| dc.description.abstract | Background Bladder cancer is the 11th most common cancer, overall, and the 8th most common one in males in the UK. It affects in excess of 10,200 people every year leading to approximately 5,500 deaths. Over the last three decades and with the exception of an emerging, role of immune checkpoint blockade therapy, there has been no significant improvement in the clinical management of this disease. In advanced bladder cancer, platinum-based chemotherapy remains the mainstay of treatment with a modest median overall survival of 14-15 months. There is an urgent need to identify therapeutic targets with validated biomarkers for this disease. Met, a Receptor Tyrosine Kinase (RTK), was shown to be overexpressed in bladder cancer and has emerged as an attractive target. A multikinase Met-VEGFR2 inhibitor; Cabozantinib has shown clinical activity in patients with refractory metastatic bladder cancer in a phase II clinical study. However, little is known about how Met exactly signals in bladder cancer, how it may interact with other potential therapeutic targets, and there are no validated biomarkers that could help selecting suitable patients for this treatment approach. Aims To unravel Met signalling in bladder cancer and identify potential biomarkers and/or possible interactions with other emerging novel therapeutic targets in bladder cancer. Methods Met-expressing T24, J82 and TCCSUP Transitional Cell Carcinoma (TCC) cell lines were used to assess Met signalling in vitro by means of classical western blotting and functional assays. Immunofluorescence was used to assess Met endosomal signalling with confocal microscopy. In addition, Immunohistochemistry was used to assess Met overexpression in 64 tissue samples from patients with advanced bladder cancer. Results Met is overexpressed in the human bladder cancer cell lines T24, TCCSUP and J82 and in 78% of invasive bladder cancer tissues as determined by immunohistochemistry (IHC) (n=64). Patients with high Met levels had a shorter median survival (12.97 months) compared to patients with low c-Met (18.05 months), but it was not significant due to a low number of patients. In addition, HGF triggers Met activation and its downstream pathways as well as cell migration in the three cell lines, all of which are reduced with Met pharmacological inhibition including Cabozantinib. PI3K-AKT pathway appears to be a major signalling pathway downstream of Met in bladder cancer cell lines as its inhibition with GDC0941 (class I PI3K inhibitor) effectively reduced phosphorylation of AKT and HGF dependent cell migration in wound healing assays. Met endocytosis is triggered with HGF and Dynasore, a dynamin inhibitor, reduces Met internalisation and downstream ERK1-2 activation. Conclusion In urinary bladder transitional cell carcinoma cells, HGF induces activation of Met and its downstream signals; ERK1-2 and AKT and induces cell migration. Such effects were reduced with Met pharmacological inhibitors. Moreover this study showed that Met is overexpressed in a large number of invasive bladder cancer tumours with prognostic correlation, suggesting that a subset of these patients may benefit from Met inhibition treatment strategies. Further research is needed to unravel Met signalling in more depth as well as its interaction with other novel therapeutic targets in bladder cancer and identify potential biomarkers in patients with advanced bladder cancer. | en_US |
