The P2RX7B splice variant modulates osteosarcoma cell behaviour and metastatic properties

Tattersall, Luke; Shah, Karan M.; Lath, Darren; Singh, Archana; Down, Jennifer M.; Marchi, Elena De; Williamson, Alex; Virgilio, Francesco Di; Heymann, Dominique; Adinolfi, Elena; Fraser, William D.; Green, Darrell; Lawson, Michelle A.; Gartland, Alison

doi:10.1016/j.jbo.2021.100398

Cited by 16 publications

(55 citation statements)

References 68 publications

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“…In this study we used the E0771 murine breast cancer cells from the C57BL/6 background, which forms spontaneous metastasis in a syngeneic model. We confirmed the presence of functional P2RX7 by assessing both ion channel activity and pore forming ability using BzATP as a specific agonist, and A740003 a potent selective and competitive antagonist, at previously reported concentrations [55,56]. P2RX7 inhibition by A740003 increased E0771 cell proliferation, consistent with a recent study by Brisson et al (2020) that showed P2RX7 knockout 4T1 breast cancer cells had increased proliferation under basal conditions, at levels similar to those observed here [35].…”

Section: Discussionsupporting

confidence: 90%

P2RX7 inhibition reduces breast cancer induced osteolytic lesions - implications for bone metastasis

Shah

Tattersall

Hussain

et al. 2022

Preprint

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Breast cancer metastasis to bone is a major contributor to morbidity and mortality in patients and remains an unmet clinical need. Purinergic signalling via the P2X7 receptor (P2RX7) in the primary tumour microenvironment is associated with progression of several cancers. It has also now become evident that intra-tumoural hypoxia facilitates cancer metastasis and reduces patient survival. In this study, we present data suggesting that hypoxia regulates the expression of P2RX7 in the primary tumour microenvironment; and importantly, inhibition with a selective antagonist (10mg/kg A740003) increased cancer cell death via apoptosis in a E0771/C57BL-6J syngeneic murine model. Furthermore, micro-computed tomography demonstrated reduced number of osteolytic lesions and lesion area following P2RX7 inhibition in absence of overt metastases by decreasing osteoclast numbers. We also demonstrate that activation of P2RX7 plays a role in the secretion of extracellular vesicles (EVs) from breast cancer cells. Mass-spectrometric analyses showed a distinct protein signature for EVs derived from hypoxic compared with normoxic cancer cells which elicit specific responses in bone cells that are associated with pre-metastatic niche formation. Thus, inhibiting P2RX7 provides a novel opportunity to preferentially target the hypoxic breast cancer cells preventing tumour progression and subsequent metastasis to bone

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Section: Discussionsupporting

confidence: 90%

P2RX7 inhibition reduces breast cancer induced osteolytic lesions - implications for bone metastasis

Shah

Tattersall

Hussain

et al. 2022

Preprint

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“…Following dehydration, sections were mounted with EUKITT (Kindler GmbH), and images acquired thanks to NIS-elements software with a Nikon Eclipse 90i digital microscope (Nikon Instruments, Europe). The percentage of positive cells was quantified using the QuPath free software for immunohistochemical analysis ( Bankhead et al, 2017 ) as previously described ( Tattersall et al, 2021 ).…”

Section: Methodsmentioning

confidence: 99%

A2A Receptor Contributes to Tumor Progression in P2X7 Null Mice

Marchi

Pegoraro

Turiello

et al. 2022

Front. Cell Dev. Biol.

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ATP and adenosine are key constituents of the tumor niche where they exert opposite and complementary roles. ATP can be released in response to cell damage or actively released by tumor cells and subsequently degraded into adenosine, which accumulates within the tumor microenvironment. Notably, while ATP promotes immune eradicating responses mainly via the P2X7 receptor (P2X7R), extracellular adenosine acts as a potent immune suppressor and facilitates neovascularization thanks to the A2A receptor (A2AR). To date, studies exploring the interplay between P2X7R and A2AR in the tumor microenvironment are as yet missing. Here, we show that, in C57/bl6 P2X7 null mice inoculated with B16-F10 melanoma cells, several pro-inflammatory cytokines, including interleukin 1 beta (IL-1β), tumor necrosis factor alpha (TNF-α), interleukin 6 (IL-6), interleukin 12 (IL-12), interleukin 17 (IL-17), interferon gamma (IFN-γ) were significantly decreased, while the immune suppressant transforming growth factor beta (TGF-β) was almost three-fold increased. Interestingly, tumors growing in P2X7-null mice upregulated tumor-associated and splenic A2AR, suggesting that immunosuppression linked to lack of the P2X7R might depend upon A2AR overexpression. Immunohistochemical analysis showed that tumor cells’ A2AR expression was increased, especially around necrotic areas, and that vascular endothelial growth factor (VEGF) and the endothelial marker CD31 were upregulated. A2AR antagonist SCH58261 treatment reduced tumor growth similarly in the P2X7 wild type or null mice strain. However, SCH58261 reduced VEGF only in the P2X7 knock out mice, thus supporting the hypothesis of an A2AR-mediated increase in vascularization observed in the P2X7-null host. SCH58261 administration also significantly reduced intratumor TGF-β levels, thus supporting a key immune suppressive role of A2AR in our model. Altogether, these results indicate that in the absence of host P2X7R, the A2AR favors tumor growth via immune suppression and neovascularization. This study shows a novel direct correlation between P2X7R and A2AR in oncogenesis and paves the way for new combined therapies promoting anti-cancer immune responses and reducing tumor vascularization.

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“…Clinical outcomes are generally poor and are related to complex genetic and epigenetic factors [ 108 ]. A recent study suggested that P2X7B expression in osteosarcoma cells greatly enhanced tumour growth and favoured metastasis [ 109 ]. However, the application of P2X7B antagonists has not been associated with the expected tumour suppressive effects [ 110 ].…”

Section: Role Of P2x7r Isoforms In Cancermentioning

confidence: 99%

Alternatively Spliced Isoforms of the P2X7 Receptor: Structure, Function and Disease Associations

Salis

Chen

et al. 2022

IJMS

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The P2X7 receptor (P2X7R) is an ATP-gated membrane ion channel that is expressed by multiple cell types. Following activation by extracellular ATP, the P2X7R mediates a broad range of cellular responses including cytokine and chemokine release, cell survival and differentiation, the activation of transcription factors, and apoptosis. The P2X7R is made up of three P2X7 subunits that contain specific domains essential for the receptor’s varied functions. Alternative splicing produces P2X7 isoforms that exclude one or more of these domains and assemble in combinations that alter P2X7R function. The modification of the structure and function of the P2X7R may adversely affect cellular responses to carcinogens and pathogens, and alternatively spliced (AS) P2X7 isoforms have been associated with several cancers. This review summarizes recent advances in understanding the structure and function of AS P2X7 isoforms and their associations with cancer and potential role in modulating the inflammatory response.

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The P2RX7B splice variant modulates osteosarcoma cell behaviour and metastatic properties

Cited by 16 publications

References 68 publications

P2RX7 inhibition reduces breast cancer induced osteolytic lesions - implications for bone metastasis

P2RX7 inhibition reduces breast cancer induced osteolytic lesions - implications for bone metastasis

A2A Receptor Contributes to Tumor Progression in P2X7 Null Mice

Alternatively Spliced Isoforms of the P2X7 Receptor: Structure, Function and Disease Associations

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