Expression of wingless-type mouse mammary tumor virus integration site family pathway effectors in lymphatic and hepatic metastases of patients with colorectal cancer: Associations with the primary tumor.

The wingless-type mouse mammary tumor virus integration site family (Wnt) pathway plays a major role in the carcinogenesis of colorectal cancer (CRC). Its most important effector, the nuclear beta-catenin, influences not only transcription but also the proliferation and dedifferentiation of the colonic mucosa. This induces an epithelial-mesenchymal transition which ultimately can lead to the development of cancer and the formation of metastases. However, little is known about the exact interaction and context-sensitive expression of Wnt-pathway effectors in the primary tumor and corresponding metastasis. Therefore, this study assessed the expression of the three most important effectors of the Wnt pathway, beta-catenin, adenomatous polyposis coli (APC) and Wnt-1, in the primary tumor and corresponding metastasis of patients with CRC. Immunohistochemical staining of beta-catenin, APC and Wnt-1 was performed in paraffin-embedded tissue samples of the primary tumor, and the corresponding hepatic and nodal metastasis samples from 24 patients with metastatic CRC. Isotype antibodies were used as negative controls. The results were visualized using the ABC-method. Analysis of the primary tumor comprised of a separate evaluation of the central tumor area as well as the invasion front. There was a significant overexpression of nuclear beta-catenin at the tumor invasion front (P<0.001). Compared to normal colonic mucosa, expression of cytoplasmic beta-catenin was significantly higher in the primary tumor (P<0.001) as well as all the corresponding hepatic and lymphatic metastases (hepatic metastases, P=0.001; nodal metastases, P=0.017). By contrast, APC expression was significantly lower in all analyzed tumor compartments compared with normal colonic mucosa (primary tumor, P=0.022; hepatic metastases, P=0.006; nodal metastases, P=0.012). Finally, Wnt-1 protein expression was significantly lower in liver metastases but not in the primary tumor or lymphatic metastases compared with normal colonic mucosa (P=0.003). The present study demonstrates that the major Wnt-effector proteins, beta-catenin, APC and Wnt-1, are heterogeneously expressed in the primary tumor and corresponding hepatic as well as nodal metastases of patients with CRC. This context-sensitive diverse expression of Wnt-effector proteins may be important for future individualized targeted therapies.