SMAD3 and neoplasm: As described above, advanced human cancer cells that retain TGF-β/SMAD signaling but lack tumor suppressive responses can make use of the SMAD pathway to their advantages, and via SMAD3/SMAD4 stimulate pro-invasive and pro-metastatic target genes (for example, IL11, CTGF, CXCR4) and reprogram (EMT) phenotypes (Aggarwal and Massague, 2012).