Environmental factors as regulators and effectors of multistep carcinogenesis

Toshinari Minamoto1, Masayoshi Mai1 and Ze'ev Ronai2

Ruttenberg Cancer Center, Mount Sinai School of Medicine, One Gustave L.Levy Place, Box 1130, New York, NY 10029, USA and
1 Cancer Research Institute Kanazawa University, Kanazawa, Japan


    Abstract
 Top
 Abstract
 Introduction
 Evidence that environmental...
 Mechanisms whereby evironmental...
 Bacterial infection
 Viral infections
 Endogenous contributing factors
 Epilogue: when environment...
 References
 
This review highlights current knowledge of environmental factors in carcinogenesis and their cellular targets. The hypothesis that environmental factors influence carcinogenesis is widely supported by both epidemiological and experimental studies. The fact that only a small fraction of cancers can be attributed to germline mutations in cancer-related genes further buttresses the importance of environmental factors in carcinogenesis. Furthermore, penetrance of germline mutations may be modified by either environmental or other genetic factors. Examples of environmental factors that have been associated with increased cancer risk in the human population include chemical and physical mutagens (e.g. cigarette smoke, heterocyclic amines, asbestos and UV irradiation), infection by certain viral or bacterial pathogens, and dietary non-genotoxic constituents (e.g. macro- and micronutrients). Among molecular targets of environmental influences on carcinogenesis are somatic mutation (genetic change) and aberrant DNA methylation (epigenetic change) at the genomic level and post-translational modifications at the protein level. At both levels, changes elicited affect either the stability or the activity of key regulatory proteins, including oncoproteins and tumor suppressor proteins. Together, via multiple genetic and epigenetic lesions, environmental factors modulate important changes in the pathway of cellular carcinogenesis.

Abbreviations: CREB, cyclic AMP response element binding protein; EGFR, epidermal growth factor receptor; HBV, hepatitis B virus; HCC, hepatocellular carcinoma; HCV, hepatitis C virus; HPV, human papilloma virus; IGFR, insulin-like growth factor receptor; MAPK, mitogen activated protein kinase; NO, nitric oxide; PKA, protein kinase A; PKC, protein kinase C; ROS, reactive oxygen species; TFIIH, transcription factor IIH; TPA, 12-O-tetradecanoylphorbol-13-acetate.


    Introduction
 Top
 Abstract
 Introduction
 Evidence that environmental...
 Mechanisms whereby evironmental...
 Bacterial infection
 Viral infections
 Endogenous contributing factors
 Epilogue: when environment...
 References
 
We will focus the discussion on three issues: (i) the evidence that events impinging on the organism from the outside foster, or protect against, carcinogenesis; (ii) mechanisms underlying environmental factors' abilities to exert their effects; and (iii) the contribution of endogenous factors to the impact of environmental factors.


    Evidence that environmental factors influence carcinogenesis
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 Abstract
 Introduction
 Evidence that environmental...
 Mechanisms whereby evironmental...
 Bacterial infection
 Viral infections
 Endogenous contributing factors
 Epilogue: when environment...
 References
 
A large body of compelling evidence either confirms or implicates various environmental factors in the development of a wide range of malignancies. Among the key factors are chemical and physical carcinogens, infectious agents and life-style. A long list of chemicals that occur in the environment has been implicated in tumor formation (reviewed in ref. 1). An increasing number of studies are documenting the ability of chemical mutagens to elicit changes at both the genomic and the protein level (discussed below).

Environmental factors known to play important roles in the etiology of human cancer include chemical carcinogens, such as those found in cigarette smoke, dietary contaminants, such as the mycotoxin aflatoxin B1, and physical carcinogens, such as UV irradiation, asbestos and radon. Other environmental factors include pathogenic bacteria and viruses, such as Helicobacter pylori, human papilloma virus (HPV), and human hepatitis B and C virus (HBV/HCV). Life-styles that ignore known risk factors, such as smoking, excess exposure to sunlight, fat consumption and stress are themselves integral environmental factors that contribute to cancer development. Conversely, life-style elements thought to reduce certain cancer risk include fiber ingestion, antioxidants and exercise.

Signature mutations
A signature mutation reflects the nature of adducts and DNA lesions formed by a specific mutagen, as confirmed for several chemical and physical mutagens (reviewed in refs 2–4). The comprehensive analysis of the p53 tumor suppressor gene has enabled the establishment of the existence of signature mutations. Classic examples for signature mutations are UV-related C->T and CC->TT conversion (5), G->T changes caused by dietary aflatoxin B1 exposure (6,7), G->T and G->C mutations associated with tobacco derived carcinogens (8,9) and the A->T and T->A alterations associated with vinyl chloride exposure (10). The identification of so-called signature mutations has provided evidence that links specific environmental factors with the mutation spectrum associated with the etiology of tumor development.

Epidemiological findings
Several lines of epidemiological evidence support the role of environmental factors in malignant disease. Non-genetic factors in cancer development have been implicated by epidemiological studies that have identified the differences in incidence and tumor type among different ethnic and geographical populations. Such studies have provided the foundation for investigating the role of environmental factors in tumor development (11,12).

Among the better-characterized examples are differences in frequency of certain types of cancer between Japanese and Western populations (1,1113). The rate of gastric cancer in Japan is as much as six times higher than in Western populations (13). Conversely, the incidence of breast cancer is three to four times lower and that of prostate cancer, seven times lower in Japan than in Western countries.

Notably, changes in environment may be associated with major shifts in cancer prevalence. Thus the incidence of gastric cancer decreased markedly among Japanese people who migrated to Western countries (11). The risk of breast cancer increases dramatically within only one generation upon moving to a higher-risk area, such as the USA (12,13). Such changes in tumor incidence within short time periods point to the contribution of environmental factors to tumor risk and tumor development.

Large databases based on extensive molecular analyses of tumors enable their comparison in different populations. Careful comparisons of cohorts within the same and among different populations reveal a diversity of mutational spectra. Recent analysis of the p53 gene in breast tumors in 11 populations from five regions of Japan and six regions of the USA did not reveal a distinct pattern of mutation within either Japanese or American populations (14). Such inter-group diversity within a given ethnic population points to a regional environmental effect. Alternatively, such diversity could result from exposure to a mixture of environmental mutagens (multiple exogenous factors), which does not permit identification of the primary mutagen, nor would it coincide with a given signature mutation (14). Comparison of p53 mutations in prostrate cancers of Japanese and Western populations have also led to identification of different mutation patterns, suggesting that different etiologic factors are involved (15).

In contrast, analyses of lung cancers among nine cohorts predominantly composed of smokers disclosed characteristic patterns among the diverse ethnic groups, suggesting that the response to mutagens in cigarette smoke overrides possible fluctuations in background mutation pattern within different ethnic groups (14).

Mutations in oncogenes have also been associated with environmental exposure. For example, the type of K-ras oncogene mutation has been widely associated with exposure to selective chemical and physical carcinogens (1618).


    Mechanisms whereby evironmental agents influence carcinogenesis and tumors
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 Abstract
 Introduction
 Evidence that environmental...
 Mechanisms whereby evironmental...
 Bacterial infection
 Viral infections
 Endogenous contributing factors
 Epilogue: when environment...
 References
 
Development
Generally, the degree to which environmental factors affect tumor formation reflects variation in susceptibility to environmental factors, which depends on the makeup of an individual's defense mechanism, including detoxification and DNA repair enzymes. Differences in one's susceptibility could be attributed to the pattern of DNA methylation and possible polymorphism within detoxification genes. Indeed, altered activity of detoxification, and deaminating enzymes has been associated with the formation of DNA adducts as well as with the degree of DNA methylation. Hypo/hypermethylation of genes because of improper deamination reactions results in altered pattern of gene expression, as has been demonstrated for key cellular regulatory proteins, p53 and p16.

Primary targets (i.e. effectors) for environmental factors include cellular regulatory proteins, which are essential for control of cell growth, DNA repair and programmed cell death. Long-term changes elicited in those proteins occur both at the genomic level, through somatic mutations that alter protein makeup and function, and at the epigenetic level, through aberrations that affect the DNA methylation pattern at CpG sites in the promoter region of certain genes, which, in turn, affect the level of mRNA and protein expression. Environmental factors are also known to transiently modify proteins by phosphorylation and acetylation, affecting their stability and activity. The short-term effect of environmental factors on protein activity is in many cases sufficient to change the cell's ability either to enable repair of damaged DNA or to elicit programmed cell death. Prolonged exposure to environmental factors can also mediate long-term effects on the functions of cellular regulatory proteins.

To address mechanisms underlying the effect of specific environmental factors on carcinogenesis, we divide these factors into the following major groups.

Chemical and physical carcinogens
In principle, carcinogens of these types are frequently capable of eliciting pleiotropic cellular changes at the genetic and epigenetic levels and can be divided into two groups: (i) DNA-damaging agents that induce formation of DNA adducts and subsequent mutations, known as somatic mutations; and (ii) those that alter cellular signal transduction pathways and result in changes in post-translational modifications that affect conformation and/or activities of key cellular regulatory proteins. Changes in the first group (i.e. somatic mutations) are permanent; whereas those in the second group (post-translational) changes are transient. The effects of environmental factors at the protein level also are transient as a result of the limited life-span of a given protein. Both types can alter control of cell growth or death. For example temporary changes can override normal defense mechanisms and result in the incorporation and possible accumulation of somatic mutations. Accordingly, transient changes may suffice to determine a cell's capacity to undergo neoplastic transformation.

Concurrent with the well-documented activities of environmental genotoxic agents at the genomic level is their effect on cell surface receptors and various signaling cascades. The formation of reactive oxygen species (ROS) result in altered cellular redox potential and lead to respective activation of protein kinases and subsequent changes in transcription factors (Table IGo; reviewed in refs 19–21). The putative mechanisms by which changes in redox potential alter protein kinases include the formation of disulfide bonds between selective cysteines on signal-transducing molecules, which results in protein dimerization; such a mechanism leads either to protein activation or to inactivation (reviewed in refs 20,21).


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Table I. Reactive oxygen species effect on protein kinases and transcription factors
 
ROS and redox potential can be considered the primary cytoplasmic changes that regulate protein kinases. The same kinases also can be activated by alterations within cell surface receptors. Cross-linking of receptors [e.g. epidermal growth factor receptor (EGFR), insulin-like growth factor receptor (IGFR)] (22,23) and subsequent trans-phosphorylation have been shown to occur in response to physical, chemical and cytokine stimuli.

A classic example of combined genetic and epigenetic changes is provided by the well-studied cellular response to UV irradiation, a potent etiologic agent in skin cancer development. While causing a signature mutation (5), post-translational modifications triggered by UV irradiation (2229) have also been documented in the membrane, cytosol and nuclear compartments (3033). In cellular plasma membrane, UV irradiation efficiently causes dimerization of receptors, as shown for IGFR and EGFR (22,23). In the nuclei, UV irradiation causes DNA lesions that lead to the formation of pyrimidine dimers and subsequent signature mutations, that coincide with activation of DNA-damage, related signaling cascades, as documented for c-jun N-terminal kinases (JNK) (34,35). Within the cytosol, UV irradiation has been implicated in the activation of various signaling cascades including protein kinase C (PKC) (36), mitogen activated protein kinase (MAPK) (37), and JNK (38) with changes in downstream effectors, as shown for transcription factors cyclic AMP-response element binding protein (CREB) (39), jun (40), fos (41), p53 (42) and NF{kappa}B (43).

Among the better-characterized stress kinases as per UV response is JNK. Activation of this stress kinase has been shown to occur within minutes of UV irradiation, and to last from 30 min to 24 h depending on the type (i.e. UVB, UVC) and dose (i.e. amount and dose rate) of irradiation (44). JNK activation by UV irradiation occurs as a result of JNK phosphorylation by its upstream kinases concurrent with inactivation of redox-sensitive JNK inhibitor (45). Activated JNK phosphorylate key regulatory transcription factors including c-jun, ATF2 and p53 (4649). Such phosphorylation contributes to the activity and stability of JNK-associated proteins, which under non-stressed growth conditions are targeted by JNK for ubiquitination and subsequent degradation (5052). It is the duration and magnitude of activity of stress-activated kinases and respective transcription factors that dictates whether the damaged cell will undergo growth arrest or apoptosis (53).

Dietary factors
An extensive and well-established database has been compiled that documents the relationship between micronutrients (vitamins, folic acid, beta carotene, calcium, selenium, isothiocyanates, dithiolthiones, indoles, phenols, protease inhibitors, plant sterols, limonene and phytoestrogens) and macronutrients (total energy, fiber, fat, protein, sodium chloride) and cancer risk (reviewed in 54–58). In general, dietary components relevant to cancer can be divided into three major categories: (i) dietary constituents that are carcinogenic including aflatoxins, heterocyclic amines, N-nitroso compounds, polycyclic aromatic hydrocarbons and trihalomethane (5961); (ii) dietary factors that promote tumor development (tumor promoters) including diverse chemical classes, such as phorbol ester derivatives, non-TPA type tumor promoters (62), chlorinated hydrocarbons (from industrial or agricultural sources), alcohol and salt (sodium chloride). Investigations of dietary effects on experimental tumor promotion (e.g. skin, breast, colon, liver) indicate that increased ingestion of fats and/or calories markedly enhances tumor promotion in most tissues examined (5863); and (iii) dietary components can also improve cellular defense mechanisms. For example, many bioactive compounds found in plants increase expression/induction of crucial detoxification enzymes, particularly glutathione synthetase, glutathione transferase and glucuonyl transferase, resulting in decreased bioavailability of potentially DNA-damaging carcinogens (6471). Table IIGo summarizes the effects of dietary factors according to their cellular targets.


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Table II. Effect of dietary factors on key cellular targets
 
It is only in recent years that the possible underlying mechanism for the effect of dietary components on tumor inhibition has begun to be better characterized. Dietary components mediate diverse effects on tumor development, including cell surface receptors, detoxification enzymes and various signaling cascades; these are summarized in Table IIGo.


    Bacterial infection
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 Abstract
 Introduction
 Evidence that environmental...
 Mechanisms whereby evironmental...
 Bacterial infection
 Viral infections
 Endogenous contributing factors
 Epilogue: when environment...
 References
 
Helicobacter pylori and gastric cancer
Accumulating epidemiological and clinical data have identified Helicobacter pylori as a risk factor for gastric carcinogenesis (72,73). Helicobacter pylori infection is more prevalent in Asian populations than in Western populations, particularly in Japan and Korea where gastric cancer is the most frequently occurring malignancy. H.pylori infection could be a factor linking the etiologic sequence between salty food intake in Asian populations and development of gastric cancer (74).

From an etiologic standpoint, early acquisition of and long-term infection with H.pylori increase the risk of developing gastric cancer (72). The virulence of H.pylori is determined by its genotypes, particularly the cytotoxin-associated gene A (cagA), which encodes a high molecular weight immunodominant antigen, and vacA (vacuolating cytotoxin A). The carcinogenic potential of Helicobacter pylori infection is also implicated in the endogenous synthesis of nitric oxide (NO) in macrophages by the induction of NO synthase (74).


    Viral infections
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 Evidence that environmental...
 Mechanisms whereby evironmental...
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HPV
Infection with HPV, particularly types 16 and 18 (among >65 types), has been shown to be associated with most forms of uterine and cervical cancer (75). To exert its transforming potential, HPV integrates its viral dsDNA into the host genome (76). Possible mechanisms by which HPV participates in the development of cancer have been shown to depend on the activity of the two viral oncoproteins encoded by the E6 and E7 genes. E6 and E7 form complexes with several cellular proteins involved in cell cycle and growth control (77,78). E6 binding to wild-type p53 promotes its degradation through the ubiquitination pathway (79,80) and abrogates its transcriptional activities (81).

E7 binds preferentially to unphosphorylated Rb, participates in cell growth regulation, and disrupts or alters cellular complexes that form between Rb and transcription factors E2F or myc (78). Importantly, continuous expression of HPV oncoproteins is required for inactivation of these tumor suppressor proteins (79).

The interaction between HPV genes and transcription factors, including AP1, NF1, Oct-1, Sp1, GRE and YY1, has been widely documented (reviewed in ref. 80). Molecular mechanisms that underlie E6 and E7 activities also include other cellular regulatory pathways.

HPV infection by itself is not sufficient for development of cervical cancer. It is the combination of HPV infection and accumulated genomic alterations that drives malignant progression (81).

Hepatitis virus
Epidemiological and clinical studies have linked HCV infection to the development of hepatocellular carcinoma (HCC), particularly in endemic area such as Korea, Japan and China (82). HCV sequences were detected in most HCV-related HCCs. The direct contribution of HCV to HCC was recently reported via the ability of HCV core protein to induce HCC in transgenic mice (83). Other regions that confer oncogenic potential include the 5' end of the HCV genome, which encodes non-structural protein 3; this protein is capable of mediating cell transformation in vitro (84). Genetic variants of HCV are determined by the nucleotide sequence corresponding to the hypervariable regions of the putative envelope protein. Whereas some variants have been shown to replicate in both malignant and non-malignant tissues, others replicate only in HCC tissue (85). Indirect evidence indicates that HCV induces genomic instability and increases the incidence of in vivo somatic cell mutations (86). Several genomic alterations of tumor suppressor genes, including p53, have been found in human HCC (87).

The prevalence of persistent HBV infection has been strongly correlated with the prevalence of HCC (88). Integration of HBV sequences in the host DNA is crucial for HCC development (88). The HBV genome contains the HBx gene, which encodes a 154 amino acid transcriptional transactivator considered to have oncogenic potential (89). HBx contains domains that share homology/similarity with several kinases (90,91). Of interest, the HBx protein independently, activates Ras in the cytoplasm and transcription factors in the nucleus (92). The oncogenic potential of HBx has been confirmed through its ability to induce HCC in HBx transgenic mice (93). The mechanisms that have been associated with HBx oncogenic potential are summarized in Table IIIGo.


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Table III. Mechanisms underlying HBV protein: HBx oncogenic potential
 

    Endogenous contributing factors
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 Evidence that environmental...
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Germline mutations
Since they are fixed as part of the genetic makeup and thus obey rules of inheritance, germline mutations provide the foundation for a given person's predisposition to a certain cancer type. The extensive efforts to identify cancer genes via genetic and linkage analysis and the accumulating data from the human genome project have provided us with a fast growing list of genes that are mutated in the germline. So far, germline mutations in more than 20 different genes have been reported as hereditary traits increasing susceptibility to cancer. Among those are the tumor suppressor genes adenomatous polyposis coli (94,95) p53 (9698), BRCA1 (99) and BRCA2 (100,101). In individuals with a family history [familial breast cancer (102), Li Fraumeni syndrome (97)] or those who have second malignancies, germline mutations are often present.

Gene polymorphism
Part of the wide variation in individual responses to exogenous agents is believed to result from the great diversity in responsiveness to risk factors in the environment. These variations, known as polymorphism, are caused by sporadic mutations caused by both endogenous and exogenous processes. In most instances, such mutations result in minor changes in the nucleotide sequence of the coding region as well as 5' and 3' untranslated regions, which are sufficient to alter expression or stability at both the RNA and protein levels. Efforts to identify functional polymorphism have been aimed primarily at enzymes associated with redox regulation and detoxification, such as glutathione S-transferase (103,104) and cytochrome p450 isozymes (105107).

The recent development of high-throughput microchip-based PCR allows extensive analysis of polymorphic patterns in populations and comparisons between populations. It is expected that a wide range of polymorphism will be identified and point to different patterns in geographical ethnic groups.


    Epilogue: when environment-dependent and -independent changes converge
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 Epilogue: when environment...
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The `multi-hit' concept of carcinogenesis is becoming better understood as germline mutations, environmental factors and their cellular targets are identified. The interaction of any of these three major components can result in cancer (Figure 1Go).



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Fig. 1. When environmental-dependent and -independent changes converge.

 
Germline mutations play a key role in the relative risk of cancer predisposition, but for the most part, they are limited to those that meet the criteria of familial cases, a finding that allows better appreciation of the importance of changes influenced by environmental factors. An environmental factor's ability to cause cellular transformation hinges on an individual's genetic makeup, as on the activity of cellular defense protein (108). Polymorphism in metabolic activation and detoxification enzymes are believed to play important roles in the acquisition of susceptibility to environmental factors. It is further believed that genetic makeup, which differs among individuals, as reflected in the ability to cope with certain carcinogens, plays an important role in determining the susceptibility and development rate of the multistep carcinogenesis process. This view is well supported by findings regarding strain differences in animal model systems. Accordingly, the emerging concept is that the combined action of environmental factors and individual susceptibility determines an individual's likelihood of developing a tumor as well as its type and incidence.


    Acknowledgments
 
We thank Ernest Wynder for inspiring the write-up of this review, Takashi Sugimura for discussions, Minako Nagao for comments and advice throughout the preparation of this review and Curtis Harris for helpful suggestions. Support by FPCR is kindly acknowledged.


    Notes
 
2 To whom correspondence should be addressed Back


    References
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 Abstract
 Introduction
 Evidence that environmental...
 Mechanisms whereby evironmental...
 Bacterial infection
 Viral infections
 Endogenous contributing factors
 Epilogue: when environment...
 References
 

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Received July 28, 1998; revised November 23, 1998; accepted December 1, 1998.