TY - BOOK

T1 - Role of P2X7 Receptor in Pancreatic Cancer Progression

AU - Giannuzzo, Andrea

PY - 2015

Y1 - 2015

N2 - Pancreatic Ductal Adenocarcinoma (PDAC) is one of the cancers with the worst 5-year survival rates due - among others - to late detection and lack of an effective therapy.A dense desmoplastic reaction is one of the main characteristics of PDACmicroenvironment, mainly due to an increase of number/activity of pancreatic stellate cells(PSCs), which are the main contributors in the production of extracellular matrix proteins,such as collagens. In this complex microenvironment, consisting of both cellular and noncellularcomponents, metabolically active cells and dying cells can release highconcentrations of ATP in the extracellular compartment. Among all the purinergicreceptors, P2X7 receptor (P2X7R), with its peculiar double-faced role in both cell death andcell proliferation, has been shown to be involved in the progression of some types ofcancer. Thus, the aim of our study was to investigate the possible role of P2X7R in PDACbehaviour in vitro and in vivo.We detected a higher P2X7R protein level in several human PDAC cells compared toa “normal” human pancreatic duct epithelial cell line, which localized mostly on theplasma membrane. From the functional point of view, we observed that a sustainedactivation of the P2X7 receptor using ATP and BzATP (a more potent agonist) resulted in acytotoxic effect, mainly ascribed to necrosis. The allosteric inhibition of the receptor led toa drastic reduction in cell proliferation in all PDAC cell lines. Moreover, P2X7R showed acrucial role in PDAC cell migration and invasion. Stimulation of the receptor with BzATPor ATP markedly increased migration and invasion compared to the control cells. Theallosteric inhibition of P2X7R reduced cancer cell migration and invasion significantly.We detected P2X7R expression in tissues deriving from an orthotopic xenograftPDAC mouse model. Furthermore, we transplanted cells that were stably transfected withluciferase (PancTu-1 Luc), to monitor tumor growth through bioluminescence detectionand confirmed in vivo the anti-proliferative effect of the allosteric inhibitor AZ10606120.In addition, staining of the primary tumor revealed a significant reduction in thenumber/activity of murine PSCs in mice treated with the inhibitor compared to the control,which correlated with a substantial reduction in collagen deposition.In conclusion, we showed that the P2X7 receptor plays multiple crucial roles in invitro and in vivo PDAC progression, opening a new possibility of PDAC treatment.

AB - Pancreatic Ductal Adenocarcinoma (PDAC) is one of the cancers with the worst 5-year survival rates due - among others - to late detection and lack of an effective therapy.A dense desmoplastic reaction is one of the main characteristics of PDACmicroenvironment, mainly due to an increase of number/activity of pancreatic stellate cells(PSCs), which are the main contributors in the production of extracellular matrix proteins,such as collagens. In this complex microenvironment, consisting of both cellular and noncellularcomponents, metabolically active cells and dying cells can release highconcentrations of ATP in the extracellular compartment. Among all the purinergicreceptors, P2X7 receptor (P2X7R), with its peculiar double-faced role in both cell death andcell proliferation, has been shown to be involved in the progression of some types ofcancer. Thus, the aim of our study was to investigate the possible role of P2X7R in PDACbehaviour in vitro and in vivo.We detected a higher P2X7R protein level in several human PDAC cells compared toa “normal” human pancreatic duct epithelial cell line, which localized mostly on theplasma membrane. From the functional point of view, we observed that a sustainedactivation of the P2X7 receptor using ATP and BzATP (a more potent agonist) resulted in acytotoxic effect, mainly ascribed to necrosis. The allosteric inhibition of the receptor led toa drastic reduction in cell proliferation in all PDAC cell lines. Moreover, P2X7R showed acrucial role in PDAC cell migration and invasion. Stimulation of the receptor with BzATPor ATP markedly increased migration and invasion compared to the control cells. Theallosteric inhibition of P2X7R reduced cancer cell migration and invasion significantly.We detected P2X7R expression in tissues deriving from an orthotopic xenograftPDAC mouse model. Furthermore, we transplanted cells that were stably transfected withluciferase (PancTu-1 Luc), to monitor tumor growth through bioluminescence detectionand confirmed in vivo the anti-proliferative effect of the allosteric inhibitor AZ10606120.In addition, staining of the primary tumor revealed a significant reduction in thenumber/activity of murine PSCs in mice treated with the inhibitor compared to the control,which correlated with a substantial reduction in collagen deposition.In conclusion, we showed that the P2X7 receptor plays multiple crucial roles in invitro and in vivo PDAC progression, opening a new possibility of PDAC treatment.

UR - https://soeg.kb.dk/permalink/45KBDK_KGL/fbp0ps/alma99122291844405763

M3 - Ph.D. thesis

BT - Role of P2X7 Receptor in Pancreatic Cancer Progression

PB - Department of Biology, Faculty of Science, University of Copenhagen

ER -