Extracellular adenosine triphosphate and adenosine in cancer

Abstract

Adenosine triphosphate (ATP) is actively released in the extracellular environment in response to tissue damage and cellular stress. Through the activation of P2X and P2Y receptors, extracellular ATP enhances tissue repair, promotes the recruitment of immune phagocytes and dendritic cells, and acts as a co-activator of NLR family, pyrin domain-containing 3 (NLRP3) inflammasomes. The conversion of extracellular ATP to adenosine, in contrast, essentially through the enzymatic activity of the ecto-nucleotidases CD39 and CD73, acts as a negativefeedback mechanism to prevent excessive immune responses. Here we review the effects of extracellular ATP and adenosine on tumorigenesis. First, we summarize the functions of extracellular ATP and adenosine in the context of tumor immunity. Second, we present an overview of the immunosuppressive and pro-angiogenic effects of extracellular adenosine. Third, we present experimental evidence that extracellular ATP and adenosine receptors are expressed by tumor cells and enhance tumor growth. Finally, we discuss recent studies, including our own work, which suggest that therapeutic approaches that promote ATP-mediated activation of inflammasomes, or inhibit the accumulation of tumorderived extracellular adenosine, may constitute effective new means to induce anticancer activity.

NTPDase3 and ecto-5′-nucleotidase/CD73 are differentially expressed during mouse bladder cancer progression

“…In addition, ATP and adenosine participates in inflammatory signaling [43]. ATP has been described as a pro-inflammatory molecule acting as a chemotactic signal to immune phagocytes [44,45] while adenosine has an immunosuppressive role Fig. 4 a The images correspond to immunofluorescent staining of ecto-5′-NT/CD73 in different times of bladder cancer induction.…”

“…* Significantly different compared to control. # Significantly different to all other groups suppressing innate and adaptative immune responses [44]. The participation of altered ectonucleotidases expression in the modulation of immune cells to contribute to cancer progress have been described to gliomas [46], that have a similar ATP/ADP/AMPase activity pattern of bladder cancer.…”

“…Furthermore, ecto-5′-NT/CD73 overexpression promotes invasion, migration, adhesion, and metastasis of human breast cancer cells [20,57], indicating higher invasiveness and metastatic capability to melanomas [56,58] and poor prognosis in human colorectal cancer [22]. Ecto-5′-NT/CD73 expression in cancer cells has been also linked with drug resistance [26,59] and immune escape [44,60]. Moreover, researchers have already targeted ecto-5′-NT/ CD73 in an attempt to develop promising therapies, for instance, ecto-5′-NT/CD73 inhibitors have shown antiproliferative effects in bladder cancer cell lines and gliomas [61,62], and decrease in ovarian cancer progression [63].…”

Adenosine arrests breast cancer cell motility by A3 receptor stimulation

“…Thus, altered expression of CD73 and other molecules that regulate the nucleotide environment of cancer cells may contribute to metastasis and an overall insidious cell phenotype that allows invasion of the extracellular matrix and the spread of tumors to other organs. This may explain the findings by Stagg et al who reported that CD73 expression contributes to in vitro cancer cell migration in a transwell chamber model and to tumor growth and metastasis in vivo [44,45]. However, the tumor-enhancing pro-migratory and prometastatic properties of CD73 are controversial.…”

“…2). The tumor microenvironment is rich in extracellular ATP [44,45]. Depending on the ectonucleotidases present, high levels of extracellular ATP and its breakdown proct adenosine could entrap cancer cells within the tumor environment or promote random motility and the spread of cancer cells outside of tumors.…”