Overexpression of activin A in stage IV colorectal cancer

Background and aims-Activins and inhibins are dimeric polypeptides that belong to the transforming growth factor beta (TGF-beta) superfamily and that bind to transmembrane receptors with serine/ threonine kinase activity. The aim of this study was to characterise, in colon cancer cell lines and in normal and malignant human colon tissues, levels of expression of inhibin subunits that are involved in activin/inhibin dimer formation, and of the type I and II activin receptors (actRI and actRII). Methods-Expression of inhibin subunits and activin receptors was analysed by northern blot analysis. Inhibin betaA and activin receptor expression were also assessed by use of polymerase chain reaction (PCR). In addition, activin A/inhibin betaA localisation in human colon samples was assessed by immunohistochemistry and in situ hybridisation. Results-Inhibin betaA mRNA was expressed in CaCo2 cells but not in SW 837 or SW 1463 cells whereas inhibin betaB and inhibin alpha were below the level of detection. In contrast, all four activin receptors were present in the three cell lines. Colon cancers overexpressed inhibin betaA mRNA in comparison with normal colon, and this overexpression was greatest in stage IV tumours. ActRIb mRNA levels were slightly higher in the normal colon than in cancer tissues. By immunohistochemistry and in situ hybridisation, activin A and inhibin VA mRNA were present in the mucosal epithelial cells in normal tissues from patients with stage I disease but were either absent or weakly present in normal tissues from patients with stage IV disease. Conversely, they were present at weak to moderate levels in stage I cancers but at high levels in stage IV cancers. Conclusions-Our findings indicate that activin A is overexpressed in human colorectal tumours, especially in stage IV disease, raising the possibility that activin A may have a role in advanced colorectal cancer.