Review articleTumor-promoting functions of adenosine
Introduction
Adenosine has multiple important functions related to heart and brain physiology. By virtue of being an immediate catabolite of adenine nucleotides, adenosine is well suited to signal physiological, as well as pathological, situations that result in adenine nucleotide degradation. This led to the development of the “adenosine hypothesis,” which proposes adenosine as an endogenous dilator of coronary vessels that is released during reduced myocardial oxygen supply or increased workload (Berne, 1963). Since many of the functions of adenosine are homeostatic and protective in nature, and in principle, equalize local energy requirements with energy supply, it has also been proposed to be a “retaliatory metabolite” Newby et al. 1990, Ely & Berne 1992, Belardinelli & Shryock 1992. The organ- and cytoprotective functions of adenosine also include stimulation of angiogenesis and inhibition of inflammatory reactions at the site of injury, and likely apply to many other tissues.
A number of observations strongly suggest that adenosine may have similar functions in cancer. Due to rapid growth, solid tumors routinely experience severe hypoxia and necrosis, which causes adenine nucleotide degradation and adenosine release. The released adenosine would then exert a broad range of effects that benefit malignancy by providing a supportive environment for the accelerated growth. This supportive environment may include protection against ischemia, stimulation of growth and angiogenesis, and suppression of immune responses. Assuming that adenosine is an important factor promoting tumor growth, the intriguing and important question is whether the genetic and epigenetic changes that underlie carcinogenesis may further augment adenosine release and provide for a more active role of adenosine in tumor progression. This review provides a comprehensive review of metabolic pathways that generate adenosine in cancer, and proposes molecular mechanisms whereby adenosine affects tumor homeostasis.
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Metabolism of adenosine
There are several independent sources of adenosine, including cell death and nucleotide degradation, ischemia and ATP breakdown, ATP/ADP release and subsequent dephosphorylation, AMP release, and S-adenosylhomocysteine hydrolysis, which would individually or in combination provide a steady-state or acute supply of adenosine (Lin et al., 1990). This constant release of adenosine is counteracted by its metabolism, which may proceed either by phosphorylation to form AMP, catalyzed by adenosine
Ecto-5′-nucleotidase
The activity of ecto-5′-NT is variable in malignant cells. Elevated activity of ecto-5′-NT was found in breast carcinoma (Canbolat et al., 1996), gastric cancer (Durak et al., 1994a), pancreatic cancer (Flocke & Mannherz, 1991), chronic myelogenous leukemia (Gutensohn et al., 1983), cutaneous T-cell lymphoma (Fukunaga et al., 1989), glioblastoma Bardot et al. 1994, Fenoglio et al. 1997, and in Walker 256 carcinoma (Clark & Goodland, 1993). A positive correlation between expression of ecto-5′-NT
Cytoprotective and growth-promoting functions of adenosine
Adenosine has potent cytoprotective functions that have been extensively studied in the context of two major organs, heart and brain Barankiewicz et al. 1997, Rudolphi et al. 1992, Schrader 1990. The term cytoprotection encompasses a wide range of cellular effects that result in adjustment of energy metabolism in ischemia, decreased responsiveness to stimuli, protection against apoptosis, and toxic insults. The cytoprotective effects include stimulation of glycolytic flux by A1 adenosine
Angiogenic functions of adenosine
Vasodilation has been a trademark of cardioprotective and cerebroprotective functions of adenosine (Belardinelli et al., 1989), and a similar role has been observed in tumors where adenosine increased intratumor blood flow by activating smooth muscle adenosine receptors (Natori et al., 1992). In addition to vasodilation, adenosine seems to regulate angiogenesis and vasculogenesis: it stimulates both the proliferation of human endothelial cells Barcz et al. 1998, Ethier et al. 1993, Meininger &
Immunosuppressive properties of adenosine
It has become increasingly evident that adenosine has an important role in the regulation of immune responses. Numerous reports have pointed to the general immunosuppressive and anti-inflammatory properties of this compound Anastassiou et al. 1992, Birch & Polmar 1986, Bouma et al. 1996, Cronstein 1992, Cronstein et al. 1985, Cronstein et al. 1995, Firestein et al. 1995, Hasko et al. 1996, Kammer et al. 1986, Lappin & Whaley 1984, Le Moine et al. 1996, and support the view that adenosine acts
Coordinate expression of adenosine-metabolizing enzymes and the molecular basis for adenosine-releasing and adenosine-removing cell phenotypes
Although there are number of examples of a good correlation of increased expression of ecto-5′-NT and/or decreased expression of ADA with cancer progression, there are a few instances where the opposite has been found. These may reflect specific types of malignancies that either are not affected by adenosine or the observed changes in the individual enzyme activities are not sufficient to alter the ability of a particular tumor to metabolize adenosine. Given that, overall, three enzymatic
Sources of adenine nucleotides for extracellular adenosine formation in solid tumors and multidrug resistance
In contrast to the intracellular formation of adenosine from cytosolic pools of adenine nucleotides catalyzed by cN-I 5′-NT in the heart (Sala-Newby et al., 1999), extracellular generation of adenosine by ecto-5′-NT, which is likely the predominant route in epithelial cells, depends entirely on the availability of AMP. There may be several sources of extracellular adenine nucleotides that may be passively or actively released from cells. Passive efflux of adenine nucleotides is common in tissue
Perspectives
The experimental data reviewed in this article strongly support the hypothesis that adenosine has tumor-promoting activities. Further studies are necessary to provide more direct evidence. One of the most important questions is to determine whether adenosine is a mere passive product of necrosis and ischemia in solid tumors or, as our recent results suggest, the release of adenosine is actively increased as a result of specific genetic alterations that occur during tumor progression. We have
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