Extracellular nucleotides are important intercellular signaling molecules that were found enriched in the tumor microenvironment. In fact, interfering with G protein-coupled P2Y receptor signaling has emerged as a promising therapeutic alternative to treat aggressive and difficult-to-manage cancers such as those affecting the gastrointestinal system. In this review, we will discuss the functions of P2Y receptors in gastrointestinal cancers with an emphasis on colorectal, hepatic, and pancreatic cancers. We will show that P2Y₂ receptor up-regulation increases cancer cell proliferation, tumor growth, and metastasis in almost all studied gastrointestinal cancers. In contrast, we will present P2Y₆ receptor as having opposing roles in colorectal cancer vs. gastric cancer. In colorectal cancer, the P2Y₆ receptor induces carcinogenesis by inhibiting apoptosis, whereas P2Y₆ suppresses gastric cancer tumor growth by reducing β-catenin transcriptional activity. The contribution of the P2Y₁₁ receptor in the migration of liver and pancreatic cancer cells will be compared to its normal inhibitory function on this cellular process in ciliated cholangiocytes. Hence, we will demonstrate that the selective inhibition of the P2Y₁₂ receptor activity in platelets was associated to a reduction in the risk of developing colorectal cancer and metastasis formation. We will succinctly review the role of P2Y₁, P2Y₄, P2Y₁₃, and P2Y₁₄ receptors as the knowledge for these receptors in gastrointestinal cancers is sparse. Finally, redundant ligand selectivity, nucleotide high lability, cell context, and antibody reliability will be presented as the main difficulties in defining P2Y receptor functions in gastrointestinal cancers.

中文翻译：

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回顾 P2Y 受体在特定胃肠道癌症中的作用。

细胞外核苷酸是重要的细胞间信号分子，被发现在肿瘤微环境中丰富。事实上，干扰 G 蛋白偶联 P2Y 受体信号传导已成为治疗侵袭性和难以控制的癌症（例如影响胃肠系统的癌症）的一种有前途的治疗替代方案。在这篇综述中，我们将讨论 P2Y 受体在胃肠道癌症中的功能，重点是结直肠癌、肝癌和胰腺癌。我们将证明，在几乎所有研究的胃肠道癌症中，P2Y ₂受体上调都会增加癌细胞增殖、肿瘤生长和转移。相反，我们将介绍 P2Y ₆受体在结直肠癌和胃癌中具有相反的作用。在结直肠癌中，P2Y ₆受体通过抑制细胞凋亡来诱导癌变，而 P2Y ₆通过降低 β-catenin 转录活性来抑制胃癌肿瘤的生长。_{P2Y 11}受体在肝癌和胰腺癌细胞迁移中的贡献将与其在纤毛胆管细胞中对该细胞过程的正常抑制功能进行比较。因此，我们将证明选择性抑制血小板中 P2Y ₁₂受体活性与降低结直肠癌和转移形成的风险相关。_{我们将简要回顾 P2Y 1}、 P2Y ₄、 P2Y ₁₃和 P2Y ₁₄受体的作用，因为对这些受体在胃肠道癌症中的了解很少。最后，多余的配体选择性、核苷酸高不稳定性、细胞背景和抗体可靠性将成为定义胃肠道癌症中 P2Y 受体功能的主要困难。