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Department of Surgery, University of Florida College of Medicine, Surgical Services, North Florida South Georgia VA Health Care System, Gainesville, FL 32608
2To whom correspondence should be addressed. E-mail: lindds{at}surgery.ufl.edu.
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ABSTRACT |
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 TOP ABSTRACT LITERATURE CITED |
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KEY WORDS: • arginine • nitric oxide • apoptosis • angiogenesis • cancer
Cancer is the endpoint of a multistep process that includes three fundamental components: initiation, promotion, and progression (Fig. 1). Arginine is involved in a number of biosynthetic pathways that significantly influence carcinogenesis and tumor biology. Since the discovery that arginine metabolism generates a ubiquitous signal transduction molecule, nitric oxide (NO),3 arginine-derived NO has been found to play a significant role in many of the specific events that lead to cancer. Although the biochemistry of NO is simplistic, its role in tumor biology is extremely complex. NO has been shown to have conflicting roles with seemingly opposite effects in tumor initiation, promotion, and progression. The net biological effect of NO production is a balancing act that is dependent upon several factors including its concentration, temporal expression, cell source, and target cell. In addition, the surrounding microenvironment significantly influences NO activity through its reactivity with reactive oxygen species, metal ions, and proteins. Thus, there are several layers of complexity regulating arginine-derived NO with multiple feedback loops that limit its ultimate effect. The purpose of this review is to review arginine metabolism and its role in cancer with specific emphasis on the role of arginine-derived NO.
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Arginine is derived primarily from dietary sources and synthesis in the kidney. Alterations in dietary arginine intake may influence splanchnic organ conversion of arginine to NO (1). Circulating arginine traverses the cell membrane via specific cell membrane amino acid transporters. Transmembrane arginine transport regulates the flow of substrate into arginine dependent biosynthetic pathways. In most mammalian cells, including tumor cells, the transport of L-arginine and other cationic amino acids is mediated principally via the Na+-independent cationic amino acid transport system y+ (2). The activity of the arginine transporter is influenced by a number of factors. The cytokines interferon and tumor necrosis factor coinduce the arginine transporter and the enzyme that synthesizes NO from arginine, nitric oxide synthase (NOS) (Fig. 2) (3). Because the rate of cellular NO synthesis is limited by the rate of arginine uptake, this coinduction of NOS acts as a mechanism to provide increased substrate for NO synthesis during inflammatory states. Furthermore, recent evidence suggests the cationic amino acid transport system y+ may be colocalized in the plasma membrane to selectively direct arginine supply towards NO synthesis (4). Intracellular arginine can be metabolized through a variety of pathways that may be present in the same cell. Evidence suggests that regulation of these pathways represents another mechanism to limit arginine-derived NO production. For example, depletion of arginine by arginase, the enzyme that catalyzes the conversion of arginine to ornithine, limits arginine availability for NO production. The end result of arginase activity is that less substrate is available for production of cytostatic NO, while more arginine is metabolized to the pro-proliferative polyamines (5). These complex interrelationships between the various arginine metabolic pathways may profoundly influence tumor growth and biology.
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Some animal and human tumors require arginine for growth (i.e., auxotrophic tumors). While normal cells are able to synthesize arginine from citrulline through the enzymes arginosuccinase synthase (AS) and arginosuccinase lyase, some human cancers, such as melanoma and hepatocellular carcinoma (HCC) (6), do not express AS and therefore are unable to synthesize arginine from citrulline. Some researchers have exploited this cancer cell arginine requirement as an antineoplastic therapy to selectively starve tumors. Arginine deiminase (ADI), an arginine-metabolizing enzyme isolated from Mycoplasma, can inhibit tumor cell growth in culture and in animal tumor models. Unfortunately, microbial ADI is highly antigenic and it has a short half-life. Therefore, ADI must be delivered in high doses to maintain its anti-tumor effect. Phase I/II studies were recently reported regarding the anti-tumor activity of ADI conjugated to polyethylene glycol in patients with unresectable hepatocellular carcinoma. Liver cancer patients with no detectable plasma arginine levels tolerated the therapy well and 2 of 19 patients treated demonstrated a complete tumor response (7). These encouraging results need to be evaluated in a larger HCC patient population and in cancer patients with other tumors auxotrophic for arginine.
In contrast to arginine depletion, arginine supplementation augments both specific and nonspecific anti-tumor mechanisms, retards tumor growth, and prolongs survival in some animal tumor models (8). Because the controversial role of arginine-enhanced nutritional diets in cancer patients is addressed elsewhere in this issue, the remainder of this review will focus on the role of arginine-derived NO in cancer.
Carcinogenesis
The association between malignancy and chronic inflammation has long been known. Chronic tissue inflammation is associated with head and neck, lung, esophageal, stomach, colon, liver, and skin cancer. Long-term exposure to NO induced by chronic inflammation may promote carcinogenesis in a number of organs (9).
A role for NO has been proposed in the pathogenesis of ulcerative colitis (UC). In some animal models of colitis, iNOS expression is increased and the inhibition of NO production can improve the colitis (10). The increased incidence of cancer in UC patients may be related to excess NO generation as a result of chronic colonic inflammation. A role for NO in sporadic colorectal cancer has also been suggested by the findings of increased iNOS activity in colon adenomas, colon cancer, and metastases (11). NO may contribute to tumor progression from a colorectal adenoma to a colorectal carcinoma.
Experimental evidence also exists implicating NO in the development of cholangiocarcinoma (12) and hepatocellular carcinoma (13). NO’s carcinogenic effects may involve several mechanisms including direct DNA and protein injury or the inhibition of programmed cell death, thus promoting abnormal cell growth. NO may also regulate key proteins involved in carcinogenesis through several posttranslational modifications. In some cholangiocarcinoma cell lines, NO-mediated modification of pro-apoptotic caspases can contribute to the carcinogenic process (14). NO may also promote tumor growth through the stimulation of tumor angiogenesis (15). NO promotes several steps required for tumor angiogenesis including endothelial cell proliferation, vascular permeability and stimulation of angiogenic growth factors. These NO-mediated mechanisms of carcinogenesis may also be relevant to the development of a variety of malignancies.
Arginine-derived NO is also implicated in carcinogenesis in several other organs. NO in cigarette smoke may contribute to the development of several smoking-related diseases including lung cancer (16). Increased NOS activity is also associated with metaplastic changes in the breast (17) and the esophagus (i.e., Barrett’s esophagus) (18). Patients with Helicobacter infection develop chronic gastritis and this persistent inflammation may contribute to the development of gastric cancer. Patients with Helicobacter pylori infection demonstrate increased iNOS expression leading to the formation of carcinogenic nitrosamines (19). Ultraviolet radiation can also induce NO production and contribute to oxidative damage of the skin leading to both melanoma and nonmelanoma skin cancers (20).
As a result of the aforementioned findings, researchers have speculated that NO may represent a potential target for chemoprevention (21). A few studies examining the chemopreventative effects of NOS inhibition have been performed in rat colon (22) and esophageal (23) cancer models and a mouse mammary adenocarcinoma model (24).
Rao et al. (25) demonstrated a reduction in the development of aberrant crypts, a precursor to colon cancer, by inhibiting iNOS in a chemically-induced rat colon cancer model. On the other hand, Schleffer et al. (26) recently demonstrated that the NOS inhibitor L-NAME promoted carcinogen-induced preneoplastic changes in a rat colon carcinogenesis model by inhibiting NOS activity and stimulating polyamine synthesis. These conflicting reports illustrate the need for further studies in this area.
Initiation
Several lines of investigation suggest that NO is involved in the initiation of numerous cancers. High levels of NO may modify DNA directly or indirectly by inhibiting DNA repair activities (27). NO can cause irreversible injury to several fundamental cancer control genes. NO and superoxide rapidly react to form peroxynitrite which can cause oxidative damage to DNA. NO can also block DNA synthesis through the inhibition of ribonucleotide reductase, the rate-limiting enzyme in DNA synthesis (28). In addition, NO can directly inhibit enzymes in mitochondrial electron transport chain or act indirectly by interfering with DNA repair mechanisms leaving the cell susceptible to other DNA damaging agents (29).
Progression
Evidence suggests that arginine-derived NO can influence the progression of established neoplasms. A solid tumor consists of a number of cell types including tumor cells, fibroblasts, lymphocytes, macrophage, neutrophils, and endothelial cells. Any of these cellular constituents of a neoplasm may serve as a source of NO. During tumor growth, NOS activity may be increased in these cell types by pro-inflammatory cytokines and hypoxia present in the tumor microenvironment. The highly lipophilic nature of NO makes transcellular passage easy and facilitates NO-mediated effects between tumor cells and other cell types. All 3 NOS isoforms (iNOS, eNOS, nNOS) have been detected in tumor cells but the role of each isoform in tumor biology is incompletely understood (30). NOS isoforms may be involved in tumor cell proliferation, survival, migration, and invasiveness. NOS activity has been detected in a variety of tumor cell lines and human tumors and its expression has been correlated with tumor grade and proliferation rate (31). Martin et al. recently found a correlation with eNOS activity and estrogen receptor positivity (32). NO also promotes tumor invasiveness by affecting matrix metalloproteinase expression (33). Some tumor cells exposed to NO exhibit increased expression of the p53 tumor suppressor gene. In turn, the accumulation of p53 protein downregulates iNOS expression through an autocrine negative feedback loop. Furthermore, the mutation or loss of the p53 tumor suppressor gene results in resistance to NO-mediated cell death providing a selective growth advantage for abnormal cells (34). Given the prevalence of p53 in neoplasia, these NO-mediated changes in oncogene expression may represent fundamental events in cancer
Experimental tumor models have provided additional evidence for a role for NO in tumor growth and metastasis. Our laboratory previously found that inflammatory mediators stimulate arginine transport and NO production in a murine breast cancer cell line (Fig. 2). Furthermore, tumor cell NO production inhibited cell growth in vitro but augmented tumorigenesis (Fig. 3A) and experimental lung metastases in vivo (35). In this model, tumor growth was enhanced in vivo through an NO-independent mechanism (Fig. 3B). We hypothesized that arginine-enhanced diets increased tumor growth and spread via increased polyamine synthesis.
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Programmed cell death is a highly regulated active process characterized by cell shrinkage, membrane blebbing, chromatin condensation, cell fragmentation, and the formation of apoptotic cell bodies. NO-mediated apoptosis or programmed cell death has been demonstrated in a variety of cell types including tumor cells. Several reports demonstrate that NO and peroxynitrite can directly cause either necrotic cell death or apoptotic or programmed cell death depending upon the NO level and cell type (36). Cytokines or LPS induced endogenous NO production can also induce apoptosis. For example, transfection of the iNOS gene into murine melanoma cells nullifies tumorigenicity and metastatic capability due to endogenous NO-mediated apoptosis (37). In addition, the antitumor toxicity of cytokine activated macrophage and endothelial cells is in part due to NO-mediated apoptosis. Some cells are intrinsically resistant to NO mediated cell death due to genetic determinants of the cell expression of p53 and other tumor suppressor or apoptosis-related proteins.
Generally, induction of apoptosis requires high NO concentrations while low NO concentrations can result in resistance to NO-mediated apoptosis. In some settings, NO may inhibit apoptosis through pathways that are dependent upon the cyclic nucleotides cyclic AMP or GMP. In hepatocytes, NO has been shown to inhibit apoptosis through suppression of caspase activity (14). NO can function in an anti-apoptotic role through the posttranslational modification of a number of proteins that regulate apoptosis (38).
Angiogenesis
Neovascularization or angiogenesis is an absolute requirement for tumor growth. Because NO is the endogenous vasodilator, its role in blood flow and established tumor microcirculation seems intuitive. Conflicting data suggest that NO can inhibit or stimulate angiogenesis depending upon the NO level and angiogenic model (39). NO can also affect angiogenesis directly or through secondary messengers. Much of the data regarding NO’s role in angiogenesis has been derived from in vitro experiments using NO donors and nonspecific NOS inhibitors. These experiments have shown that NO promotes new vessel growth through NO-medicated upregulation of angiogenic factors such as vascular endothelial growth factor and basic fibroblast-derived growth factor (40). NO also affects the proliferation of vascular cells such as endothelial and smooth muscle cells through the cGMP signaling pathway (41). Modulation of NO and its effect on tumor microcirculation and new vessel formation represents a novel anti-tumor strategy.
Immune response
NO plays a central role in the immune response. Consistent with the aforementioned roles of arginine-derived NO in cancer, NO also has disparate roles in tumor immunity. Hibbs and colleagues first described the role of NO in activated macrophage cytotoxicity in 1987 (42). Subsequent to this landmark observation, NO-mediated tumor cell cytotoxicity has been demonstrated in a variety of immune cells including natural killer cells, T-cells and endothelial cells (43). Recent data have shown that the metastatic capability of human colorectal cancer cells correlates with their sensitivity to NO-mediated liver sinusoidal endothelial cell cytotoxicity (44). NO also modulates the expression of cell adhesion molecules critical to the inflammatory response, such as vascular cell adhesion molecule, and P-selectin (45). In addition, NO influences chemokine signal transduction pathways (46). Several different immune cells not only produce NO but also exhibit diverse responses to its production. NO overproduction has been implicated in tumor-induced immunosuppression through the inhibition of immune cell activation pathways. It is evident that since Hibbs initial report, NO’s role in tumor immunity is complex and understanding the multifaceted roles of NO in the immune response to cancer is essential to developing NO-based strategies for tumor treatment.
Metastasis
Most cancer patients die as a result of distant tumor spread that is resistant to conventional anti-tumor therapies. Therefore, understanding the biology of the metastatic cascade is essential to developing novel therapies. The selective process of tumor metastasis involves a series of interrelated rate-limiting steps. Increasing evidence suggests that NO influences the metastatic process. This review has previously summarized the role of NO in apoptosis, adhesion, invasion, and the host immune response to cancer. While the vast majority of circulating tumor cells die rapidly in the circulation, NO mediates several events that promote tumor cell dissemination and survivability. NO affects cell deformability and the ability to form tumor cell:platelet aggregates. Aggregation with platelets can protect tumor cells from immune cell attack. Murine melanoma cell line NOS activity inversely correlated with metastatic capability. When these tumor cells were genetically transduced to overexpress iNOS, tumor cells lost their tumorigenic and metastatic capability through NO-mediated tumor cell apoptosis (37). NO production may represent a novel approach to controlling tumor growth and metastasis.
Arginine-derived NO and anti-tumor therapies
Nitric oxide has significant antineoplastic potential but its clinical application has been limited by the adverse hypotension produced with systemic administration of NO-delivering drugs. Previous work in our laboratory showed that NO is responsible in part for the anti-tumor efficacy of conventional cancer therapies. In the murine mammary adenocarcinoma cell line EMT-6, Adriamycin simulated NO production. Adriamycin’s tumor cell cytotoxicity was NO-independent in vivo but partially NO-dependent in a syngeneic mouse tumor model (47).
NO can also enhance the effectiveness of radiation. NO is a potent radiosensitizer of hypoxic cells and at high concentrations NO enhances apoptosis. Some investigators recently demonstrated that iNOS overexpression augments radiation-induced apoptosis in colorectal cancer cells (48).
Unfortunately, many cancers are either inherently resistant to chemotherapy or they develop resistance during the course of therapy. Therefore, there is an intense interest in identifying biological markers that predict treatment response and in developing biologically based methods for reducing chemoresistance. NO has also been shown to affect the antitumor activity of chemotherapeutic agents such as Adriamycin (49), Gemcitabine (50), and Melphalan (51). In animal models, pretreatment with NO delivery agents can sensitize tumor cells to Cisplatin (52). Undoubtedly, a better understanding of the precise role of NO in cancer will have profound therapeutic implications and could lead to novel antineoplastic strategies.
Summary
Arginine has numerous roles in cellular metabolism that may influence the multistep process that results in cancer. Arginine-derived NO has many overlapping and conflicting regulatory roles in tumor initiation, promotion, and progression. Further mechanistic studies are necessary to develop biologically based anti-neoplastic strategies targeted at arginine’s metabolic pathways.
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FOOTNOTES |
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3 Abbreviations used: ADI, argine deiminase; AS, arginosuccinase synthase; HCC, hepatocellular carcinoma; NO, nitric oxide; NOS, nitric acid synthase.
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