Journal
CTS-CLINICAL AND TRANSLATIONAL SCIENCE
Volume 1, Issue 2, Pages 163-167Publisher
WILEY-BLACKWELL PUBLISHING, INC
DOI: 10.1111/j.1752-8062.2008.00040.x
Keywords
colorectal cancer; paracrine deficiency syndrome; hormone replacement therapy
Categories
Funding
- NIH [CA75123, CA95026]
- Targeted Diagnostic and Therapeutics, Inc.
- Pennsylvania Department of Health
- Prevent Cancer Foundation
- Measey Foundation
Ask authors/readers for more resources
The most commonly lost gene products in colorectal carcinogenesis include the paracrine hormones guanylin and uroguanylin, the endogenous ligands for guanylyl cyclase C (GCC), the intestinal receptor for diarrheagenic bacterial enterotoxins. Recently, GCC-cyclic guanosine monophosphate (GMP) signaling has emerged as a principal regulator of proliferation, genetic integrity, and metabolic programming in normal human enterocytes and colon cancer cells. Elimination of GCC in mice produced hyperplasia of the proliferating compartment associated with increases in the rapidly cycling progenitor cells and reprogrammed enterocyte metabolism, with a shift from oxidative phosphorylation to glycolysis. In addition, in the colons of mice carrying mutations in adenomatous polyposis coli gene Apc (Apc(Min/+)) or exposed to the carcinogen azoxymethane, elimination of GCC increased tumor initiation and promotion by disrupting genomic integrity and releasing cell cycle restriction. These previously unrecognized roles for GCC as a fundamental regulator of intestinal homeostasis and as an intestinal tumor suppressor suggest that receptor dysregulation reflecting paracrine hormone insufficiency is a key event during the initial stages of colorectal tumorigenesis. Together with the uniform overexpression of GCC in human tumors, these novel roles for GCC underscore the potential of oral replacement with GCC ligands for a targeted prevention and therapy of colorectal cancer.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available