Emerging roles of purinergic signaling in anti-cancer therapy resistance

Abstract

Cancer is a complex disease with a rapid growing incidence and often characterized by a poor prognosis. Although impressive advances have been made in cancer treatments, resistance to therapy remains a critical obstacle for the improvement of patients outcome. Current treatment approaches as chemo-, radio-, and immuno-therapy deeply affect the tumor microenvironment (TME), inducing an extensive selective pressure on cancer cells through the activation of the immune system, the induction of cell death and the release of inflammatory and damage-associated molecular patterns (DAMPS), including nucleosides (adenosine) and nucleotides (ATP and ADP). To survive in this hostile environment, resistant cells engage a variety of mitigation pathways related to metabolism, DNA repair, stemness, inflammation and resistance to apoptosis. In this context, purinergic signaling exerts a pivotal role being involved in mitochondrial function, stemness, inflammation and cancer development. The activity of ATP and adenosine released in the TME depend upon the repertoire of purinergic P2 and adenosine receptors engaged, as well as, by the expression of ectonucleotidases (CD39 and CD73) on tumor, immune and stromal cells. Besides its well established role in the pathogenesis of several tumors and in host–tumor interaction, purinergic signaling has been recently shown to be profoundly involved in the development of therapy resistance. In this review we summarize the current advances on the role of purinergic signaling in response and resistance to anti-cancer therapies, also describing the translational applications of combining conventional anticancer interventions with therapies targeting purinergic signaling.

Neighboring macrophage-induced alteration in the phenotype of colorectal cancer cells in the tumor budding area

“…Chemotherapy diminishes the subpopulation with high sensitivity to chemotherapy so that the subpopulation with less sensitivity could be replaced. Selective pressure, including chemotherapy, metastatic cascade, and tumor–stromal interactions, has been proposed to generate cancer cells with a highly malignant phenotype [ 29 – 31 ]. Because cancer cells with a highly malignant phenotype have been shown to be involved in chemoresistance, selective pressure may play important roles in the acquisition of chemoresistance.…”

Anti-Tumor Secondary Metabolites Originating from Fungi in the South China Sea’s Mangrove Ecosystem

“…Because nucleotides are significant chemicals that must be generated to sustain the state of proliferation in cancer, nucleotide metabolism is regarded as the most crucial link in oncogenesis and progression [ 75 ]. On the one hand, targeted regulation of the level of nucleotide metabolism can make tumor cells more sensitive to chemotherapy drugs, mediate anti-tumor response, and enhance the efficacy of chemotherapy and immunotherapy in the treatment of tumors [ 75 , 76 ]. A good anti-tumor impact may also be obtained by altering the amount of nucleotide metabolism, such as by providing exogenous UDP (uridine diphosphate) to modify the tumor microenvironment [ 77 ].…”

The P2X7 Receptor in Oncogenesis and Metastatic Dissemination: New Insights on Vesicular Release and Adenosinergic Crosstalk

“…Extracellular ATP (eATP) is an established tumor microenvironment (TME) component that can be released following tumor and adjacent tissue necrosis via active release, mediated by proteins such as those of the ABC cassette family, or inside vesicles released from the tumor, immune, and stroma cells [ 1 , 2 ] ( Figure 1 ). The live measurement of eATP in murine models was made possible by the development of the luciferase-based probe pmeLUC that, thanks to its specific placement at the extracellular facet of the plasma membrane, allows for distinguishing it from intracellular ATP [ 3 , 4 , 5 ].…”

“…eATP is the natural ligand of two families of purinergic receptors: ionotropic P2Xs and metabotropic P2Ys [ 11 ]. Both classes of proteins are expressed at different levels by the cells of the TME and activate signaling pathways favoring growth, invasion, angiogenesis, and chemotherapy resistance, but also regulate, in a tumor-promoting or tumor-eradicating fashion, the immune system [ 1 , 2 , 12 , 13 ]. This overview focuses on the role of probably the most studied ATP receptor in cancer: P2X7.…”

“…The TME is rich in eATP due to necrosis and active release of the nucleotide. eATP acts on P2X7 and is then degraded by CD39 and CD73 to adenosine (ADO) acting as the primary source of this purine in the extracellular milieu [ 1 , 2 ]. The P2X7 receptor, the ectonucleotidases CD39 and CD73, and the A2A receptor are expressed by different immune cells involved in both tumor immune-eradication and suppression.…”