Activin signaling is an essential component of the TGF-β induced pro-metastatic phenotype in colorectal cancer

Advanced colorectal cancer (CRC) remains a critical health care challenge worldwide. Various TGF-beta superfamily members are important in colorectal cancer metastasis, but their signaling effects and predictive value have only been assessed in isolation. Here, we examine cross-regulation and combined functions of the two most prominent TGF-beta superfamily members activin and TGF-beta in advanced colorectal cancer. In two clinical cohorts we observed by immune-based assay that combined serum and tissue activin and TGF-beta ligand levels predicts outcome in CRC patients and is superior to single ligand assessment. While TGF-beta growth suppression is independent of activin, TGF-beta treatment leads to increased activin secretion in colon cancer cells and TGF-beta induced cellular migration is dependent on activin, indicating pathway cross-regulation and functional interaction in vitro. mRNA expression of activin and TGF-beta pathway members were queried in silico using the TCGA data set. Coordinated ligand and receptor expression is common in solid tumors for activin and TGF-beta pathway members. In conclusion, activin and TGF-beta are strongly connected signaling pathways that are important in advanced CRC. Assessing activin and TGF-beta signaling as a unit yields important insights applicable to future diagnostic and therapeutic interventions.