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A colorectal cancer expression profile that includes transforming growth factor beta inhibitor BAMBI predicts metastatic potential

Item Type:Article
Title:A colorectal cancer expression profile that includes transforming growth factor beta inhibitor BAMBI predicts metastatic potential
Creators Name:Fritzmann, J. and Morkel, M. and Besser, D. and Budczies, J. and Kosel, F. and Brembeck, F.H. and Stein, U. and Fichtner, I. and Schlag, P.M. and Birchmeier, W.
Abstract:BACKGROUND & AIMS: Much is known about the genes and mutations that cause colorectal cancer (CRC), yet only a few have been associated with CRC metastasis. We performed expression-profiling experiments to identify genetic markers of risk and to elucidate the molecular mechanisms of CRC metastasis. METHODS: We compared gene expression patterns between metastatic and nonmetastatic stage-matched human colorectal carcinomas by microarray analysis. Correlations between BAMBI and metastasis-free survival were examined by quantitative real-time polymerase chain reaction (PCR) using an independent set of human colon carcinomas. Human colon cancer cell lines were analyzed for BAMBI regulation, cell motility, and experimental metastasis. RESULTS: We established a signature of 115 genes that differentiated metastatic from nonmetastatic primary tumors. Among these, the transforming growth factor (TGF) beta inhibitor BAMBI was highly expressed in approximately half of metastatic primary tumors and metastases but not in nonmetastatic tumors. BAMBI is a target of canonical Wnt signaling that involves the beta-catenin coactivator BCL9-2. We observed an inverse correlation between level of BAMBI expression and metastasis-free survival time of patients. BAMBI inhibits TGF-beta signaling and increases migration in colon cancer cells. In mice, overexpression of BAMBI caused colon cancer cells to form tumors that metastasized more frequently to liver and lymph nodes than control cancer cells. CONCLUSIONS: BAMBI regulates CRC metastasis by connecting the Wnt/beta-catenin and TGF-beta-signaling pathways. The metastatic expression signature we describe, along with BAMBI levels, can be used in prognosis. Developmental signaling pathways appear to act in hierarchies and cooperate in tumor cell migration, invasion, and metastasis.
Keywords:Adenocarcinoma, Tumor Cell Line, Cell Movement, Cell Shape, Colorectal Neoplasms, Gene Expression Profiling, Neoplastic Gene Expression Regulation, Genetic Predisposition to Disease, HCT116 Cells, Kaplan-Meiers Estimate, Membrane Protein, Neoplasm Invasiveness, Neoplasm Staging, Oligonucleotide Array Sequence Analysis, Phenotype, Reverse Transcriptase Polymerase Chain Reaction, Risk Factors, Signal Transduction, Transforming Growth Factor beta, Treatment Outcome, Biological Tumor Markers, Wnt Proteins, beta Catenin, Animals, Mice
Publisher:Elsevier / Saunders
Page Range:165-175
Date:July 2009
Official Publication:https://doi.org/10.1053/j.gastro.2009.03.041
PubMed:View item in PubMed

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