Molecular Mechanisms and Therapies of Colorectal Cancer 2.0

<p>Colorectal cancer (CRC) is currently the third leading cause of cancer-related mortality. Transforming growth factor beta (TGF-?) signaling has been associated with CRC growth and metastasis due to its involvement in proliferation epithelial-to-mesenchymal transition (EMT) and angiogenesis. The TGF-? superfamily contains over forty members including TGF-?s Nodal Activin and bone morphogenetic proteins (BMPs). Three types of TGF-? receptors (TGF?Rs) have been identified: types 1 2 and 3. After ligand binding TGF-?R2 recruits and phosphorylates TGF-?R1 which in turn phosphorylates downstream SMAD (small mother against decapentaplegic) proteins. Phosphorylated SMAD4 translocates into the nucleus where it activates the transcription of numerous target genes (including <em>SERPINE1 LTBP2 CDKN1A ARID3B ATXN1 PTPRK RAB6A SMAD7 EHBP1</em> etc.) acting predominantly as a tumor suppressor gene. Interestingly alterations in <em>SMAD4 </em>are frequent in metastatic CRC and together with <em>TGF-?R2 </em>gene mutations have been reported as late events able to promote CRC progression. The study of the TGF-?<em> </em>pathway in metastatic CRC is challenging because of the great genetic heterogeneity of CRC. However the increasing availability of targeted and whole-exome DNA sequencing techniques makes it possible to identify genetic mutations in complex dynamic and heterogeneous clinical contexts and make correlations with clinical outcomes.</p>