Wnt/beta-catenin/Tcf signaling: A critical pathway in gastrointestinal tumorigenesis

Cancers of the gastrointestinal tract, including the liver, bile
ducts, and pancreas, constitute the largest group of malignant
tumors. Colorectal cancer is one of the most common neoplastic
diseases in Western countries and one of the leading causes of
cancer-related deaths. Inactivation of the adenomatous polyposis
coli (APC) tumor-suppressor gene during early adenoma formation is
thought to be the first genetic event in the process of colorectal
carcinogenesis followed by mutations in oncogenes like K-Ras and
tumor-suppressor genes like p53. Identification of the interaction
of APC with the proto-oncogene beta-catenin has linked colorectal
carcinogenesis to the Wnt-signal transduction pathway. The main
function of APC is thought to be the regulation of free
beta-catenin in concert with the glycogen synthase kinase 3beta
(GSK-3beta) and Axin proteins. Loss of APC function, inactivation
of Axin or activating beta-catenin mutations result in the cellular
accumulation of beta-catenin. Upon translocation to the nucleus
beta-catenin serves as an activator of T-cell factor
(Tcf)-dependent transcription leading to an increased expression of
several specific target genes including c-Myc, cyclin D1, MMP-7,
and ITF-2. While APC mutations are almost exclusively found in
colorectal cancers, deregulation of Wnt/beta-catenin/Tcf signaling
is also common in other gastrointestinal and extra-gastrointestinal
human cancers. In a fraction of hepatocellular carcinomas the Writ
pathway is deregulated by inactivation of Axin or stabilizing
mutations of beta-catenin. The majority of hepatoblastomas and a
group of gastric cancers also carry beta-catenin mutations.
Clearly, this pathway harbors great potential for future
applications in cancer diagnostics, staging, and therapy. Copyright
(C) 2002 S. Karger AG, Basel.