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Down-Regulation of the Homeodomain Factor Cdx2 in Colorectal Cancer by Collagen Type I

An Active Role for the Tumor Environment in Malignant Tumor Progression

¹ Department of Pathology, University of Erlangen-Nürnberg, Erlangen, Germany; ² Department of Surgery, University of Munich, Munich, Germany; and ³ INSERM, Unit 381, Strasbourg, France

The homeobox transcription factor Cdx2 specifies intestinal development and homeostasis and is considered a tumor suppressor in colorectal carcinogenesis. However, Cdx2 mutations are rarely found. Invasion of colorectal cancer is characterized by a transient loss of differentiation and nuclear accumulation of the oncoprotein ß-catenin in budding tumor cells. Strikingly, this is reversed in growing metastases, indicating that tumor progression is a dynamic process that is not only driven by genetic alterations but also regulated by the tumor environment. Here we describe a transient loss of Cdx2 in budding tumor cells at the tumor host interface, and reexpression of Cdx2 in metastases. Cell culture experiments show that collagen type I, through ß₁ integrin signaling, triggers a transient transcriptional down-regulation of Cdx2 and its intestine-specific target gene sucrase isomaltase, associated with a loss of differentiation. These data indicate an active role for the tumor environment in malignant tumor progression.

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