Purinergic signalling in osteosarcoma

Osteosarcoma (OS) is the most common type of primary bone cancer affecting adolescents and children attributed to rapid bone growth and turnover, it is a rare incurable and often fatal disease. Current treatments include standard chemotherapy, limb salvage surgery or amputation. Survival statistics have remained constant with no advances in treatments options for decades. Patients with metastasis continue to have a poor 5-year survival rate of around 20%. This highlights an urgent need for development of novel therapeutic strategies for the treatment of OS. Purinergic signalling, involves extracellular nucleotides binding to purinergic receptors and has been found on osteoblasts with different functions including differentiation, apoptosis and bone remodelling. They are also highly expressed on many cancers. ATP is at a high concentration in the tumour microenvironment, yet absent from surrounding healthy tissue. ATP can modify the tumour microenvironment in favour of cancer growth and potentially result in disease progression. The P2X7 receptor (P2X7R) is a ATP gated ion channel which has received an increasing amount of attention due to evidence of its overexpression and function in carcinogenesis of a range of different tumours. Studies exploring the role of the P2X7R in OS are limited. In this thesis the hypothesis that the P2X7R and related splice variants play a role in OS progression and metastasis and it’s potential as therapeutic target has been tested both in vitro and in vivo.