| Summary: | cancer exhibits a propensity to metastatize to bone, resulting in debilitating skeletal complications associated with significant morbidity and poor prognosis. The interactions between metastatic cells and bone are critical to the development and progression of bone metastases and their unravelling could lead to novel therapeutic approaches. This PhD thesis intended to investigate the contribution of the HGH/c-Met pathway to the pathogenesis of bone metastasis. An experimental breast cancer bone metastatic model were used, in combination with in vivo imaging techniques, to demonstrate the involvement of HGF/c-Met system in tumor-bone interaction contributing to bone metastatisation. Moreover, the efficacy of three therapeutic approaches able to interfere with the HGC/c-Met pathway has been investigated. Firstly, I demonstrated that NK4, an HGF antagonist, induces a delay in the progression of bone metastasis probably via its bifunctional properties to act as an HGF antagonist and an angiogenesis inhibitor. Secondly, the efficacy of strategies directed against c-Met receptor, including both a c-Met inhibitor, ARQ197, and a specific shRNA, has been evaluated. Dual c-Met inhibition induces a pronounced tumor growth suppression with concomitant marked decreases of lytic lesions and prolongation of survival. Finally, the effect of targeting PLCyl, one of the c-Met downstream effectors, has been explored. Surprisingly, PLCyl silencing by shRNA significantly accelerates the formation and progression of bone metastases. Overall, these findings highlighted the efficacy of HGF/c- Met inhibition in delaying the onset and progression of bone metastases and strongly suggested that targeting the HGF ligand or the c-Met receptor may have promising therapeutic value in the treatment of breast cancer bone metastases. Despite that, special attention should be paid to block PLCyl since its inhibition could potentiate the aggressive phenotype of breast cancer cells stimulating bone metastatic disease. Therefore, PLCyl should not be considered as a therapeutic candidate for the management of bone metastasis.
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