The mechanism by which reactive oxygen species (ROS) are produced by tumour cells remained incompletely understood until the discovery over the last 15 years of the family of NADPH oxidases (NOXs 1–5 and dual oxidases DUOX1/2) which are structural homologues of gp91phox, the major membrane-bound component of the respiratory burst oxidase of leucocytes. Knowledge of the roles of the NOX isoforms in cancer is rapidly expanding. Recent evidence suggests that both NOX1 and DUOX2 species produce ROS in the gastrointestinal tract as a result of chronic inflammatory stress; cytokine induction (by interferon-γ, tumour necrosis factor α, and interleukins IL-4 and IL-13) of NOX1 and DUOX2 may contribute to the development of colorectal and pancreatic carcinomas in patients with inflammatory bowel disease and chronic pancreatitis, respectively. NOX4 expression is increased in pre-malignant fibrotic states which may lead to carcinomas of the lung and liver. NOX5 is highly expressed in malignant melanomas, prostate cancer and Barrett's oesophagus-associated adenocarcinomas, and in the last it is related to chronic gastro-oesophageal reflux and inflammation. Over-expression of functional NOX proteins in many tissues helps to explain tissue injury and DNA damage from ROS that accompany pre-malignant conditions, as well as elucidating the potential mechanisms of NOX-related damage that contribute to both the initiation and the progression of a wide range of solid and haematopoietic malignancies.

INTRODUCTION

Oxidation–reduction imbalance occurs in tissues during episodes of chronic inflammation and contributes to the pathogenesis of a variety of human cancers [1]. Oxidant stress leading to tumour initiation or progression may result from overproduction of reactive oxygen species (ROS) by members of the NADPH oxidase (NOX) family of proteins [2], although other potential sources of ROS, such as the mitochondrial electron transport chain, xanthine oxidase, the cytochrome P450 system, uncoupled nitric oxide synthase and myeloperoxidase, can also make substantial contributions to the oxidative milieu of the tumour microenvi-ronment [35]. Pre-cancerous, frankly malignant, immune and stromal cells engage in a complex cross-talk that modulates tumour growth, development, maintenance and metastasis; ROS formation by tumour cells and cells of the microenvironment plays a critical role in controlling the balance between proliferative and anti-proliferative signalling pathways in vivo [6,7]. Evidence suggests, furthermore, that ROS production by NOX species can strongly influence both tumour growth and survival [810].

Although there is still much to be learned about the mechanisms by which the tumoral microenvironment interacts with membrane-bound NOX isoforms, emerging evidence suggests that a variety of immune responses enhances NOX-dependent ROS production under circumstances wherein oxidant species act as positive signalling intermediates for tumour growth [1115]. Cancer cells acquire a symbiotic relationship with the inflammatory microenvironment which facilitates adaptation for survival, invasion, metastasis and evasion of host immune systems [16]. Inflammatory cells in the tumour microenvironment also serve to stimulate ongoing NOX-mediated ROS production by tumour cells, which enhances the angiogenic process and alters DNA integrity, facilitating genomic instability [1720]. Unequivocal evidence indicates that bacterial and viral infections cause profound cytokine production, which strongly enhances NOX-mediated ROS formation [2123]. The molecular mechanisms responsible for immune regulation of NOX-mediated ROS production in cancer are just starting to be elucidated. However, in view of the differences that exist in the response of various NOX gene family members in different tissues, to a broad range of human cytokines, it can be hypothesized that NOX-dependent ROS production will differ with both the origin of the tumour and the NOX isoform and cytokine receptor expression levels in that malignant disease [24].

The present review focuses on the expression and activation of NOX isoforms in cancer, both cultured cancer cells and in vivo tumour systems. We attempt to isolate the direct effects of NOX-mediated ROS production in human malignancies and pre-cancerous conditions. Overall, we suggest that up-regulation of several members of the NOX family plays a critical role in the tissue injury produced during pre-cancerous chronic inflammation, as well as the entire process of tumour initiation, proliferation, angiogenesis and migration.

NADPH OXIDASE GENE FAMILY

The NOX family of proteins produces ROS in an enzymatic process wherein NADPH-dependent, one- or two-electron reduction of oxygen occurs to produce the superoxide radical (O2•-) or H2O2 across biological membranes [25]. In mammals, seven NOX isoforms generate ROS; isoform-specific production of H2O2 is unique to NOX4 and the dual oxidases (DUOX-1 and -2). The remaining four family members (NOX1–3 and NOX5) produce superoxide [26,27].

Structurally, each NOX/DUOX protein is anchored to the plasma membrane through six transmembrane helices which bind two haem cofactors. A C-terminal FAD-/NADPH-binding domain facilitates electron transfer to the haem molecules for ROS production. Beyond these conserved structural features, the DUOX and NOX5 isoforms possess cytosolic N-terminal EF-hand calcium-binding regions not present in other NOX family members. In addition, DUOX-1 and -2 possess extracellular peroxidase-like domains that are responsible for their descriptive nomenclature. DUOXs function as neither a peroxidase nor a superoxide dismutase; a mechanistic understanding of how these enzymes produce H2O2 directly remains an area of major research interest [2832].

The first identification of a NOX family protein came from the discovery that an X-linked syndrome, characterized by ineffective killing of bacteria and yeast by leucocytes in young patients, was due to mutation in the gp91phox complex (renamed NOX2), leading to an ineffective respiratory burst. Mutations in the multi-component NOX2 complex, which diminish or eliminate ROS production by leucocytes, are the underlying cause of chronic granulomatous disease in which phagocytic cells fail to kill invading pathogenic organisms that they have engulfed [3335]. NOX2 activity relies on specific interactions between a series of other proteins; the oxidase function depends on binding by another membrane protein, p22phox, to anchor gp91phox to the plasma membrane. Recruitment of several other cytosolic proteins including p47phox, p40phox, p67phox and the GTP-binding protein Rac to the membrane is essential for the regulation of the oxidase activity of NOX2 [3642].

Originally, it was thought that NADPH oxidase existed only in phagocytic cells to protect the host against pathogenic organisms. However, over the last 15 years, six homologues of NOX2 have been discovered in a variety of different cell and tissue types. Non-phagocytic cells express NOX analogues; however, isoform expression is restricted by tissue and subcellular context [43,44]. Except for NOX5, activation of all non-phagocytic NOXs involves the assembly of cytosolic and integral membrane proteins to form a multi-subunit enzyme complex [45,46].

For optimal functional activity, NOX1 associates with membrane-bound p22phox and soluble subunit analogues of both p47phox and p67phox, known respectively as NOX organizer 1 (NOXO1) and NOX activator 1 (NOXA1), as well as the small GTPase Rac1, for efficient electron transport across the membrane [4750]. NOX1, originally discovered using Caco-2 human colon cancer cells, is expressed in both normal and malignant colonic epithelia, and has been found at lower levels in vascular smooth muscle and other non-malignant tissues [51,52]. A homologous NOX3 isoform utilizing the same interaction partners for activation is, on the other hand, limited to the cochlear and vestibular sensory epithelial cells of the inner ear. NOX3 activity has been related to the biogenesis of the dynamic otolith and plays a role in maintaining the perception of gravity and balance [53,54].

NOX4 is expressed in the distal tubular cells of the cortex of the kidney and in endothelial cells. A lower level of expression has also been demonstrated in cardiomyocytes, adipocytes, skeletal muscle, brain and airway epithelium. NOX4 expression has been found in tumours of the ovary, kidney and brain, as well as in malignant melanoma [5562].

NOX5 is predominantly expressed in pachytene spermatocytes of the testis, uterine smooth muscle, and lymphocyte-rich areas of the spleen and lymph nodes which contain mature B- and T-lymphocytes, respectively. Its expression was also detected in the ovary, placenta and cardiac fibroblasts. Elevated NOX5 levels have been found in some breast tumours relative to adjacent non-tumour tissue, as well as in breast cancer cell lines, Barrett's oesophageal cancers, hairy cell leukaemia, prostate cancer, and primary and metastatic malignant melanomas [51,55,6367].

DUOX1 is prominent in airway epithelial cells, where it plays a critical role in host defence [68], and in the thyroid gland, where the generation of H2O2 by DUOX proteins is essential for thyroid hormone synthesis [69]. However, DUOX1 expression is significantly diminished in lung cancer samples compared with adjacent normal lung tissues, probably because of site-specific methylation of the DUOX1 promoter [70]. Furthermore, the expression of DUOX1 in human tumours that have been examined has, uniformly, been low [51].

DUOX2 was also initially described as an H2O2-producing enzyme in the thyroid and has an important role in thyroid hormone biosynthesis [71]. Subsequent research has highlighted its host defence role in bronchial epithelium and throughout the gastrointestinal tract [7277]. Expression levels of the DUOX2 gene had not previously been extensively evaluated in human tumours other than lung and thyroid carcinomas [70,78], until our laboratory found high levels of DUOX2 in colonic and pancreatic cancers [1,79].

NADPH OXIDASES AND CANCER

Role of NOX expression in pre-malignant conditions

Chronic inflammation and NOX-derived ROS play an important pathogenic role for several pre-malignant disease processes. ROS production by certain NOX isoforms in vascular tissues can be induced over a relatively short timeframe by growth factors, such as epidermal growth factor (EGF) and platelet-derived growth factor (PDGF); on the other hand, sustained activation by inflammatory cytokines, such as tumour necrosis factor α (TNF-α) and interleukin 1β (IL-1β), is often required to demonstrate substantive NOX-related ROS production [13,8087].

Elevation of proinflammatory cytokine levels is an established feature of inflammation associated with cancer [88,89]. In an inflammatory milieu, ROS originating from immune or epithelial cells can facilitate the proliferation of tissues expressing oxidatively induced mutations [2,90,91]. Furthermore, T-cell function and survival, critical to the control of tumour cell growth, appear to depend on cytokine-related NOX-mediated apoptotic events [9294].

Adenomatous polyps of the large bowel are well known to predispose individuals to the development of adenocarcinoma of the colon [95]. NOX1 has been demonstrated to be over-expressed in well-differentiated adenomas of the colon [96,97]. Furthermore, expression of DUOX2 is significantly increased in so-called ‘flat’ adenomas of the large bowel which have a higher malignant potential than more typical adenomatous polyps [98].

Ulcerative colitis and Crohn's disease are debilitating, pre-malignant inflammatory bowel diseases (IBDs) of unknown aetiology, characterized by chronic, fluctuating episodes of large and distal small bowel inflammation that is immunologically mediated [99]. It has been observed that, in patients with IBD, the by-products of ROS production can be demonstrated in the bowel mucosae [100]. In IBD, ROS are generated by NOX1 and DUOX2 in the colonic epithelium [101,102], as well as by NOX2-containing inflammatory cell infiltrates in the gastrointestinal microenvironment [100,103,104]. Collectively, several studies have shown that ROS production by colonic epithelial NOXs may be involved in host defence, hence it has been suggested that dysregulation of pathogen recognition with a concomitant exaggerated ROS response plays a role in the development of IBD. The most compelling evidence for this hypothesis is derived from genetic mutation studies in which genes encoding epithelial cell components of the NADPH complex have been associated with IBD-susceptibility responses at mucosal surfaces [105110]. In genetically engineered mouse models of IBD, both NOX1 and DUOX2 have been shown to play an aetiological role [74,111]; furthermore, both NOX isoforms have been demonstrated to be up-regulated in the bowel mucosae of patients with these chronic inflammatory conditions [101,102,112].

In addition to chronic inflammation of the intestine, inflammation-related fibrosis of the lung and liver, produced by infectious, genetic and/or environmental factors, contributes to malignancies of these organs [113,114]. Patients with idiopathic pulmonary fibrosis have a significantly enhanced risk of developing either adenocarcinomas or squamous carcinomas of the lung [115]; chronic hepatitis C infection increases the incidence of hepatocellular carcinoma through inactivation of tumour-suppressor genes and dysregulation of a variety of signal transduction pathways [114]. In both of these pre-malignant conditions, there appears to be a relationship between enhanced fibrotic reactions and signalling by way of the transforming growth factor-β (TGF-β) pathway that stimulates the transition of normal epithelial cells to cells expressing mesenchymal characteristics, both genetically and phenotypically, a phenomenon that is associated with increased tissue fibrosis [116]. There is, furthermore, increasing evidence that ROS production by NOX4 is involved in the development of both hepatitis C-related liver fibrosis [117,118] and idiopathic pulmonary fibrosis [119], and that TGF-β may be responsible for the up-regulation of NOX4 and ROS-related tissue injury in these conditions.

NOX expression and function in cultured human cancer cells

Several cell culture model systems have been used to study the role of NOX-dependent ROS production in tumour cell growth, adhesion and angiogenesis [51,62,120122]. However, until relatively recently, a modest number of tumour cell lines had been examined. Using real-time (RT)–PCR, our laboratory performed a detailed examination of over 100 human tumour lines for the expression of all the NOX family members as well as critical accessory genes [51,120]. This effort can be summarized as follows: (i) NOX1 expression at high levels was observed in four of ten colon cancer cell lines and in H226 non-small-cell lung cancer; (ii) NOX2 was expressed only in haematopoietic malignancies (HL-60 and RPMI-8226 leukaemia cells); (iii) NOX3 expression was not observed at any substantive level in the cell lines evaluated; (iv) robust NOX4 expression was found in some melanoma (M14) and ovarian (A2780) cancer cell lines; (v) intermediate to high levels of NOX5 expression were observed in UACC-257 melanoma cells, PC-3 prostate cancer cells and EKVX non-small-cell lung cancer cells; and (vi) both DUOX-1 and -2 levels were low across all the cell lines examined, except for two pancreatic cancer cell lines (BxPC-3 and ASPC-1). The accessory proteins p22phox and Rac1 were widely distributed at a high level across most of the members of the human tumour cell panel examined. These results strongly suggest that the NOX enzymes are distributed in a highly tissue-specific fashion in human tumour cell lines.

In addition to expression level studies, tumour cell culture experiments have demonstrated that immunomodulatory and proinflammatory cytokines, particularly IL-4, IL-13, TNF-α and interferon (IFN)-γ, play an important role in mediating critical signal transduction pathways that control NOX expression, cell growth and inflammation [24,123127]. It has been shown that IL-4 or IL-13 could up-regulate DUOX1-mediated ROS in keratinocytes through the signal transducer and activator of transcription (STAT) 6 pathway [128]. It has also been reported that a component of the bacterial cell wall, lipopolysaccharide (LPS), causes activation of nuclear factor κB (NF-κB) signalling pathway that is responsible for the induction of NOX1 expression in mouse macrophages and guinea-pig gastric mucosal cells [129]. Finally, as noted above for pre-malignant lesions, an accumulating body of evidence suggests that the multi-functional protein, TGF-β contributes to the regulation of NOX4 in human tumour cells and may be involved in stimulating the epithelial-to-mesenchymal transition in that context [130].

As repetitive bouts of pancreatic inflammation, cytokine release and ROS production have been associated with the development and progression of pancreatic ductal adenocarcinoma [131,132], the role of proinflammatory proteins in the regulation of NOX isoform expression was examined in pancreatic cancer cells [24]. These studies showed that IFN-γ, but not other cytokines or growth factors, specifically up-regulated DUOX2, and its maturation factor, DUOXA2 (dual oxidase 2 maturation factor), but not other members of the NOX family (NOX1–5 or DUOX1). Enhanced expression of DUOX2/DUOXA2 produced significant constitutive levels of H2O2. IFN-γ increased DUOX2/DUOXA2 expression by activating the Janus kinase (JAK)/STAT pathway to phosphorylate STAT1 at Tyr701 and to initiate IFN-γ-induced binding of STAT1 to the endogenous DUOX2 promoter in BxPC-3 pancreatic cancer cells. As LPS can play a critical role in the invasiveness of pancreatic cancer cells [133], we also examined the effect of LPS (with and without IFN-γ) on DUOX2 expression in pancreatic cancer cells [8]. The combination of LPS and IFN-γ synergistically increased DUOX2/DUOXA2 expression by activating NF-κB, while markedly increasing the production of H2O2. The consequence of increased ROS production included initiation of a peroxide-dependent DNA-damage response.

Increased expression of NOX homologues (DUOX2 and NOX1), as described above, has also been demonstrated in IBD, a pre-malignant condition. Investigations have suggested that IL-4 and IL-13 enhance the proliferative rate of human tumour cells, including colon and pancreatic cancer cell lines [134], and can increase ROS production in intestinal epithelial cells [123]. Experiments from our laboratory have demonstrated that IL-4 significantly increases the growth rate of parental HT-29 human colon cancer cells but not of stable clonal HT-29 variants, in which NOX1 expression has been inhibited by stable expression of NOX1 shRNA [125]. NOX1 expression is up-regulated by both IL-4 and IL-13 in HT-29 and other human colon cancer lines in a GATA-3-dependent fashion (GATA-3 is GATA-binding protein 3 or globin transcription factor 1) [125]. TNF-α, which contributes significantly to the pathology of IBD [111,135], is also known to up-regulate NOX1 in colonic epithelial cells [136]. On the other hand, NOX4-mediated ROS function in the converse fashion, inducing proinflammatory cytokine expression (IL-6, IFN-γ, TNF-α) in squamous cell carcinoma cells of the head and neck rather than being induced by cytokines [137].

These and related investigations strongly suggest that there is a link between cytokine secretion and NOX expression in a variety of tumour model systems. A study using a bioinformatic approach indicated that NOX1 expression levels in human tumour cell lines correlate significantly with inflammatory and immune signalling pathways including JAK/STAT and extracellular-signal-regulated kinase (ERK) kinase [120]. As shown in Figure 1, the engagement of receptors for several different immunomodulatory proteins activates downstream signalling cascades, leading to induction of NOX gene expression, probably through redox-sensitive transcription factors such as NF-κB, activator protein 1 (AP-1), GATA-3, GATA-6, STAT1/STAT3/STAT6 and hypoxia-inducible factor 1α (HIF-1α), signalling through both mitogen-activated protein kinase (MAPK) and Akt [125,138141].

Effects of growth factors, cytokines and NOXs on tumour cell growth and progression

Figure 1
Effects of growth factors, cytokines and NOXs on tumour cell growth and progression

Inflammatory proteins, such as IFN-γ, TNF-α, IL-1, -4 and -13, and TGF-β, are secreted by immune and stromal cells in the extracellular matrix of the tumour. Specific cytokine receptors are then engaged which activate signal transduction pathways (including MAPK and Akt), culminating in the activation of oxidant-sensitive transcription factors (such as members of the STAT family or NF-κB) which enhance the expression of NOX isoforms. Up-regulation of NOX expression leads to oxidation of essential cysteine residues in protein tyrosine and serine/threonine phosphatases (including protein tyrosine phosphatase 1B, PTP1B), limiting their ability to control transcription factor activation and NOX expression. The concomitant increase in intracellular ROS levels can produce genetic instability that facilitates DNA damage and a proangiogenic environment conducive to further tumour cell proliferation and metastasis.

Figure 1
Effects of growth factors, cytokines and NOXs on tumour cell growth and progression

Inflammatory proteins, such as IFN-γ, TNF-α, IL-1, -4 and -13, and TGF-β, are secreted by immune and stromal cells in the extracellular matrix of the tumour. Specific cytokine receptors are then engaged which activate signal transduction pathways (including MAPK and Akt), culminating in the activation of oxidant-sensitive transcription factors (such as members of the STAT family or NF-κB) which enhance the expression of NOX isoforms. Up-regulation of NOX expression leads to oxidation of essential cysteine residues in protein tyrosine and serine/threonine phosphatases (including protein tyrosine phosphatase 1B, PTP1B), limiting their ability to control transcription factor activation and NOX expression. The concomitant increase in intracellular ROS levels can produce genetic instability that facilitates DNA damage and a proangiogenic environment conducive to further tumour cell proliferation and metastasis.

There is also an accumulating body of evidence indicating that NOX-dependent ROS production contributes to the oxidation of DNA bases (primarily guanine) as well as DNA strand breaks in tumour cells, contributing to genetic heterogeneity [15,142,143]. DNA base oxidation is one of the most common causes of somatic mutation in human solid tumours [144]. In cell culture, NOX1 also plays an important role in tumour cell migration mediated by α-integrins [145,146], and in signalling through the Wnt pathway [121], which is critical for the development of both colorectal cancers and malignant melanoma. The growth-promoting effects of NOX4 in ovarian cancer and melanoma cell lines, and of NOX5 in prostate and oesophageal cancer, have also been described [61,62,67,147].

Overall, cell culture studies are consistent with the hypothesis that the growth-enhancing effects of chronic inflammation may be mediated, at least in part, by the effect of cytokine or growth factor secretion on the expression of several different members of the NOX family. Furthermore, whether or not NOX-mediated ROS production is mediated by an inflammatory process, NOX activation appears to play an important role in producing DNA damage, enhancing proliferation and modifying the invasiveness of human tumour cells, at least when examined in vitro.

NOX expression and function in human solid tumours

The role of the NOX family in tumour biology has primarily been examined in vitro using cell culture model systems. Unfortunately, culture media are often devoid of biologically active heat-labile cytokines and growth factors [148,149]. In addition, through decades of use, uncontrolled passing and unregulated distribution among colleagues, cross-contamination between cell lines, as well as pathogenic contamination, have resulted in the loss of many of the initial gene expression characteristics of such lines [150154]. Furthermore, although examination of human tumour cell lines for NOX isoforms has provided some initial models for the study of NOX biology, the limited expression frequencies of individual members of the NOX family in these cells has diminished their utility for understanding whether, and to what degree, the expression of NOX homologues is associated with human tumours in the clinic.

To determine the comparative expression of NOX isoforms in a range of human tumours and adjacent normal tissues, RT-PCR was performed on a panel of surgically resected malignancies and adjacent non-malignant tissues [51]. For NOX1 and its cofactors (NOXO1 and NOXA1), significantly higher expression was found in colon cancers versus uninvolved adjacent large bowel. DUOX2 expression levels were also extraordinarily high for some patient samples of colorectal cancer. NOX1 and NOX4 were significantly increased in adenocarcinomas of the stomach compared with uninvolved adjacent gastric tissue, NOX4 was elevated in certain ovarian cancers, and NOX4 and NOX5 expression levels were intermediate or high in several melanoma samples.

To expand our understanding of the role of NOX proteins in human tumour biology, monoclonal antibodies were developed against human NOX5 and DUOX homologues; immunohistochemical (IHC) studies using human tumour tissue microarrays were then performed [66,79]. We found high levels of NOX5 expression in melanomas, and breast, colon, lung and prostate cancers, whereas DUOX expression was elevated in colon, prostate, breast and lung cancers. This broad range of expression across several diseases suggests that multiple NOX isoforms may be up-regulated together in human tumours and may contribute to the development or behaviour of these malignancies in the clinic. These observations also raise the question of why the prevalence NOX isoform expression is relatively low across a wide range of human tumour histologies in two-dimensional tissue culture.

Relevant to the issue of why NOX homologue expression determined by IHC appears to be substantially greater in tumours than in tumour cell lines, we found that a single passage of BxPC-3 human pancreatic cancer cells in vivo in murine xenograft models, without exogenous cytokine exposure, up-regulated DUOX2 expression >20-fold, to the same level of expression that cytokine treatment for 24 h in cell culture produced [8]. We also found that normal pancreas demonstrated no evidence of DUOX membrane staining; however, in 34 of 48 patients with chronic pancreatitis, multifocal increases in DUOX expression were demonstrable in both the membrane and the cytoplasm of pancreatic duct cells (Figure 2). Increased DUOX expression was often closely associated with areas of inflammatory cell infiltrates [8]. Thus, one explanation for the discordance between DUOX expression determined by IHC in human tumours and that quantified by RT-PCR in human tumour cell lines is up-regulation of NOX expression by tumour-associated proinflammatory cytokines in vivo.

Increased expression of DUOX in human cases of pancreatitis associated with areas of inflammation

Figure 2
Increased expression of DUOX in human cases of pancreatitis associated with areas of inflammation

(A) Normal human pancreas: minimal staining evident by IHC using a DUOX-specific monoclonal antibody. (BD) Three different cases of pancreatitis: increased staining intensity is multifocal with propensity towards areas of inflammatory cell infiltration. Initial magnification ×5; variation in size of spots is due to different sized microarrays (48 compared with 100 spots). IN, inflammation; L, islet. (Originally published in Wu et al. [8], © 2013 The American Association of Immunologists, Inc.)

Figure 2
Increased expression of DUOX in human cases of pancreatitis associated with areas of inflammation

(A) Normal human pancreas: minimal staining evident by IHC using a DUOX-specific monoclonal antibody. (BD) Three different cases of pancreatitis: increased staining intensity is multifocal with propensity towards areas of inflammatory cell infiltration. Initial magnification ×5; variation in size of spots is due to different sized microarrays (48 compared with 100 spots). IN, inflammation; L, islet. (Originally published in Wu et al. [8], © 2013 The American Association of Immunologists, Inc.)

To examine the effect of the level of NOX1 expression on colon cancer growth in vivo, stable shRNA knockdown was used to produce HT-29 cells in which NOX1 expression was decreased by 80–90%. Inhibition of NOX1 expression was associated with a significant arrest of cells at the G1/S interface without substantial apoptosis and a dramatic reduction in the growth of NOX1 knockdown cells as xenografts. Decreased growth in vivo was also associated with a marked reduction in blood vessel proliferation and the expression of proangiogenic genes including vascular endothelial growth factor (VEGF) and HIF-1α [10,155].

In addition to the up-regulation of NOX1 and DUOX2 in colorectal cancer and DUOX2 in pancreatic cancer, there is a significant body of evidence supporting enhanced mRNA expression (by microarray) of NOX4 in several human solid tumours [10], increased NOX5 protein in prostate cancer [67] and increased expression of DUOX isoforms in cancers of the thyroid [156]. As broad levels of expression of NOX homologues in surgically resected human tumours have been demonstrated only recently, evidence about the function of these oxidases in cancer patients is only now being developed.

Finally, in view of the apparent contribution to tumour growth by NOX isoforms both in vitro and in vivo, recent efforts have been directed towards the development of NOX inhibitors that might be appropriate for cancer prevention or treatment [157,158]. Although isoform-specific NOX inhibitors have been difficult to define, it is clear that NOX inhibition by small molecules appears to decrease tumour growth in vivo [157]. Furthermore, because of the expression of several NOX isoforms (sometimes simultaneously) in human tumours, it may be appropriate to develop therapeutic agents with a broader degree of NOX engagement that could potentially be useful against a variety of NOX species in tumours and in their oxidative microenvironment.

Role of NOX expression in haematopoietic malignancies

Although it has been known for the last 15 years that chronic myelogenous leukaemia (CML) cells harbouring the BCR-ABL translocation generate ROS as a function of their tyrosine kinase activity [159], only more recently has it been appreciated that ROS produced by NOX2 play an important role in preventing apoptosis in human acute myeloid leukaemia (AML) [160]. Patient-derived CML cells express relatively high levels of NOX2 [51]; much lower levels of DUOX2 and NOX5 mRNA have also been found in the tumour cells of a small number of patients with CML [161]. In both human CML cell lines and circulating tumour cells from patients with CML, growth-promoting signals originating from Bcr-Abl appear to be derived, at least in part, from ROS generated by NOX2; furthermore, combination treatment with imatinib (to block the Bcr-Abl kinase) and diphenylene iodonium (to inhibit NOX2) produces synergistic growth inhibition in cell culture and improved disease control in xenograft models of CML in vivo [161].

The appreciation that ROS play an important role in myeloid leukaemias has sparked considerable additional interest in this area of NOX research [162]. Increased NOX2 expression associated with production of NOX2-dependent extracellular ROS has been demonstrated in >60% of patients with AML [163]; increased oxidative stress in AML cells is reflected by decreased total GSH pools that occur in the context of a defective p38 MAPK stress response. Furthermore, in both cultured AML lines and blasts from AML patients, tumour cell proliferation is enhanced by exposure to low micromolar concentrations of H2O2, produced continuously by glucose oxidase added to tissue culture medium. As ROS generated by AML cells can depress the anti-leukaemic T-cell response in the haematopoietic microenvironment [16], the up-regulation of NOX2 in AML cells could contribute to the clonal expansion of malignant myeloid precursors. These observations, as in the case of CML, suggest that the addition of NOX inhibitors to standard targeted therapies might improve the utility of treatment for patients with AML [161].

CONCLUSIONS

Increasing evidence suggests that the generation of ROS by NOX homologues, either constitutively or as a consequence of chronic inflammation, plays a significant role in the proliferative and invasive potential of certain types of malignancies [164,165]. Primed leucocytes and macrophages (sources of activated NOX2), along with other inflammatory and endothelial cells within the tumour microenvironment, can also encourage tumour growth, in part by secretion of cytokines and other co-stimulatory molecules. NOX expression can then play a critical role in the development of an oxidative microenvironment wherein ROS generation provides proangiogenic survival signals advantageous for tumour cell replication and metastasis [166,167]. There is a growing body of evidence demonstrating that one major effect of inflammation-induced cytokine secretion is the up-regulation of NOX homologues that generate ROS; site- and tumour tissue-specific ROS formation appears to contribute to direct tissue injury, DNA damage and activation of a DNA-repair response [15]. Thus, efforts to ban NOX up-regulation or to interfere with NOX function in chronic inflammatory states may be one important approach to preventing oxidative-stress-related carcinogenesis.

Abbreviations

     
  • AML

    acute myeloid leukaemia

  •  
  • AP-1

    activator protein 1

  •  
  • CML

    chronic myelogenous leukaemia

  •  
  • DUOX

    dual oxidase

  •  
  • DUOXA2

    dual oxidase 2 maturation factor

  •  
  • ERK

    extracellular-signal-regulated kinase

  •  
  • GATA-3

    GATA-binding protein 3 (globin transcription factor 1)

  •  
  • HIF-1α

    hypoxia-inducible factor 1α

  •  
  • IBD

    inflammatory bowel disease

  •  
  • IFN

    interferon

  •  
  • IHC

    immunohistochemical

  •  
  • IL

    interleukin

  •  
  • JAK

    Janus kinase

  •  
  • LPS

    lipopolysaccharide

  •  
  • MAPK

    mitogen-activated protein kinase

  •  
  • NF-κB

    nuclear factor κB

  •  
  • NOX

    NADPH oxidase

  •  
  • NOXA1

    NOX activator 1

  •  
  • NOXO1

    NOX organizer 1

  •  
  • PDGF

    platelet-derived growth factor

  •  
  • ROS

    reactive oxygen species

  •  
  • RT-PCR

    real-time PCR

  •  
  • STAT

    signal transducer and activator of transcription

  •  
  • TGF-β

    transforming growth factor β

  •  
  • TNF-α

    tumour necrosis factor α

FUNDING

This work was supported by federal funds from the Center for Cancer Research and the Division of Cancer Treatment and Diagnosis, National Cancer Institute, National Institutes of Health. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services.

Disclosures

None of the authors has a financial relationship to disclose relevant to this manuscript.

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