P2Y12 Purinergic Receptor and Brain Tumors: Implications on Glioma Microenvironment

Abstract

Gliomas are the most common malignant brain tumors in adults, characterized by a high proliferation and invasion. The tumor microenvironment is rich in growth-promoting signals and immunomodulatory pathways, which increase the tumor’s aggressiveness. In response to hypoxia and glioma therapy, the amounts of adenosine triphosphate (ATP) and adenosine diphosphate (ADP) strongly increase in the extracellular space, and the purinergic signaling is triggered by nucleotides’ interaction in P2 receptors. Several cell types are present in the tumor microenvironment and can facilitate tumor growth. In fact, tumor cells can activate platelets by the ADP-P2Y12 engagement, which plays an essential role in the cancer context, protecting tumors from the immune attack and providing molecules that contribute to the growth and maintenance of a rich environment to sustain the protumor cycle. Besides platelets, the P2Y12 receptor is expressed by some tumors, such as renal carcinoma, colon carcinoma, and gliomas, being related to tumor progression. In this context, this review aims to depict the glioma microenvironment, focusing on the relationship between platelets and tumor malignancy.

The functional role of p38 MAPK pathway in malignant brain tumors

“…Malignant brain tumors are rapidly growing cancer with high invasion potential to surrounding healthy brain structures, which include gliomas and neuronal or mixed neuronal-glial tumors (Lapointe et al, 2018). Gliomas are the most common central nervous system (CNS) cancers, comprising approximately 80% of all brain malignancies in adults (Hanif et al, 2017;Morrone et al, 2021). The heterogeneity and high invasiveness are hallmarks implicated in the poor prognosis of these tumors (Colquhoun, 2017;Reni et al, 2017).…”

Platelets in the tumor microenvironment and their biological effects on cancer hallmarks

“…Tumor cells have the fundamental hallmarks of sustaining proliferative signaling, evading growth suppressors, and resisting cell death. As has been demonstrated, platelets promote tumor growth and proliferation in ovarian, breast, lung, glioma, and hepatocellular carcinoma, as well as osteosarcoma (27)(28)(29)(30)(31)(32). Activation of platelets was reported to contribute to tumor growth in vivo in pancreatic cancer (33).…”

Cellular Components of the Tumor Environment in Gliomas—What Do We Know Today?

“…In adenocarcinomas of the lung, Fan and colleagues found a significant correlation between the expression of the purinergic receptor P2Y12 (P2RY12) and the degree of tumor infiltration with immunosuppressive TAMs [56]. Expression of P2RY12 by microglia and platelets in gliomas is thought to promote the proliferative capacity and chemotaxis of tumor cells [57]. Another view of microglia in gliomas is supported by a histomorphological study of P2RY12-immunostained microglia in human glioblastomas.…”

“…A survival analysis revealed significantly longer overall survival for patients with a high proportion of P2RY12-positive microglia, but this result was not significant considering the number of microglia labeled with the microglia marker Tmem119 [58]. Although the specificity of this purinergic receptor molecule for microglia and for platelets can be considered certain, its role in the pathobiology of gliomas needs further investigation [56][57][58]. DEAD/DEAH-box helicase 9 (DHX9) belongs to the family of DEAD-box proteins, which are highly conserved regulators of RNA metabolism in prokaryotes and eukaryotes.…”