TGF-beta receptor inactivation and mutant Kras induce intestinal neoplasms in mice via a beta-catenin-independent pathway.

Abstract

BACKGROUND & AIMS:

During colorectal cancer pathogenesis, mutations and epigenetic events cause neoplastic behavior in epithelial cells by deregulating the Wnt, Ras-Raf-extracellular signal-regulated kinase (ERK), and transforming growth factor (TGF)-beta-signaling pathways, among others. The TGF-beta-signaling pathway is often inactivated in colon cancer cells by mutations in the gene encoding the TGF-beta receptor TGFBR2. The RAS-RAF-ERK pathway is frequently up-regulated in colon cancer via mutational activation of KRAS or BRAF. We assessed how these pathways interact in vivo and affect formation of colorectal tumors.

METHODS:

We analyzed intestinal tumors that arose in mice that express an oncogenic (active) form of Kras and that have Tgfbr2 inactivations-2 common molecular events observed in human colorectal tumors. LSL-KrasG12D mice were crossed with Villin-Cre;Tgfbr2E2flx/E2flx mice, which do not express Tgfbr2 in the intestinal epithelium.

RESULTS:

Neither inactivation of Tgfbr2 nor expression of oncogenic Kras alone was sufficient to induce formation of intestinal neoplasms. Histologic abnormalities arose in mice that expressed Kras, but only the combination of Tgfbr2 inactivation and Kras activation led to intestinal neoplasms and metastases. The cancers arose via a beta-catenin-independent mechanism; the epidermal growth factor-signaling pathway was also activated. Cells in the resulting tumors proliferated at higher rates, expressed decreased levels of p15, and expressed increased levels of cyclin D1 and cdk4, compared with control cells.

CONCLUSIONS:

A combination of inactivation of the TGF-beta-signaling pathway and expression of oncogenic Kras leads to formation of invasive intestinal neoplasms through a beta-catenin-independent pathway; these adenocarcinomas have the capacity to metastasize.

• Authors: Patty Trobridge, Sue Knoblaugh, M Kay Washington, Nina M Munoz, Karen D Tsuchiya, Andres Rojas, Xiaoling Song, Cornelia M Ulrich, Takehiko Sasazuki, Senji Shirasawa, William M Grady
• Journal: Gastroenterology (Gastroenterology) Vol. 136 Issue 5 Pg. 1680-8.e7 (May 2009) ISSN: 1528-0012 [Electronic] United States
• PMID: 19208363 (Publication Type: Journal Article, Multicenter Study, Research Support, N.I.H., Extramural, Research Support, U.S. Gov't, Non-P.H.S.)

Chemical References

• Receptors, Transforming Growth Factor beta
• Wnt Proteins
• beta Catenin
• Protein Serine-Threonine Kinases
• raf Kinases
• Receptor, Transforming Growth Factor-beta Type II
• Mitogen-Activated Protein Kinase Kinases

Topics

• Animals
• Cell Line, Tumor
• Cell Proliferation
• Gene Expression
• Genes, ras (genetics)
• Humans
• Intestinal Mucosa (metabolism)
• Intestinal Neoplasms (genetics, metabolism, physiopathology)
• Mice
• Mice, Transgenic
• Mitogen-Activated Protein Kinase Kinases (metabolism)
• Mutation
• Phosphorylation
• Protein Serine-Threonine Kinases (antagonists & inhibitors, genetics, metabolism)
• Receptor, Transforming Growth Factor-beta Type II
• Receptors, Transforming Growth Factor beta (antagonists & inhibitors, genetics, metabolism)
• Signal Transduction
• Transcriptional Activation
• Transfection
• Wnt Proteins (metabolism)
• beta Catenin (metabolism)
• raf Kinases (metabolism)