Adenosine metabolism and cancer. Focus on “Adenosine downregulates DPPIV on HT-29 colon cancer cells by stimulating protein tyrosine phosphatases and reducing ERK1/2 activity via a novel pathway”

Abstract

ADENOSINE FACILITATES tumor survival by a variety of mechanisms. In this issue, Tan et al. (Ref. 16; see p. C433 of this issue) describe a signaling cascade by which adenosine downregulates the cell surface protein CD26 on HT-20 colorectal carcinoma cells. Because CD26 binds extracellular soluble adenosine deaminase (ADA) to the cell surface, this downregulation is expected to increase adenosine concentration in the microenvironment of the tumor cell membrane. This is one of several mechanisms by which tumors facilitate their own survival by influencing adenine nucleotide and adenosine metabolism and signaling.Adenosine accumulates in solid tumors and stimulates tumor growth and tumor angiogenesis while imparting tumor resistance to the immune system (15). Part of this resistance is due to adenosine signaling through A 2A and possibly A 2B adenosine receptors to inhibit the activation of macrophages (9, 10) and lymphocytes (6). Imiquimod, an immune system activator with anti-tumor activity, has recently been shown to block A 2A receptors (14). This is consistent with the notion that adenosine in tumors suppresses the immune system. CD26 EXPRESSION IN TUMORSWhile adenosine is generated as a result of hypoxia and cell necrosis in the core of tumors, there is emerging evidence that some tumors modify purine metabolism to facilitate production or retard degradation of adenosine. One such mechanism is the subject of the article by Blay and co-workers (16), featured on page C433 of this issue. These investigators and others have noted in previous studies that the cell surface protein, CD26, is downregulated in many cancers. In human (but not murine) cells CD26 serves as a binding protein for ecto-ADA, and, by localizing ADA to the cell surface, facilitates adenosine metabolism to inosine. Downregulating CD26 likely results in increased adenosine, especially near the cell surface. This could contribute to immune suppression in the tumor environment (Fig. 1). In their study, Blay and coworkers show that high levels of adenosine downregulate CD26 on the surface of HT-29 colorectal carcinoma cells, possibly resulting in the following positive feedback mechanism: decreased adenosine degradation 3 increased adenosine 3 decreased CD26 expression 3 decreased adenosine degradation. The downregulation of CD26 in tumor cells is correlated with increased protein tyrosine phosphatase and ERK activity and a decrease in CD26 transcription, although it is not clear that all of these effects are causally related. The downregulation of CD26 in response to adenosine is not significantly blocked by adenosine receptor antagonists, suggesting that CD26 regulation may not be mediated by G protein-coupled adenosine receptors, although it is possible that adenosine levels become high enough to overcome competitive receptor blockade. ADENINE NUCLEOTIDE METABOLISM IN TUMOR HOSTS AND IN TUMORSThe downregulation of CD26 is one of several means by which cancer cells may elevate extracellular adenosine to promote tumor angiogenesis and escape immun...

Oxidative stress in relation to adenosine deaminase, nitric oxide, nitric oxide synthase and xanthine oxidase in oral cavity cancer

“…However there was a significant correlation between serum and salivary ADA activity and tumor stage or histopathological grade in the studies [16][17][18], in the present study no significant correlations were determined between the activity levels of enzyme-molecule (normal and tumor tissue) and age or clinicopathological T stage (Tables 3 and 4). This finding in agreement with some studies [19][20] can be explained as increased ADA activity is independent from the stage of the tumor. Another substantial finding of our study is no statistically significant difference was observed in terms of XO activities, in spite of increased activity levels of ADA in the same pathway.…”

“…However, a statistically significant difference in preoperative and postoperative activity levels of ADA were not observed in patient groups. The low ADA activities in patients with the oral cavity cancer were reported as a compensatory mechanism to the high metabolism of purine and DNA [19,20]. Our study reveals that ADA activity was increased in the tumor tissues of the patients with oral cavity carcinoma.…”

CNS macrophages and peripheral myeloid cells in brain tumours

“…Nucleosides like adenosine modulate in an auto-and paracrine fashion the fine-tuning of the tumour-stromainteraction [15]. Extracellular adenosine itself is not only a passive product of tumour induced ischemia, hypoxia and necrosis but also actively released due to altered purine metabolism [85]. [88,145].…”

Purinergic signalling in the gastrointestinal tract and related organs in health and disease

“…Adenosine facilitates tumour survival [443,641]. Proliferation in poorly differentiated HT-29 cells is promoted by adenosine via A 1 receptors and there is inhibition of tumour growth by adenosine deaminase or A 1 receptor antagonists [432].…”