New drug target
Researchers at the Max Delbrück Centre for Molecular Medicine, and the Robert Rössle Cancer Clinic, both in Berlin-Buch, Germany, along with collaborators at the US National Cancer Institute, in Frederick, Maryland, have discovered how a gene involved in the formation of metastases in colon cancer is controlled, providing a new drug target and opening up an important new avenue for colon cancer diagnosis and treatment.
The researchers demonstrated that the S100A4/metastasin gene, which controls the proliferation and invasion of tumor cells, is regulated by a specific signaling cascade that is directly related to colon cancer metastasis formation. They have called this the beta catenin/TCF signalling cascade.
In microarray studies, S100A4/metastasin was identified as the gene most strongly expressed by mutated beta-catenin protein. One of the functions of beta-catenin is to regulate cellular adhesion. If it becomes mutated, cells dissociate from their neighboring cells and are thus able to migrate and settle in other organs, forming metastases.
The researchers were able also to pinpoint the binding site on the S100A4/metastasin gene for the mutated beta-catenin protein, from where it regulates the gene. The expression of the S100A4/metastasin gene triggered by beta-catenin, leads to increased migration and to invasion of tumor cells. If this signaling chain is interrupted, the tumor cells can no longer migrate.
In animal experiments, it was shown that switching on the S100A4 gene greatly increases the rate of metastasis, and this finding has been substantiated over the course of the disease in colon cancer patients. Patients with elevated S100A4/metastasin levels in tumour biopsy samples were more likely to get metastases in the liver or lung.
The findings uncovered the interconnection of two previously unrelated cellular mechanisms, which have been shown to be important for tumor progression and metastasis formation: the beta catenin/TCF signaling pathway and the S100A4/metastasin gene, which controls migration and invasion.
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