Paneth cell marker expression in intestinal villi and colon crypts characterizes dietary induced risk for mouse sporadic intestinal cancer

Donghai Wang, Karina Peregrina, Elena Dhima, Elaine Y. Lin, John M. Mariadason, Leonard H. Augenlicht

Research output: Contribution to journalArticle

24 Citations (Scopus)

Abstract

Nutritional and genetic risk factors for intestinal tumors are additive on mouse tumor phenotype, establishing that diet and genetic factors impact risk by distinct combinatorial mechanisms. In a mouse model of dietary-induced sporadic small and large intestinal cancer in WT mice in which tumor etiology, lag, incidence, and frequency reflect >90% of intestinal cancer in Western societies, dietary-induced risk altered gene expression profiles predominantly in villus cells of the histologically normal mucosa, in contrast to targeting of crypt cells by inheritance of an Apc 1638N allele or homozygous inactivation of p21 Waf1/cip1, and profiles induced by each risk factor were distinct at the gene or functional group level. The dietary-induced changes in villus cells encompassed ectopic expression of Paneth cell markers (a lineage normally confined to the bottom of small intestinal crypts), elevated expression of the Wnt receptor Fzd5 and of EphB2 (genes necessary for Paneth cell differentiation and localization to the crypt bottom), and increased Wnt signaling in villus cells. Ectopic elevation of these markers was also present in the colon crypts, which are also sites of sporadic tumors in the nutritional model. Elevating dietary vitamin D3 and calcium, which prevents tumor development, abrogated these changes in the villus and colon cells. Thus, common intestinal cancer driven by diet involves mechanisms of tumor development distinct from those mechanisms that cause tumors induced by the rare inheritance of a mutant adenomatous polyposis coli (Apc) allele. This is fundamental for understanding how common sporadic tumors arise and in evaluating relative risk in the population.

Original languageEnglish (US)
Pages (from-to)10272-10277
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume108
Issue number25
DOIs
StatePublished - Jun 21 2011

Fingerprint

Paneth Cells
Intestinal Neoplasms
Colon
Neoplasms
Adenomatous Polyposis Coli
Wnt Receptors
Alleles
Nutrigenomics
Diet
Cholecalciferol
Transcriptome
Genes
Cell Differentiation
Mucous Membrane
Calcium
Phenotype

Keywords

  • Colon cancer
  • Microarray
  • Sporadic
  • Western diet

ASJC Scopus subject areas

  • General

Cite this

Paneth cell marker expression in intestinal villi and colon crypts characterizes dietary induced risk for mouse sporadic intestinal cancer. / Wang, Donghai; Peregrina, Karina; Dhima, Elena; Lin, Elaine Y.; Mariadason, John M.; Augenlicht, Leonard H.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 108, No. 25, 21.06.2011, p. 10272-10277.

Research output: Contribution to journalArticle

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