The ATP-gated receptor P2X₇ is expressed in multiple malignant tumours including neuroblastoma, melanoma, prostate, lung and breast. P2X₇ has a significant role in mediating diverse cell responses, which upon dysregulation are associated with tumour initiation and development. The rapid, ATP-mediated activation of P2X₇ induces a fast-inward cation current in cells. However, prolonged ATP-mediated activation of P2X₇ leads to formation of a pore that increases membrane permeability and eventually causes cell death. This presents a potential paradox, as the tumour microenvironment contains extracellular ATP at levels sufficient to activate the P2X₇ pore and trigger cell death. However, P2X₇ expression is associated with enhanced cancer cell survival, proliferation and metastatic potential. At least one distinct conformational form of P2X₇, termed non-pore functional P2X₇ (nfP2X₇), has been described, which is not able to form a functional pore. We demonstrate for the first time in this study that exposure to a high ATP concentration, equivalent to those measured in the tumour microenvironment, drives nfP2X₇ expression and also that nfP2X₇ is essential for tumour cell survival. We show that monoclonal antibodies raised against a P2X₇ amino acid sequence (200-216), whose conformation is distinct from that of wild-type (WT) P2X₇, bind specifically to nfP2X₇ expressed on the surface of tumour cells. We also show that nfP2X₇ is broadly expressed in patient-derived tumour sections from a wide range of cancers. Therefore, antibodies raised against E200 provide tools that can differentiate between forms of the P2X₇ receptor that have a key role in cancer.

中文翻译：

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肿瘤微环境中的 ATP 驱动 nfP2X7 的表达，这是癌细胞存活的关键介质。

ATP 门控受体 P2X ₇在多种恶性肿瘤中表达，包括神经母细胞瘤、黑色素瘤、前列腺、肺和乳腺。P2X ₇在介导多种细胞反应方面具有重要作用，这些反应在失调时与肿瘤的发生和发展有关。ATP 介导的 P2X ₇的快速激活会在细胞中诱导快速内向的阳离子电流。然而，延长 ATP 介导的 P2X ₇激活会导致形成孔，从而增加膜通透性并最终导致细胞死亡。这提出了一个潜在的悖论，因为肿瘤微环境中包含的细胞外 ATP 水平足以激活 P2X ₇孔并引发细胞死亡。然而，P2X ₇表达与增强的癌细胞存活、增殖和转移潜能有关。已经描述了至少一种不同构象形式的 P2X ₇，称为非孔功能性 P2X ₇ (nfP2X ₇ )，它不能形成功能性孔。我们在本研究中首次证明，暴露于高 ATP 浓度（相当于在肿瘤微环境中测量的浓度）会驱动 nfP2X ₇表达，并且 nfP2X ₇对肿瘤细胞存活至关重要。我们展示了针对 P2X ₇氨基酸序列 (200-216)产生的单克隆抗体，其构象不同于野生型 (WT) P2X ₇，特异性结合在肿瘤细胞表面表达的nfP2X ₇。我们还表明，nfP2X ₇在来自多种癌症的患者来源的肿瘤切片中广泛表达。因此，针对 E200 产生的抗体提供了可以区分在癌症中起关键作用的 P2X ₇受体形式的工具。