Carcinogenesis is a complex multistage process often taking decades until malignancy appears. Conventionally, the carcinogenic process has been divided into three main stages: initiation, promotion, and progression. Initiation requires an irreversible genetic damage causing mutations in transcribed genes. Promotion consists of a potentially reversible oxidant-mediated conversion step followed by a clonal expansion of the initiated cells into benign tumors, which can progress to malignancy when they acquire many additional genetic changes. Those genetic changes include modification of DNA bases, insertions and deletions, genetic instability consisting of loss of heterozygosity, chromosomal translocations, and sister chromatid exchanges, activation of oncogenes, and suppression of tumor suppressor genes. Although cell initiation is a frequent occurrence, tumor promotion and progression usually require a long time because of all of the genetic changes that have to accumulate within the same few cells.
It has been known for many years that antioxidants inhibit formation of tumors, even though they might not decrease DNA adducts, thought to be the initiating lesions. Hence, antioxidants are likely to interfere with the oxidant formation during promotion and/or progression stages of tumor development. Since then, numerous publications have shown that various types of reactive oxygen species (ROS) are generated during all stages of carcinogenesis, but especially during that long time required to take an initiated cell to a fully disseminated cancer. This long period between the initiation stage and cancer development provides a wide-open window of opportunity to interfere with and suppress the carcinogenic process. This can be accomplished more readily when processes of tumor promotion/progression and factors responsible for them are known. Some of those factors are discussed in this entry.
The importance of oxidative stress to human cancer is underscored by the existence of cancer-prone syndromes characterized by the formation of high levels of oxidants and/or impairment(s) in their degradation or repair of the DNA damage they evoke. Those human congenital syndromes include Fanconi's anemia, xeroderma pigmentosum, Bloom's syndrome, ataxia telangectasia, Wilson's disease, and hemochromatosis, among others. The last two conditions also point to the contribution of an excess of bioavailable transition metal ions, such as copper and iron, to an overload of oxygen radicals in the liver and to the progression and outcome of those diseases. Hussain and colleagues clearly showed that livers of patients with Wilson's disease and hemochromatosis contain increased levels of inducible nitric oxide synthase (iNOS), as well as mutations in the p53 tumor suppressor gene, especially G:C to T:A transversions at codon 249. This finding is particularly important because hydrogen peroxide (H2O2)/iron treatment, as well as lipid peroxide-derived mutagenic aldehydes, such as 4-hydroxynonenal (HNE), cause the same type of mutations at codon 249. High levels of etheno compounds are present in liver DNA from patients having these two diseases. Interestingly, HNE causes formation of etheno derivatives in DNA and induces mutations at the 249 codon of the p53 gene in HNEtreated lymphoblastoid cells. Notably, not only congenital syndromes exhibit mutations in the p53 gene, but also noncancerous colon tissues from ulcerative colitis patients, a colorectal cancer-prone chronic inflammatory disease. Frequencies of p53 mutations at codons 247 and 248 were strongly correlated with the progression of the disease being appreciably higher ininflamed than in noninflamed tissues. These studies strengthen the idea that chronic inflammation contributes to cancer, and the results are consistent with the hypothesis that p53 mutations at 247-249 codons are due to chronic inflammation-associated oxidative stress.
Oxidants are continuously formed and degraded during various normal cellular processes. ROS are required for the normal functioning of an organism and for the protection from invading bacteria. They are produced or utilized during mitochondrial respiration, metabolism of fats and xenobiotics, melanogenesis, and other peroxidatic reactions. Many types of cellular defenses keep these oxidants under control, but when they fail, extensive repair systems remove the damage from DNA and try to restore its integrity. ROS produced in small amounts can serve as second messengers in signal transduction. However, when ROS are formed at a time when they are not needed and/or in amounts exceeding antioxidant defenses and DNA repair capacity, then ROS can contribute to various diseases, with cancer being prominent among them. Tumor promoters and complete carcinogens induce chronic inflammation, ROS production, and oxidative DNA damage. Some of the oxidized DNA base derivatives are mutagenic, cytotoxic, and cross-linking agents. They can also cause hypomethylation, known to induce accelerated expression of some genes. This process might perhaps account for the ROS-mediated enhanced levels of various growth and transcription factors, and genes involved in antioxidant defenses.
II. OXIDANTS: REACTIVE OXYGEN SPECIES (ROS) AND REACTIVE NITROGEN SPECIES (RNS)
Extensive amounts of reactive oxygen and nitrogen species (ROS and RNS) are produced during inflammation, a normal bactericidal and tumoricidal process. However, chronic inflammation contributes to the long-lasting pathologic effects of the carcinogenic course of action, regardless of the type of cancer. ROS and RNS are generated by the activated "professional" phagocytic cells polymorphonuclear leukocytes (PMNs, neutrophils, granulocytes) and both circulating and resident macrophages. Target cells (i.e., epidermal keratinocytes or hepatocytes) can also form them in response to treatment with appropriate stimuli, such as tumor promoters or allergens. Although absolute amounts of ROS and RNS are much lower than those produced by stimulated phagocytes, these oxidants can set off a release and a synthesis of a cascade of various cytokines and chemotactic factors, which are instrumental to the initiation of inflammatory responses by phagocytic cells. ROS and RNS also mediate increased formation of growth and transcription factors needed for the accelerated growth of initiated cells.
Major ROS include superoxide anion radicals (O2.-), their dismutation product hydrogen peroxide (H2O2), hypochlorous acid/hypochlorite (HOCl/ OCl-), singlet oxygen (1O2), and hydroxyl radicals (∙OH) (Table I). RNS are also produced during inflammation and contribute to its pathologic effects, with nitric oxide (∙NO), a product of iNOS, being a major player. The distinction between ROS and RNS is further blurred because of an avid interaction between O2∙- and ∙NO, which produces peroxynitrite (ONOO-, a potent oxidant) at a near diffusion rate. One of the most potent oxidants is ∙OH. This can be generated by ionizing radiation and by iron autooxidation, as well as through the reduction of H2O2 by transition metal ions, such as iron or copper, in the well-known Fenton or Haber-Weiss reactions. Although to a lesser extent, ∙OH can also be formed in the absence of transition metal ions, when there is an opportunity for a homolytic scission. Because ∙OH are the most potent oxidizing species, they cause damage only within a short distance from their generation.
For this reason, H2O2, a neutral and not very reactive oxidant, is most likely responsible for reaching nuclear DNA and forming ∙OH-like species at sites harboring transition metal ions. Even H2O2 generated outside of the target cells (i.e., by PMNs or macrophages) can pass through membranes of the target cells and cause damage in the neighboring or distant cells. Other ROS cannot cross cell membranes because they are charged (i.e., O2∙-), lipophilic (1O2) reacting with membrane lipids, or react too rapidly (HOCl/OCl-) with amino groups within membranes forming much longer acting chloramines. Of the RNS, ∙NO can cross membranes. Although very reactive, ONOO- can diffuse within cells and might cross membranes of certain cells via anion transporters.
TABLE I Major ROS and RNS Produced during Inflammation
|ROS or RNS||→||Secondary ROS, RNS, and other reactive species|
|O2∙-||H2O2, ∙ OH, ONOO-|
|HOCl/OCl-||1O2, RNHCl, RNCl2, Cl2, NO2Cl|
|Lipid peroxides||Lipid hydroperoxides, aldehydes|
|∙NO||ONOO-, N2O3, NOx|
|ONOO-||1O2, NO2-, NO3-, NOx|
III. DIRECT OXIDATION OF DNA BASES
Both ROS and RNS can induce a plethora of genetic changes. Much is already known about the formation of oxidatively modified bases in cellular DNA. Figure 1 shows structures of oxidized DNA bases selected from well over 30 that are produced. The most extensively studied DNA base derivatives are thymidine glycol (dTG), 5-hydroxymethyl-2'-deoxyuridine (HMdU), and 5-hydroxy-2'-deoxyuridine (5-HdU), 5-hydroxy- 2'-deoxycytidine (5-HdC), and 5-hydroxymethyl-2'- deoxycytidine (HMdC), 8-hydroxy-2'-deoxyguanosine (8-OHdG), 8-hydroxy-2'-deoxyadenosine (8-OHdA), and their open-ring pyrimidine derivatives FaPy G and FaPy A. Many of these oxidized base derivatives are mutagenic (i.e., HMdU, 5-HdC, and 8-OHdG), whereas others block DNA replication (i.e., dTG). These oxidized bases can be formed directly by ROS, such as a site-specific attack by ∙OH (or ∙OH-like species), 1O2 (i.e., 8-OHdG), or peroxyl radicals (HMdU). HOCl/OCl- can oxidize DNA bases through the evolution of 1O2 in the presence of excess H2O2 and chlorinate cytosine and adenine residues in DNA and tyrosines in proteins. ONOO- oxidizes the guanine moiety in DNA to 8-OHdG but it reacts even more readily with 8-OHdG, which results in oxazolone derivative, cyanuric acid, and oxaluric acid as the end products. Hence, 8-OHdG might not be the best marker of oxidative stress and oxidative DNA damage if there is a possibility for ONOO- formation.
FIGURE 1 Selection of oxidized DNA nucleosides formed in DNA of humans, animals, and/or mammalian cells grown in culture. FAPYdG, formamido-aminopyrimidine product of opening of the imidazol ring of dG.
IV. INDIRECT ROS-MEDIATED MODIFICATION OF DNA BASES
In addition to the direct attack of oxidants on DNA bases, they can also be indirectly modified through interactions with electrophilic species produced by a ROS attack on other molecules or during ROS formation by such molecules.
A. Etheno-Base Derivatives Formed in DNA due to Lipid Peroxidation
ROS attacking unsaturated lipids cause the formation of lipid peroxides, which upon decomposition release aldehydes, such as malondialdehyde (MDA) and HNE. Both MDA and HNE are mutagenic and capable of binding to the amino group-containing dG, dA, and/or dC to form etheno derivatives, which contribute an additional ring to purines and pyrimidines (Fig. 2). Etheno compounds are present in DNA isolated from various types of tumors or from nontumorous sections of tumor-bearing animals and humans attesting to the existence of ROS and lipid peroxides in those tumors or tissues.
FIGURE 2 Selected products of interactions between aldehydes derived from lipid hydroperoxides (i.e., malondialdehyde or 4-hydroxynonenal) and amino group-containing 2'-deoxyribonucleosides in DNA of humans and animals.
B. Quinone-DNA Adducts Formed Due to ROS
An important example of processes leading to reactions of quinones with DNA is the redox cycling of the quinone-semiquinone couple derived from catecholestrogens. These evolve during estrogen metabolism by cytochrome P450 1A1 (CYP 1A1). Interestingly, lipid hydroperoxides acting as cofactors for peroxidatic oxidation also contribute to the formation of catecholestrogens (Fig. 3). Oxidation of semiquinone to quinone by molecular oxygen produces O2 ∙- and H2O2 and, in the presence of iron or copper, forms ∙OH, which can oxidize unsaturated lipids to lipid peroxides or, if formed in situ, cause oxidation of DNA bases. Thus, during metabolic estrogen transformation, several types of DNA modification should be anticipated: oxidized bases, etheno products derived from aldehydes released by lipid hydroperoxides, and quinone adducts. It is no wonder that estrogens have been implicated as contributors to hormonal cancers in humans.
Another example of the importance of quinones in carcinogenesis and ROS generated during metabolism is benzo[a]pyrene (BP), a polycyclic aromatic hydrocarbon (PAH) and a major pollutant. Long and co-workers showed that up to 50% of female knockout mice lacking NAD(P)H:quinone oxidoreductase (NQO1, enzyme reducing quinones by two electrons to the nonredox-cycling hydroquinones) develop tumors when initiated with BP and promoted with phorbol ester 12-O-tetradecanoylphorbol-13-acetate (TPA) by the end of the experiment at 31 weeks, whereas the wild-type mice had none. Some (25%) of these tumors in NQO1(-/-) mice progressed to malignancy. BP is metabolically activated by CYP 1A1 and related enzymes to a variety of oxygenated derivatives, including three BP quinines (Fig. 4), which in the presence of P450 reductase form semiquinones. Hence, again quinone-semiquinone couples can redox cycle and generate ROS. These results also underscore the important role that antioxidant enzymes, such as NQO1, play in carcinogenesis.
FIGURE 3 Redox cycling of quinone-semiquinone couples leading to the formation of three general types of modified bases in DNA: quinone-DNA adducts, oxidized bases, and etheno compounds, which are products of lipid hydroperoxide (LPH)-derived aldehydes' reactions with amino group-containing DNA bases. This redox cycling is illustrated by the metabolism of estradiol, a physiological hormone, which is suspected as a contributor to human cancers, such as those of breast, endometrium, and prostate. It also applies to other carcinogens, which are metabolized to quinones and semiquinones that can redox cycle. Adapted from JNCI Monograph No. 27, p. 86, 2000, published by the Oxford Univ. Press, with permission from the publisher.
C. Effects of Inflammation-Derived ROS
on Metabolism of Exogenous Carcinogens Stansbury and colleagues showed that HOCl/OCl- (a powerful oxidant generated during inflammation by H2O2-mediated oxidation of chloride ions catalyzed by myeloperoxidase, an enzyme released by PMNs during activation) oxidizes BP 7,8-dihydrodiol to pyrene dialdehyde (Fig. 4), a novel BP-derived product that binds to DNA. These results point to ROS generated during inflammation as having a potential to change PAH metabolism and form DNAbinding species different from diol epoxides or quinones (Fig. 4). Oxidation and activation of polyaromatic amines by HOCl/OCl- have been known for many years. These could be some of the reasons why chronic inflammation contributes to carcinogenesis.
FIGURE 4 Metabolism of benzo[a]pyrene (BP, a carcinogenic polycyclic aromatic hydrocarbon) to metabolites that can form adducts with DNA bases and depurinating adducts, as well as contribute to the oxidation of bases in DNA through the redox cycling of quinone-semiquinone couples. The newly described pyrene dialdehyde potentially can form mono-adducts with DNA bases, as well as form intra- and interstrand DNA cross-links and DNA-protein cross-links. Pyrene dialdehyde is produced by oxidation of BP 7,8-dihydrodiol with HOCl/OCl- generated by activated PMNs during inflammation.
D. Oxidative Deamination and Nitration of DNA Bases
Although ∙NO has many physiological functions, when it is generated during chronic inflammation, it can oxidatively deaminate 5-methylcytosine, cytosine, guanine, and adenine, leading to the formation of thymine, uracil, xanthine, and hypoxanthine moieties in DNA. If not repaired, deaminated bases can mispair during DNA replication and cause mutations. Moreover, the nitrosating potential of ∙NO contributes to the formation of carcinogenic nitrosamines.
In the presence of O2∙-, ∙NO produces a powerful oxidant, ONOO-, which oxidizes dG and 8-OHdG and also has nitrating properties evident from the formation of 8-nitroguanine in DNA and 3- nitrotyrosine in proteins. Upregulated iNOS and 3-nitrotyrosine have been found in tumor tissues and, in some cases, such as in metastatic melanoma, were correlated with poor survival of the patients, according to Ekmekcioglu and co-workers.
V. CARCINOGEN-MEDIATED INFLAMMATORY AND OXIDATIVE RESPONSES
As already mentioned, carcinogens, such as PAHs, can be metabolized by ROS-mediated pathways and they also contribute to ROS formation. Virtually all types of complete carcinogens and tumor promoters tested cause oxidative DNA base damage in vivo and, when analyzed, H2O2 is also evident in the target tissues. Carcinogens have been known to evoke inflammation thought to be necessary for tumorigenesis. An important question arises as to the mechanism(s) by which inflammatory responses are induced. Tumor promoters, such as TPA, induce inflammation very rapidly through protein kinase C, which provides a signal for a plethora of responses. A prominent response among them is a rapid release of interleukin (IL)-1α from suprabasal keratinocytes, which initiates a cascade of other cytokines and chemotactic factors synthesis, including IL-1α, tumor necrosis factor (TNF)-α, IL-8, granulocyte/macrophage-colony stimulating factor, and others. Frenkel and colleagues and Li and co-workers showed that similar to TPA, 7,12- dimethylbenz[a]anthracene (DMBA, a carcinogenic PAH) also induces IL-1α and TNF-α release and causes mRNA upregulation, which leads to further cytokine production in mouse skin. DMBA-induced IL-1α was responsible for PMN infiltration into mouse skin, as >65% of that infiltration was inhibited by preinjection of mice with anti-IL-1α antibody (Ab).
Interestingly, anti-IL-1α Ab did not have appreciable effects on the incidence of DMBA-induced papillomas or carcinomas, but very potently inhibited the carcinoma volume, whereas anti-TNF-α Ab suppressed the incidence and volume of benign tumors but not carcinomas. DMBA mediated a substantial increase in HMdU and 8-OHdG in mouse skin, levels of which declined over time but remained elevated after tumors appeared. It will be important to establish whether DMBA-induced oxidative DNA base damage is modulated by anti-IL-1α and/or anti- TNF-α Ab and whether these two Abs have comparable or different effects on that DNA base damage.
Upregulation of proinflammatory cytokines causes infiltration of phagocytic cells into the affected area. Circulating phagocytes are primed by IL-1α, whereas infiltrating cells may be further primed by TNF-α, which increases ROS production when those cells are activated by an appropriate stimulus. It is not yet known which of the DMBA metabolites is responsible for the start of this inflammatory process and whether the same or a different metabolite is needed for PMN activation. However, H2O2, HMdU, and 8- OHdG formation in DMBA-treated mouse skin attests to that activation. It appears then that immune responses to carcinogen treatment are very important in the determination of which pathway predominates and culminates in a preferential formation of benign and/or malignant tumors. Elevated levels of inflammatory cytokines have been found in many types of human cancer, including ovarian, lung, skin, and liver, as well as in many chronic inflammatory conditions, which are known cancer risk factors.
VI. FACTORS CONTRIBUTING TO CYTOKINE UPREGULATION
Upregulation of inflammatory cytokines' mRNAs requires binding of transcription factors, such as activator protein (AP)-1 and/or nuclear factor (NF)-κB, to the specific sites in the promoter or enhancer regions of the cytokine genes. Formation and activation of transcription factors required for cytokine upregulation depend on the redox status of the cell and its effect on those factors. Increased H2O2 production causes rapid phosphorylation of the inhibitor (IκB) and its dissociation from the NF-κB complex, which allows for NF-κB translocation from cytosol into the nucleus. Before binding to the appropriate consensus sequence giving a signal for the initiation of the transcription process, NF-κB must be reduced by the thioredoxin system, which itself depends on glutathione (GSH), a major cellular reductant in the nucleus. Often, more than one binding site is needed for the transcription to occur or more than one type of a transcription factor is required. AP-1, another transcription factor, is formed from c-fos and c-jun, two immediate early genes produced under conditions of oxidative stress. Interestingly, AP-1 binding also requires reduced sulfhydryl groups in the cysteine residues, which is accomplished under conditions of increased reductive power of GSH, NAD(P)H, and antioxidant enzymes. For this reason, the AP-1 pathway is often referred to as an antioxidant-regulated pathway. Interestingly, recent results show that the presence of oxidized bases at the recognition sequence can modulate binding of the transcription factors and, thus, interfere with gene expression, including those of cytokines. This is a very exciting area of investigation, which might show how oxidation of bases at specific sites of DNA could interfere directly with or enhance the carcinogenic process.
VII. OXIDIZED DNA BASES IN HUMAN CANCER
Elevated levels of oxidized purines were found in DNA isolated from human breast tumors, whereas increased levels of oxidized pyrimidines (HMdU) were present in white blood cell (WBC) DNA of women at high risk for breast cancer, as well as those diagnosed with breast cancer. Changes in the diet to lower the consumption of fat and increase that of fruits and vegetables caused a statistically significant decline in HMdU present in WBC DNA of the dieting high risk subjects. The formation of oxidized bases in the DNA of breast cancer patients is due to extensive oxidative stress that is evident in breast cancer patients, whose phagocytes produce more O2∙- and H2O2 than those of healthy controls (Ray et al.). At the same time, antioxidant enzymes superoxide dismutase (SOD) and GSH peroxidase are appreciably increased, whereas catalase is decreased. The high SOD content could rapidly dismutate O2∙- to H2O2, which cannot be completely degraded to water because of the decreased catalase activity. Thus, the accumulated H2O2 can migrate into other cells and their nuclei, where it generates ∙OH-like species in a site-specific manner that oxidize DNA bases. Results obtained by Gowen and colleagues further underscore the importance of oxidative DNA base damage to breast cancer. The authors discovered that the BRCA1 gene product is required for the transcription-coupled repair of oxidative DNA base damage. BRCA1 mutations confer susceptibility to human breast cancer, which provides strong evidence that oxidative DNA base damage contributes to breast cancer, at least in women carrying the mutated BRCA1 gene.
In comparison to healthy controls, autoantibodies (aAb) that recognize HMdU were increased in sera of women diagnosed with breast cancer, thus providing another proof of oxidative stress and a biologic response to the consequences of that stress in cancer. More importantly, sera of apparently healthy women, who 1 to 6 years after that blood donation, were diagnosed with breast, colon, or rectal cancers, and sera of those at high risk for cancer contained elevated anti-HMdU aAbs. Thus, the enhanced presence of oxidized bases (i.e., HMdU) in WBC DNA, anti- HMdU aAb in serum, and possibly other antioxidized DNA base aAb can potentially serve as biomarkers of susceptibility to cancer. These biomarkers may allow preventive measures to be undertaken before an overt malignancy develops and, therefore, may also serve as efficacy markers of cancer-preventive agents.
Studies of factors contributing to the carcinogenic process, especially those modulated by oxidative stress, are by necessity correlative in nature. However, a discovery of more specific inhibitors and an increased use of molecular biology techniques have started to yield more direct proof of the involvement of oxidative stress and oxidative DNA base damage in carcinogenesis. Oxidative stress is characterized by increased ROS production, decreased antioxidant defenses, and impaired DNA repair capacity. All are evident during chronic inflammation evoked by a variety of agents or health conditions, many of which are known risk factors for different types of cancer. In summary, there is ever increasing scientific evidence that changes occurring during chronic inflammation, which include increased expression of inflammatory cytokines and downregulation of protective cytokines leading to further exacerbation of oxidative stress, play a direct role in the process of carcinogenesis. Oxidative modification of DNA bases present at specific sites of tumor suppressor genes, such as p53, which plays a pivotal role in cell cycling and apoptosis, causes a decline in their expression. Oxidized bases are also capable of changing binding patterns of transcription factors, and thus affect gene expression of many genes, which can lead to the disregulation of genetic machinery responsible for normal cell functioning.
Support by NCI (CA37858), NIA (AG14587), and NIEHS (ES00260) is gratefully acknowledged.
New York University School of Medicine
CHEMICAL MUTAGENESIS AND CARCINOGENESIS ; HORMONAL CARCINOGENESIS ; HYPOXIA AND DRUG RESISTANCE ; TOBACCO CARCINOGENESIS
autoantibodies Antibodies recognizing antigen present in the same organism.
bioavailable Form that is not sequestered and is available for biochemical or chemical reactions within cells.
complete carcinogen A carcinogen that causes cell initiation and promotes cell transformation and growth to benign tumors, as well as mediates progression to malignancy.
chemokines Agents that even in minute amounts cause directed migration of cells.
cytokines Proteins produced by cells in response to inflammatory stimuli that affect the same or other cells in their growth, activation, priming, and death. Cytokines are an important part of the intercellular communication network.
growth factors Low molecular weight substances produced by cells that induce growth of the same (autocrine response) or other (paracrine response) cells.
inflammation A very complex process that is initiated by a release of cytokines and chemokines leading to the infiltration of phagocytic cells. Upon stimulation, phagocytes generate copious amounts of reactive oxygen and nitrogen species, proteases, as well as other enzymes and proteins. It can be manifested by fever, edema, hyperplasia, phagocytic infiltration, and oxidative stress.
oxidative stress Excessive production of and/or impaired removal of oxidants with a concomitant decrease in reducing capacity of cells.
oxidative modification of DNA bases Direct oxidation is characterized by a decrease in electron density. Such a modification can occur by oxidation of a double bond in a normal DNA base, of a methyl group, or by the addition of oxygen to a free pair of electrons. Indirect oxidative modification occurs when another molecule or macromolecule is oxidized and the product or by-product of that oxidation binds to DNA.
reactive oxygen species (ROS) and reactive nitrogen species (RNS) These are important players in normal physiology and signal transduction. They also participate in a plethora of damaging reactions, which lead to the disregulation of normal cell controls, thus contributing to various pathologies, including cancer.
transcription factors Factors needed for the transcription of genes into mRNA by binding to the specific recognition sequences in the promoter or enhancer regions of DNA.
tumor promoters Agents that support the development of initiated cells into transformed cells and tumors.
tumor suppressor genes Genes that prevent cell transformation and growth of tumors. Mutation of such genes usually abrogates their normal functioning and facilitates tumor development.
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