title: A colorectal cancer expression profile that includes transforming growth factor beta inhibitor BAMBI predicts metastatic potential.
abstract: OBJECTIVE
  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.
authors.affiliation: Max Delbrueck Center for Molecular Medicine, Berlin, Germany.
authors.forename: Johannes
authors.initials: J
authors.lastname: Fritzmann
authors.forename: Markus
authors.initials: M
authors.lastname: Morkel
authors.forename: Daniel
authors.initials: D
authors.lastname: Besser
authors.forename: Jan
authors.initials: J
authors.lastname: Budczies
authors.forename: Frauke
authors.initials: F
authors.lastname: Kosel
authors.forename: Felix H
authors.initials: FH
authors.lastname: Brembeck
authors.forename: Ulrike
authors.initials: U
authors.lastname: Stein
authors.forename: Iduna
authors.initials: I
authors.lastname: Fichtner
authors.forename: Peter M
authors.initials: PM
authors.lastname: Schlag
authors.forename: Walter
authors.initials: W
authors.lastname: Birchmeier