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.
We decided to develop a murine model of colorectal cancer liver metastases and to evaluate the role of a specific pharmacologic Hedgehog inhibitor in the natural history of the CRC. This would allow to study the differences between the original tutor and the metastatic cells, ultimately focusing on a personalised therapy of CRC. Therefore, our study, exploring the possibility to interfere with liver metastasis, may have a high translational relevance and further therapeutic applications.