Invasion of common colorectal adenocarcinomas is coupled with a transient loss of epithelial differentiation of tumor cells. Previously, we have shown that dedifferentiated tumor cells at the invasive front (IF) accumulate the transcriptional activator β‐catenin in the nucleus, in contrast to cells of the tumor center. To characterize the cells of these two morphogenic tumor areas, gene expression profiling was performed. Our study demonstrates that intratumorous heterogeneity in colorectal cancer correlates with differential expression of 510 genes between the central tumor region (TC) and the IF. Many genes differentially expressed at the IF are involved in cellular invasion processes like cell motility, cell adhesion and extracellular matrix interaction. This in vivo analysis shows overexpression of known Wnt/β‐catenin target genes either in the entire tumor tissue (compared to normal mucosa) or specifically at the IF. Thus, even though all tumor cells overexpress β‐catenin, the existence of at least 2 groups of Wnt/β‐catenin target genes selectively activated in different tumor regions is suggested. The concomitant high expression of inflammation‐ and tissue repair‐related genes at the IF supports the hypothesis that an inflammation‐activated microenvironment may trigger selective Wnt/β‐catenin target gene expression and contribute to the malignant progression of colorectal cancer. © 2007 Wiley‐Liss, Inc.