Top-down morphogenesis of colorectal tumors

Shih, Ie Ming; Wang, Tian Li; Traverso, Giovanni; Romans, Kathy; Hamilton, Stanley R.; Ben‐Sasson, Shmuel A.; Kinzler, Kenneth W.; Vogelstein, Bert

doi:10.1073/pnas.051629398

Cited by 316 publications

(270 citation statements)

References 25 publications

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“…5,24 Accordingly, during carcinogenesis, potentially preneoplastic crypts expand and form multicryptal lesions that evolve into adenoma and cancer. 25,26 We also found that the number of MDF increased with the dosage of carcinogen administered. By contrast, the multiplicity of MDF and ACF was not affected by the dose of DMH, a result in agreement with McLellan et al 6 in ACF induced by a single dose of DMH.…”

Section: Discussionmentioning

confidence: 59%

Mucin‐depleted foci have β‐catenin gene mutations, altered expression of its protein, and are dose‐ and time‐dependent in the colon of 1,2‐dimethylhydrazine‐treated rats

Femia

Bendinelli

Giannini

et al. 2005

Intl Journal of Cancer

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Mucin-depleted foci (MDF) are purported preneoplastic lesions that can be easily visualized in the unsectioned colon of carcinogen-treated rats stained with high-iron diamine alcian blue (HID-AB). In F344 rats treated twice with 150 mg/kg of 1,2-dimethylhydrazine (DMH) and sacrificed after 5, 9, 13 and 28 weeks, MDF increased over time from 5 to 13 weeks, whereas they decreased at 28 weeks, when tumors appear. MDF multiplicity (crypts/MDF) linearly increased with time. Increasing doses of DMH (100, 150 and 200 mg/kg 3 2 times) caused a dose-related increase in MDF. Mutations in Ctnnb1 gene codifying for b-catenin were identified with PCR amplification and direct sequencing in 6/15 tumors (40%), 7/28 MDF (25%) and 2/27 (7%) aberrant crypt foci (ACF) identified in HID-AB-stained colon. All mutations in tumors and MDF caused amino acid substitution, while one mutation in ACF was silent. b-catenin detected at membrane level by immunohistochemistry was markedly reduced in MDF and tumors and, to a lesser extent, in ACF identified with HID-AB. By contrast, nuclear localization of b-catenin was significantly increased in MDF and tumors, while no variation was observed in ACF. b-catenin cytoplasmic expression was also significantly increased in MDF and tumors but to a lesser extent in ACF. In conclusion, MDF are induced dose-dependently by DMH, increase in size with time, have mutations in the b-catenin gene and marked alterations in b-catenin cellular localization. Since all these phenomena are considered specific steps for colon tumorigenesis, these results further support the hypothesis that MDF are cancer precursors and can be proposed as endpoints in short-term carcinogenesis experiments. ' 2005 Wiley-Liss, Inc.

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Section: Discussionmentioning

confidence: 59%

Mucin‐depleted foci have β‐catenin gene mutations, altered expression of its protein, and are dose‐ and time‐dependent in the colon of 1,2‐dimethylhydrazine‐treated rats

Femia

Bendinelli

Giannini

et al. 2005

Intl Journal of Cancer

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“…Once this happens, the transition to adenoma occurs and, given further genetic changes, overt carcinomas are seen. This expansion of the colon cancer progression pathway answers some of the puzzles posed by the FearonVogelstein pathway, namely the lack of APC mutations in the stem cell compartment (Shih et al, 2001), but poses new ones. For example, what is the significance of finding HPPs together with polyps known as sessile serrated adenomas that have increased levels of hypermethylated genes (Batts, 2004)?…”

mentioning

confidence: 89%

CEACAM1 and hyperplastic polyps: new links in the chain of events leading to colon cancer

Shively

2004

Oncogene

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“…Crypt expansion in colon cancer and polyposis can be caused by 'bottom-up' crypt fission (division of an existing crypt starting at its base), or by 'top-down' de novo crypt formation (budding of a new crypt from a crypt or villus) 9,10,[30][31][32][33] . We found that both mechanisms of crypt expansion occurred in PTEN-deficient intestines and were associated with an excessive production of M + ISC/p cells ( Fig.…”

Section: Musashi + Stem and Progenitor Cells Initiate Polyp Formationmentioning

confidence: 99%

PTEN-deficient intestinal stem cells initiate intestinal polyposis

et al. 2007

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Intestinal polyposis, a precancerous neoplasia, results primarily from an abnormal increase in the number of crypts, which contain intestinal stem cells (ISCs). In mice, widespread deletion of the tumor suppressor Phosphatase and tensin homolog (PTEN) generates hamartomatous intestinal polyps with epithelial and stromal involvement. Using this model, we have established the relationship between stem cells and polyp and tumor formation. PTEN helps govern the proliferation rate and number of ISCs and loss of PTEN results in an excess of ISCs. In PTENdeficient mice, excess ISCs initiate de novo crypt formation and crypt fission, recapitulating crypt production in fetal and neonatal intestine. The PTEN-Akt pathway probably governs stem cell activation by helping control nuclear localization of the Wnt pathway effector β-catenin. Akt phosphorylates β-catenin at Ser552, resulting in a nuclear-localized form in ISCs. Our observations show that intestinal polyposis is initiated by PTEN-deficient ISCs that undergo excessive proliferation driven by Akt activation and nuclear localization of β-catenin. Accession codes. Gene Expression Omnibus (GEO): GSE6078.URLs. GEO: http://www.ncbi.nlm.nih.gov/projects/geo/.Supplementary information is available on the Nature Genetics website. COMPETING INTERESTS STATEMENTThe authors declare that they have no competing financial interests. HHS Public AccessAuthor manuscript Nat Genet. Author manuscript; available in PMC 2015 December 16. Published in final edited form as:Nat Genet. 2007 February ; 39(2): 189-198. doi:10.1038/ng1928. Author Manuscript Author ManuscriptAuthor Manuscript Author ManuscriptThe failure of most current therapies to cure cancer has led to the hypothesis that treatments targeted at malignant proliferation spare a more slowly cycling 'cancer stem cell' population that has the ability to regenerate the tumor 1 . Recently, cancer stem cells have been identified and shown to seed tumors upon transplantation into a secondary host [2][3][4] . However, little is known about the process by which mutation(s) in a stem cell result in primary tumor initiation.Although there are many 'causes' of intestinal cancer, it is well established that almost all cases begin with the development of benign polyps, mainly involving benign neoplastic proliferation of epithelium. The epithelium of the small intestine is composed of a proliferation compartment (crypt) and a differentiation compartment in the villus (Fig. 1a). ISCs, located near the crypt base and above Paneth cells 5,6 , give rise to enterocytes, goblet cells, enteroendocrine cells and Paneth cells [6][7][8] . Intestinal polyposis features a substantial increase in the number of crypts (crypt expansion) and a reduction in epithelial cell differentiation 6,7,9,10 . A key question 7,9,11 is whether stem cells are involved in the abnormal crypt expansion during polyp initiation.Studies of human hereditary intestinal polyposis syndromes (which typically, but not uniformly, predispose affected individuals to gastrointes...

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Top-down morphogenesis of colorectal tumors

Cited by 316 publications

References 25 publications

Mucin‐depleted foci have β‐catenin gene mutations, altered expression of its protein, and are dose‐ and time‐dependent in the colon of 1,2‐dimethylhydrazine‐treated rats

Mucin‐depleted foci have β‐catenin gene mutations, altered expression of its protein, and are dose‐ and time‐dependent in the colon of 1,2‐dimethylhydrazine‐treated rats

CEACAM1 and hyperplastic polyps: new links in the chain of events leading to colon cancer

PTEN-deficient intestinal stem cells initiate intestinal polyposis

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