also induced depletion of the intestinal stem cell (ISC) pool. Histological and gene expression analyses indicate that ISCs collectively converted to short-lived progenitor cells after BRAF activation. As Wnt/β-catenin signals encourage ISC identity, we asked whether β-catenin activity could counteract oncogenic BRAF. Indeed, we found that intestinal organoids could be partially protected from deleterious oncogenic BRAF effects by Wnt3a or by small-molecule inhibition of GSK3β. Similarly, transgenic expression of stabilized β-catenin in addition to oncogenic BRAF partially prevented loss of stem cells in the mouse intestine. We also used BRAF V637E knock-in mice to follow changes in the stem cell pool during serrated tumor progression and found ISC marker expression reduced in serrated hyperplasia forming after BRAF activation, but intensified in progressive dysplastic foci characterized by additional mutations that activate the Wnt/β-catenin pathway. Our study suggests that oncogenic alterations activating the MAPK and Wnt/β-catenin pathways must be consecutively and coordinately selected to assure stem cell maintenance during colon cancer initiation and progression. Notably, loss of stem cell identity upon induction of BRAF/MAPK activity may represent a novel fail-safe mechanism protecting intestinal tissue from oncogene activation.

show abstract

Section: Discussionmentioning

confidence: 99%

Transgenic expression of oncogenic BRAF induces loss of stem cells in the mouse intestine, which is antagonized by β-catenin activity

et al. 2014

View full text Add to dashboard Cite

show abstract

“…However, because Vil-Cre recombines in all IEC types (including ISCs), another possibility is that the effects of Xbp1 deletion could also have yet-to-be-defined direct effects on ISCs themselves. However, ISCs express only minute levels of Xbp1 and do not exhibit evidence of Xbp1 splicing Schwitalla et al, 2013) under basal conditions. Neither of these hypotheses are mutually exclusive.…”

Section: Isc Expansion Is Individually Determined In Each Xbp1-deficimentioning

confidence: 99%

ER stress transcription factor Xbp1 suppresses intestinal tumorigenesis and directs intestinal stem cells

Niederreiter¹,

Fritz²,

Adolph³

et al. 2013

J Cell Biol

View full text Add to dashboard Cite

“…However, recruitment of a certain population of differentiated cells into the stem cell pool is observed in several disease models, where the intrinsic ISCs are severely impaired or lost due to inflammation-induced tissue damage [97,98]. Accordingly, activation of NF-jB signaling may de-differentiate villus nonstem cells and guide those cells to initiate ''Top-down'' type of tumorigenesis [99]. In addition, tuft cells seem to have the potential to initiate tumors exclusively after exposure to the inflammatory environment [98].…”

Section: Colitis-associated Cancer Represents Another Aspect Of Iec-dmentioning

confidence: 99%

Role of epithelial cells in the pathogenesis and treatment of inflammatory bowel disease

2015

View full text Add to dashboard Cite

In the past decades, continuous effort has been paid to deeply understanding the pathophysiology of inflammatory bowel diseases (IBD), such as ulcerative colitis or Crohn's disease. As the disease typically arises as chronic inflammation of the gastrointestinal mucosa, research has been focused on how such an uncontrolled, deleterious immune response may arise and persist in a certain cohort of patients. Based on those immunologic analyses, the establishment of anti-TNF-a therapy, and the following series of biologic agents achieved great success and dramatically changed the therapeutic strategy of IBD patients. However, to guarantee long-term remission of the disease, the therapeutic standard has been raised to achieve ''mucosal healing'', which requires complete repair of the gastrointestinal mucosa. Recent studies have revealed the unexpected importance of epithelial cells in the pathophysiology of IBD. The general barrier function as well as the cell lineage-specific functions have been deeply attributed to the development of chronic intestinal inflammation. Also, the groundbreaking establishment of the in vitro intestinal stem cell culture system has opened up a way of developing stem cell transplantation therapy to treat otherwise refractory ulcers that may persist in IBD patients. In this review, we would like to focus on the role of epithelial cells in the pathophysiology of IBD, and also give a perspective to the upcoming development of regenerative therapies that may become one of the therapeutic choices to achieve mucosal healing in refractory patients of IBD.

show abstract

Intestinal Tumorigenesis Initiated by Dedifferentiation and Acquisition of Stem-Cell-like Properties

Cited by 926 publications

References 48 publications

Transgenic expression of oncogenic BRAF induces loss of stem cells in the mouse intestine, which is antagonized by β-catenin activity

Transgenic expression of oncogenic BRAF induces loss of stem cells in the mouse intestine, which is antagonized by β-catenin activity

ER stress transcription factor Xbp1 suppresses intestinal tumorigenesis and directs intestinal stem cells

Role of epithelial cells in the pathogenesis and treatment of inflammatory bowel disease

Contact Info

Product

Resources

About