Adenosine Inhibits Tumor Cell Invasion via Receptor-Independent Mechanisms

Abstract

Extracellular adenosine mediates diverse anti-inflammatory, angiogenic, and other signaling effects via binding to adenosine receptors, and it also regulates cell proliferation and death via activation of the intrinsic signaling pathways. Given the emerging role of adenosine and other purines in tumor growth and metastasis, this study evaluated the effects of adenosine on the invasion of metastatic prostate and breast cancer cells. Treatment with low micromolar concentrations of adenosine, but not other nucleosides or adenosine receptor agonists, inhibited subsequent cell invasion and migration through Matrigel-and laminin-coated inserts. These inhibitory effects occurred via intrinsic receptor-independent mechanisms, despite the abundant expression of A2B adenosine receptors (ADORA2B). Extracellular nucleotides and adenosine were shown to be rapidly metabolized on tumor cell surfaces via sequential ecto-5 0 -nucleotidase (CD73/NT5E) and adenosine deaminase reactions with subsequent cellular uptake of nucleoside metabolites and their intracellular interconversion into ADP/ATP. This was accompanied by concurrent inhibition of AMP-activated protein kinase and other signaling pathways. No differences in the proliferation rates, cytoskeleton assembly, expression of major adhesion molecules [integrin1b (ITGB1), CD44, focal adhesion kinase], and secretion of matrix metalloproteinases were detected between the control and treated cells, thus excluding the contribution of these components of invasion cascade to the inhibitory effects of adenosine. These data provide a novel insight into the ability of adenosine to dampen immune responses and prevent tumor invasion via two different, adenosine receptor-dependent and -independent mechanisms.Implications: This study suggests that the combined targeting of adenosine receptors and modulation of intracellular purine levels can affect tumor growth and metastasis phenotypes.

Adenosine arrests breast cancer cell motility by A3 receptor stimulation

“…Importantly, these effects of adenosine were well within the adenosine concentration range that has been measured in the tumor microenvironment [48]. In line with these findings, Virtanen et al recently described an inhibitory effect of exogenous adenosine on cancer cell invasion and migration [18]. They suggested that receptor-independent mechanisms were responsible for this effect.…”

“…Cells were cultured for a maximum of 15 passages to minimize the risk of experimental variance due to mutations. This is particularly important as there are contradictory reports about the expression levels of adenosine receptor subtypes in breast cancer cell lines [18][19][20]. Prior to experiments, the cells were trypsinized and washed once with serum-containing medium and three times with serum-free medium containing 20 mM HEPES and 0.1 % bovine serum albumin (BSA).…”

Adenosine deaminase inhibition suppresses progression of 4T1 murine breast cancer by adenosine receptor‐dependent mechanisms

“…Moreover, the effect of the dCF on tumour invasion and migration was also clearly visible in more invasive human breast cancer cells, MDA‐MB‐231 and T47D. It has been shown previously, that this could be a receptor‐independent effect mediated by adenosine via inhibition of AMP‐activated protein kinase . However, based on our study, the significant role of adenosine receptors in these processes should also be noticed.…”

MiR-422a promotes loco-regional recurrence by targeting NT5E/CD73 in head and neck squamous cell carcinoma

“…In meduloblastoma cell lines, the metastatic potential is inversely correlated with CD73 expression and activity [35]. Pharmacological inhibition of CD73 reduces adhesion but increases the invasion/migration capacities in vitro [17, 36], and treatment with adenosine (produced by CD73) inhibits cell migration and invasion [37]. More recently, loss of CD73 has been involved in epithelial barrier misstructuration and endometrial tumor progression [17].…”