Tumour cell life depends upon the alterations of oncogenes that can affect cell growth, matrix infiltration, neo-vascularisation, metastatization and/or interactions of the neoplasia with the surrounding environment. Cancer microenvironment was recently shown to be rich in extracellular ATP but the signalling pathways activated by purines in tumour are still obscure. One of the main purinergic ATP receptors is P2X7. This protein is an ATP gated ion channel formed in man by either homo or hetero-trimers of its two biologically active isoforms (P2X7A and P2X7B). P2X7 may also assemble with another member of the P2X family, P2X4. P2X7 receptor has become a focus of increasing attention because several key cell responses depend on its activity. Such responses comprise cytotoxicity, cytokine secretion, immune system modulation and cell proliferation, all of which are relevant for cancer. Several malignancies overexpress P2X7, including chronic and acute lymphocytic leukaemia, prostatic, pancreatic, breast and thyroid carcinoma and neuroblastoma. Previous data from our laboratory showed that P2X7 is overexpressed in a large cohort of neuroblastoma patients. Furthermore, in neuroblastoma cells, P2X7 is uncoupled from its well known cytotoxic effect, but rather provides strong growth stimulation. Neuroblastoma is a cancer causing around 15% paediatric deaths due to lack of good treatment for its disseminated metastatic forms. For these reasons new therapeutic targets are urgently required. Our working hypothesis is that P2X7 is involved in neuroblastoma proliferation, progression and bone metastatization. Preliminary in vivo data from our laboratory show a direct role of P2X7 in tumour engraftment, growth and neo-vascularisation. We will further extend these findings in the neuroblastoma model investigating whether: 1) The expression or knock down of P2X7A, P2X7B and P2X4 (thereafter collectively referred to as P2Xs) in neuroblastoma cell lines can alter cell growth, infiltration kinetics, and metastatization both in vitro and in vivo. 2) P2Xs affect mitochondrial morphology, energy production and PI3K/PKB-Akt, NFATc1 signalling pathways, thus leading to increased neuroblastoma proliferation. 3) P2Xs cause the increase of ATP in tumour microenvironment. 4) P2Xs modulate tumour angiogenesis through VEGF secretion, and cause microvesicles secretion. 5) P2Xs affects the formation of ostelytic metastases acting at neuroblastoma-osteoblasts/osteoclast interactions. 6) The expression of P2X7A, B and P2X4 is altered in a cohort of neuroblastoma patients, and overexpression of the receptors correlates to disease progression, with particular attention to metastatic bone invasion. This proposal is aimed at elucidating the signalling pathways activated by P2X7 in cancer and might lead to the identification of P2X7 as an oncogene.

My first AIRC Grant 11630: The purinergic P2X7 receptor as an ocogene: focus on neuroblastoma

ADINOLFI, Elena
2011

Abstract

Tumour cell life depends upon the alterations of oncogenes that can affect cell growth, matrix infiltration, neo-vascularisation, metastatization and/or interactions of the neoplasia with the surrounding environment. Cancer microenvironment was recently shown to be rich in extracellular ATP but the signalling pathways activated by purines in tumour are still obscure. One of the main purinergic ATP receptors is P2X7. This protein is an ATP gated ion channel formed in man by either homo or hetero-trimers of its two biologically active isoforms (P2X7A and P2X7B). P2X7 may also assemble with another member of the P2X family, P2X4. P2X7 receptor has become a focus of increasing attention because several key cell responses depend on its activity. Such responses comprise cytotoxicity, cytokine secretion, immune system modulation and cell proliferation, all of which are relevant for cancer. Several malignancies overexpress P2X7, including chronic and acute lymphocytic leukaemia, prostatic, pancreatic, breast and thyroid carcinoma and neuroblastoma. Previous data from our laboratory showed that P2X7 is overexpressed in a large cohort of neuroblastoma patients. Furthermore, in neuroblastoma cells, P2X7 is uncoupled from its well known cytotoxic effect, but rather provides strong growth stimulation. Neuroblastoma is a cancer causing around 15% paediatric deaths due to lack of good treatment for its disseminated metastatic forms. For these reasons new therapeutic targets are urgently required. Our working hypothesis is that P2X7 is involved in neuroblastoma proliferation, progression and bone metastatization. Preliminary in vivo data from our laboratory show a direct role of P2X7 in tumour engraftment, growth and neo-vascularisation. We will further extend these findings in the neuroblastoma model investigating whether: 1) The expression or knock down of P2X7A, P2X7B and P2X4 (thereafter collectively referred to as P2Xs) in neuroblastoma cell lines can alter cell growth, infiltration kinetics, and metastatization both in vitro and in vivo. 2) P2Xs affect mitochondrial morphology, energy production and PI3K/PKB-Akt, NFATc1 signalling pathways, thus leading to increased neuroblastoma proliferation. 3) P2Xs cause the increase of ATP in tumour microenvironment. 4) P2Xs modulate tumour angiogenesis through VEGF secretion, and cause microvesicles secretion. 5) P2Xs affects the formation of ostelytic metastases acting at neuroblastoma-osteoblasts/osteoclast interactions. 6) The expression of P2X7A, B and P2X4 is altered in a cohort of neuroblastoma patients, and overexpression of the receptors correlates to disease progression, with particular attention to metastatic bone invasion. This proposal is aimed at elucidating the signalling pathways activated by P2X7 in cancer and might lead to the identification of P2X7 as an oncogene.
2011
Adinolfi, Elena
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11392/1600065
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