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(American Journal of Pathology. 2007;170:733-744.)
© 2007 American Society for Investigative Pathology
DOI: 10.2353/ajpath.2007.060696

The Microenvironment Controls CDX2 Homeobox Gene Expression in Colorectal Cancer Cells

Fairouz Benahmed*, Isabelle Gross*, Dominique Guenot*, Frédéric Jehan{dagger}, Elisabeth Martin*, Claire Domon-Dell*, Thomas Brabletz{ddagger}, Michèle Kedinger*, Jean-Noël Freund* and Isabelle Duluc*

From INSERM U682 and University Louis Pasteur,* Strasbourg, France; INSERM U561 and University Paris Descartes,{dagger} Paris, France; and the University of Erlangen-Nürnberg,{ddagger} Erlangen, Germany

The homeobox gene CDX2 plays a major role in development, especially in the gut, and it also acts as a tumor suppressor in the adult colon. Using orthotopic and heterotopic xenografts of human primary colorectal tumor cells and cell lines in nude mice, we addressed the effect of the microenvironment on CDX2 expression. In cells expressing CDX2 at a high level in culture, this level was maintained in subcutaneous grafts but was reduced when implanted into the cecum wall. Reciprocally, in cells with low CDX2 expression in culture, the level remained low in grafts into the cecum wall but was stimulated subcutaneously. In vitro co-cultures showed that CDX2 expression was activated in cells grown on layers of skin fibroblasts but not on intestinal fibroblasts. The stimulation was transcriptional, as assessed by transfection experiments with reporter plasmids containing the murine Cdx2 promoter. Together, these data demonstrate experimentally that CDX2 expression is adaptable and strongly dependent on the microenvironment surrounding the tumor cells. We exclude a role of the Notch pathway in this regulation. The regulation of CDX2 by the microenvironment might be relevant during the process of metastatic dissemination when the gene is transiently turned down in invasive cells.




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Copyright © 2007 by the American Society for Investigative Pathology.