Purinergic signaling and tumor microenvironment in cervical Cancer

Abstract

Cervical cancer is the fourth most common type of cancer incidence in the world female population, and it has become a public health problem worldwide. Several factors are involved in this type of cancer, including intrinsic factors related to the inflammatory process, such as extracellular nucleotides and adenosine-components of the purinergic system. The present review focuses on the role of the purinergic system in cervical cancer, especially regarding the interaction of extracellular nucleotides with their respective receptors expressed in the tumor microenvironment of cervical cancer and their role in the host immune response. The high concentrations of extracellular nucleotides in the tumor microenvironment of cervical cancer interfere in the regulation, proliferation, differentiation, and apoptosis of cancer cells of the uterine cervix through different P1 and P2 receptor subtypes. Such diverse cellular processes that are mediated by adenosine triphosphate and adenosine across the tumor microenvironment and that also have effects on host immune defense will be reviewed here in detail.

Keywords: Cervical cancer; Ectonucleotidases; Human papillomavirus; Purinergic receptors.

Fig. 1

The high concentration of extracellular ATP, characteristic of the microenvironment of CeCa, activates the P2X7 receptor, which triggers the increase of Ca²⁺ inflow. Nonetheless, situations in which the extracellular ATP interacts with the P2X7 for long periods cause the appearance of non-selective and irreversible pores that allow up to 900-Da molecules to pass through. The opening of such pores would collaborate for intracellular ionic deregulation and, consequently, for the apoptotic process. The influx of Ca²⁺ in these conditions would induce the activation of the mitochondrial caspases pathway, whose function is to conduct the apoptotic process, and the GLUT1 upregulation, related to the increase in oxidative phosphorylation and the consequent production of EROS. The result of these factors is, therefore, the increased ATP production, decreased pH, and, finally, cell apoptosis tumoral cervicals through immunosuppression generated by extracellular ATP and its activation with P2RX7. Cancerous cells of the uterine cervix, on the other hand, express a P2X7j variant that affects the formation of non-selective pores, decreasing cell permeability and cellular death, which facilitates the widespread proliferation of cells

Fig. 2

P2Y2 receptors are coupled to G protein and activate the PLC pathway. The PLC leads to the formation of InsP3, which in turn leads to the release of intracellular Ca⁺². When the PLC is activated, it also causes the generation of DAG, which in turn is a PKC activator that promotes the inhibition of the Na⁺/K⁺ATPase activity. Besides, the P2Y2 receptor also activates the MAPK pathway. All these intracellular effects caused by the activation of P2Y2 are promoters of tumor progression

Fig. 3

Different mechanisms are triggered when stimulated by the different nucleotides in the CeCa TME. P2X7R, when activated, promotes an increase in intracellular ATP production and, via PI3K-AKT, through the signaling dependent on HIF1α, triggers mitogenic and angiogenic pathways, stimulating tumor progression. P2Y-type receptors are coupled to protein G and activate the PLC pathway. When the P2Y2R is activated, it leads to an increase in cell proliferation, while the P2Y6R, through the MAPK/EK1,2 pathway, also participates in processes that promote cellular proliferation. On the other hand, P2Y1R mediates the mitogenic signals of endogenously released nucleotides through transactivating the epidermal growth factor receptor (EGFR) pathway—which is related to cell differentiation and proliferation and, ultimately, also promotes tumor progression. Adenosine, present in high amounts in the TME, leads to the activation of A2a receptor in T lymphocyte cells, which promotes the decrease of proliferation, activation, and effector function of these cells