Aspects of the endothelin system in colorectal cancer

Endothelin system members including endothelin-1, endothelin-2, endothelin-3, endothelin receptors, and endothelin converting enzyme are considered major regulating factors in cancer cell biology and cancer microenvironment. Endothelins are members of the matrix metalloproteinase superfamily of proteases, which are released from pre-proteins, bind to their receptors with differential affinity, and are degraded following cellular uptake. For their structural similarity, endothelin-2 and endothelin-3 can be regarded as natural competitors for the endothelin-1 receptors and as natural antagonists of endothelin-1. Endothelin-1 is regulated at several levels, primarily at the level of transcription. Remarkably, endothelin-1 is overexpressed in colorectal cancer, and elevated plasma levels were found in colorectal cancer patients. Endothelin receptor type A has an unequal distribution in the colon, as it is over-expressed in the proximal and distal segments of the colon. Compared with normal mucosal tissue, there is high expression of endothelin receptor type A and low expression of endothelin receptor type B in colorectal cancer at all Dukes stages. By binding to endothelin receptor type A, endothelin-1 leads to down-regulation of epithelial and increased expression of mesenchymal markers. Also, endothelin-1 acts as anti-apoptotic factor through multiple pathways like PI3K-dependent AKT activation or NF-κB signaling. Members of the endothelin system might be used as cancer biomarker and from a therapeutic point of view, targeting the endothelin axis is a promising aim. In effect, potential drugs may include endothelin converting enzyme inhibitors as well as selective and non-selective antagonists of endothelin receptor types A and B. Biomedical Reviews 2014; 25: 1-13.