Role of TGF-β in metastatic colon cancer: it is finally time for targeted therapy

Colorectal cancer (CRC) is one of the most frequent tumor types in Western countries. Approximately 20% of patients show metastasis at the time of diagnosis, with the liver being one of the most affected organs. Transforming growth factor-beta (TGF-beta) plays a regulatory role not only in the physiology of the normal colon but also in the development of CRC and its metastatic process. In this review, we analyze the molecular mechanisms leading to TGF-beta dysregulation in tumor and stroma cells and the modification of the microenvironment that fosters CRC metastasis. Recent genomic studies have identified a CRC subtype with a mesenchymal and aggressive phenotype having TGF-beta as a hub gene of this signature. Consistent with these findings, the inhibition of TGF-beta signaling has been shown to impair experimental CRC metastasis to the liver. Based on these and other results conducted in various tumor types, the pharmaceutical industry has developed a variety of strategies to target TGF-beta. We provide up-to-date information of these therapies, which are currently in preclinical or clinical trials.