Ricerc@Sapienza

Reactivation or alteration of molecular pathways that control cellular differentiation and proliferation play a role in the development and progression of both familiar and sporadic colon cancer. It has been demonstrated that the presence of active Hedgehog-GLI activity in epithelial tumor cells of colorectal cancer is essential for tumor growth, recurrence and metastatic growth, and regulates the behavior of human colorectal cancer (CRC) stem cells in vivo. Our data demonstrate that Hepatocellular Carcinoma (HCC) regulates Hepatic Stellate Cells¿ (HSC) viability via paracrine signaling by modulating Hedgehog pathway. These data suggest that the use of an Hedgehog (Hh) inhibitor may interfere with the metastatic spread and in particular with the liver localization of Colon Cancer metastases. Moreover, there are evidences of interplay between Hedgehog and TGF-ß pathways in both normal and malignant tissues. In particular, TGF-ß induces GLI1 in a GLI2-dependent manner independently from Smoothened (SMO). Therefore, we decided to develop a murine model of colorectal cancer liver metastases and to evaluate the role of a pharmacologic Hedgehog inhibitor in the natural history of the CRC. In addition to that, the effect of the synergic inhibition of Hh and TGF-ß pathways will be tested both in our in-vitro settings and in our animal model of liver metastasis, to study the changes in metastases spreading and invasiveness.