Reviewing the role of P2Y receptors in specific gastrointestinal cancers.

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.