Dottorato in MORFOGENESI E INGEGNERIA TISSUTALE

Titolo della tesi: Cholangiocarcinoma malignant traits are promoted by Schwann cell-derived Transforming Growth Factor-beta in Perineural invasion

The term cholangiocarcinoma (CCA) defines a class of epithelial malignancies originating from bile ducts. Although it has been demonstrated that CCA patients with perineural invasion (PNI) have a worse prognosis, the biological features of this phenomenon are yet unclear. Our data show that in human intrahepatic CCA specimens with documented PNI, nerve-infiltrating CCA cells display an expression level of the epithelial marker cytokeratin 7 lower respect to the rest of the tumor mass. In an in vitro 3D model, CCA cells move towards a peripheral nerve explant getting contact with Schwann cells (SCs) emerging from the nerve. Here we show that SCs produce soluble factors that favor the migration, invasion, survival and proliferation of CCA cells in vitro. This effect is accompanied by a cadherin switch suggestive of an epithelial-mesenchymal transition. The influence of SCs in promoting the ability of CCA cells to migrate and to invade the extracellular matrix is hampered by a specific TGFβ receptor 1 (Tβ1R) antagonist. Differential proteomic data indicate that the exposure of CCA cells to SCs secreted factors induces the upregulation of key oncogenes and the concomitant downregulation of some tumor suppressors. Taken together these data concur in identifying SCs as possible promoters of a more aggressive CCA phenotype ascribing to TGFβ-signaling a central role in regulating this process.