Short chain fatty acids and colon cancer

Leonard H. Augenlicht, John M. Mariadason, Andrew Wilson, Diego Arango, WanCai Yang, Barbara G. Heerdt, Anna Velcich

Research output: Contribution to journalArticle

67 Citations (Scopus)

Abstract

The development of intestinal cancer involves complex genetic and epigenetic alterations in the intestinal mucosa. The principal signaling pathway responsible for the initiation of tumor formation, the APC-βcatenin-TCF4 pathway, regulates both cell proliferation and colonic cell differentiation, but many other intrinsic and extrinsic signals also modulate these cell maturation pathways, The challenge is to understand how signaling and cell maturation are also modulated by nutritional agents, Through gene expression profiling, we have gained insight into the mechanisms by which short chain fatty acids regulate these pathways and the differences in response of gene programs, and of the specific regulation of the c-myc gene, to physiological regulators of intestinal cell maturation, such as butyrate, compared with pharmacological regulators such as the nonsteroidal antiinflammatory drug sulindac. Moreover, we used a combination of gene expression profiling of the response of cells in culture to sulindac and the response of the human mucosa in subjects treated with sulindac for 1 month, coupled with a mouse genetic model approach, to identify the cyclin dependent kinase inhibitor p21WAF1/Cip1 as an important suppressor of Apc-initiated intestinal tumor formation and a necessary component for tumor inhibition by sulindac. Finally, the mucous barrier, secreted by intestinal goblet cells, is the interface between the luminal contents and the intestinal mucosa. We generated a mouse genetic model with a targeted inactivation of the Muc2 gene that encodes the major intestinal mucin. These mice have no recognizable goblet cells due to the failure of cells to synthesize and store mucin. This leads to perturbations in intestinal crypt architecture, increased cellular proliferation and rates of cell migration, decreased apoptosis and development of adenomas and adenocarcinomas in the small and large intestine and the rectum.

Original languageEnglish (US)
JournalJournal of Nutrition
Volume132
Issue number12
StatePublished - Dec 1 2002

Fingerprint

Sulindac
Volatile Fatty Acids
short chain fatty acids
colorectal neoplasms
Colonic Neoplasms
neoplasms
Goblet Cells
goblet cells
mucins
Genetic Models
Gene Expression Profiling
Mucins
Intestinal Mucosa
intestinal mucosa
cell proliferation
mice
Cell Proliferation
cells
intestinal crypts
Intestinal Neoplasms

Keywords

  • Cell maturation
  • Gene expression profiling
  • Intestinal cancer
  • Mouse genetic models
  • Mucin

ASJC Scopus subject areas

  • Medicine (miscellaneous)
  • Food Science

Cite this

Augenlicht, L. H., Mariadason, J. M., Wilson, A., Arango, D., Yang, W., Heerdt, B. G., & Velcich, A. (2002). Short chain fatty acids and colon cancer. Journal of Nutrition, 132(12).

Short chain fatty acids and colon cancer. / Augenlicht, Leonard H.; Mariadason, John M.; Wilson, Andrew; Arango, Diego; Yang, WanCai; Heerdt, Barbara G.; Velcich, Anna.

In: Journal of Nutrition, Vol. 132, No. 12, 01.12.2002.

Research output: Contribution to journalArticle

Augenlicht, LH, Mariadason, JM, Wilson, A, Arango, D, Yang, W, Heerdt, BG & Velcich, A 2002, 'Short chain fatty acids and colon cancer', Journal of Nutrition, vol. 132, no. 12.
Augenlicht LH, Mariadason JM, Wilson A, Arango D, Yang W, Heerdt BG et al. Short chain fatty acids and colon cancer. Journal of Nutrition. 2002 Dec 1;132(12).
Augenlicht, Leonard H. ; Mariadason, John M. ; Wilson, Andrew ; Arango, Diego ; Yang, WanCai ; Heerdt, Barbara G. ; Velcich, Anna. / Short chain fatty acids and colon cancer. In: Journal of Nutrition. 2002 ; Vol. 132, No. 12.
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