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Introduction

Esophageal cancer is the eighth most common cancer in the world and ranks sixth as a cause of cancer mortality.1 , 2 An estimated 482,300 new esophageal cancer cases and 406,800 deaths occurred worldwide in 2008. Esophageal cancer usually occurs as either esophageal squamous cell carcinoma (ESCC) in the middle or upper one-third of the esophagus or as esophageal adenocarcinoma (EAC) in the lower one-third or at the junction of the esophagus and stomach.1 , 2 ESCC is the predominant type of esophageal malignancy in the world, although adenocarcinomas are more prevalent in the USA and other western countries.3 , 4 Worldwide, more than 90% of esophageal cancers are ESCC.5 ESCC develops through a progressive sequence from mild to severe dysplasia, carcinoma in situ, and finally invasive cancer5 – 7 (Fig. 4.1). The principal precursor of ESCC is epithelial dysplasia, characterized by accumulation of atypical cells with nuclear hyperchromasia, abnormally clumped chromatin, and loss of polarity.6 , 7 Because most esophageal cancer patients have advanced metastatic cancers at the time of diagnosis, only 1 in 5 esophageal cancer patients survive more than 3 years after initial diagnosis.8 , 9

Fig. 4.1
figure 00041

Progression of normal esophageal squamous mucosa to high-grade squamous dysplasia and invasive squamous cell carcinoma (Hematoxylin and Eosin stains). In normal squamous epithelium, the cells mature towards the surface where squamous cells show abundant cytoplasm and small nuclei. In high-grade squamous dysplasia, the epithelial cells show atypical features with increased nuclear to cytoplasmic ratios and loss of the normal maturation pattern towards the surface. However, the epithelial cells remain contained within the epithelial basement membrane. Invasive squamous cell carcinomas are characterized by irregularly shaped islands of tumor cells with increased cytologic atypia and invading into the adjacent tissues. Photomicrograph courtesy of Dr. Antonia Sepulveda

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Epidemiology of Esophageal Squamous Cell Carcinoma

The incidence of ESCC shows marked variation in its geographic distribution with the highest rates found in southern and eastern Africa and eastern Asia and the lowest rates observed in western and middle Africa and Central America.2 , 5 , 10 – 13 The highest risk area, stretching from northern Iran through the central Asian republics to North-Central China is often referred to as the “esophageal cancer belt”.14 , 15 Areas located in the southern parts of the Taihang mountains on the borders of Henan, Shansi, and Hopei provinces have amongst the highest incidence and mortality rates for ESCC worldwide.16 The major risk factors for ESCC within these regions are not well understood, but are thought to include poor nutritional status and drinking beverages at higher temperatures.17 – 19 In the USA and other developed countries, smoking and excessive alcohol consumption are responsible for approximately 90% of ESCC.3 Obesity and chronic gastro-esophageal reflux disease (GERD), which triggers Barrett’s esophagus, are thought to be the risk factors for EAC but not ESCC in the USA and other Western countries.3 , 4

Risk Factors

Many factors have been investigated in relation to esophageal squamous cell carcinoma. These factors include habits (consumption of alcohol and tobacco), nutritional deficiencies (low intake of fresh fruits and vegetables), infections (H. pylori, HPV), predisposing conditions (achalasia, tylosis, poor oral health) and low socioeconomic status (Table 4.1).

Table 4.1 Risk factors for esophageal squamous cell carcinoma
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Habits

Tobacco Smoke

Cigarette smoke is a contributing factor in the development of several cancers including ESCC.15 , 20 – 24 Numerous studies indicate a 3–6-fold increase in the risk of ESCC among current smokers.25 – 29 Smoking cigars or pipes confers a risk similar to cigarette smoke.25 Chewing betel quid, which often includes tobacco, a common practice in south and south-east Asia, can also cause ESCC as determined by the International Agency for Research on Cancer (IARC).30 Cigarette smoke contains more than 2,550 known compounds; greater than 60 have been evaluated by the IARC to be carcinogenic to humans and/or experimental animals.15 , 20 – 24 , 31 – 34 Among these carcinogens, exposure to polyaromatic hydrocarbons (PAHs) such as benzo-a-pyrene and N-nitrosamine are ­considered to be the most significant.33 , 34 A strong association between a variety of smoking-induced cancers and these carcinogens exists.35 The mechanisms underlying their roles in carcinogenesis are believed to be induction of DNA adducts, gene methylation and mutation, and chromosomal translocation in target organs.20 , 22 , 36

Benzo-a-pyrene undergoes metabolic transformation to electrophilic intermediates like benzo-a-pyrene diol epoxide (BPDE) that react with cellular macromolecules forming DNA adducts (carcinogen metabolites covalently bound to DNA usually at guanine or adenosine residues).20 , 37 , 38 Several studies indicate a permanent mutation in the DNA if DNA adducts escape cellular repair mechanisms.20 , 38 , 39 Cells with damaged DNA may be removed by apoptosis.40 If a permanent mutation occurs in a critical region, an oncogene may be activated or a tumor suppressor gene deactivated, leading to aberrant cells with loss of normal growth control and migration ultimately leading to cancer.20 , 38 , 39 Several studies have reported a direct association between benzo-a-pyrene exposure and mutations in the K-RAS and p53 genes.41 , 42 The major adduct of benzo-a-pyrene produces a G-to-T transversion43; the frequency of this transversion is significantly higher in smokers than nonsmokers.35 Methylated CpG dinucleotides are the preferred sites for G-to-T transversion and the striking sequence specificity of BPDE for producing G-to-T transversion at methylated CpG sequences is similar to the distribution of G-to-T transversion hotspots in cancer patients.35 , 41 , 44

Alcohol Consumption

Like tobacco use, alcohol consumption is a major risk factor for esophageal squamous cell carcinoma.21 , 23 Chronic and excessive consumption of alcohol can impair the body’s biochemical metabolism and alter gene expression in target tissues.45 When used in excessive amounts (3 or more drinks per day), alcohol has almost universally been associated with an elevated risk of ESCC.27 , 46 – 48 While there appears to be no association between alcohol intake and ESCC risk at levels below 170 g/week,49 above this threshold, a 3% increase in ESCC risk is observed for each additional 10 g/week of alcohol intake. In the human body, ethanol is metabolized by alcohol dehydrogenase resulting in the generation of acetaldehyde which is further metabolized to acetate by aldehyde dehydrogenase. Acetaldehyde is toxic and carcinogenic, inducing gene mutations and inhibiting retinoic acid biosynthesis.45 , 50 , 51 In turn, reduced retinoic acid levels in the cells alter gene expression leading to reduced RAR-β2 (retinoic acid receptor) expression and increased expression of EGFR, Erk 1/2, AP-1, COX-2.52 , 53

The joint effect of tobacco smoking and alcohol consumption on ESCC is synergistic rather than additive.54 – 57 Active smoking plus ethanol challenge results in a sevenfold higher level of salivary acetaldehyde than that in nonsmokers.58 A classic animal experiment revealed that alcohol acted as a solvent to increase the transportation of benzo-a-pyrene to the esophageal mucosa.59

Predisposing Conditions

Achalasia

Achalasia is a motility disorder of the esophagus characterized by aperistalsis in the distal esophagus from loss of LES (lower esophageal sphincter) relaxation. This condition leads to stasis in the esophagus, resulting in increased fermentation of food and a higher risk for esophageal cancer.60 ESCC is found in 3–7% of achalasia patients,61 a rate significantly higher than rates in the normal population.62 – 65 For example, a long-term study from Sweden shows a tenfold increased risk of both ESCC and EAC in achalasia patients when compared to the rest of the population.65

Tylosis

Tylosis, a rare autosomal dominant disease characterized by hyperkeratosis of the squamous epithelia of the esophagus, palms of the hand, and soles of the feet, is associated with ESCC.66 The early dermatologic manifestation usually begins between 7 and 8 years of age, and approximately 50% of patients will develop ESCC by the age of 45 and 95% by the age of 65.67 , 68 Two types of tylosis have been identified: late-onset (type A) tylosis that is associated with high incidence of ESCC; and early-onset (type B) tylosis, which appears to be benign.69 Using linkage analysis, the tylosis-esophageal cancer gene locus has been mapped to 17q25.70

Infectious Agents

Helicobacter pylori

H. pylori infection is a known cause of gastric adenocarcinoma and is associated with EAC.4 However, no consistent association is observed between H. pylori and ESCC. Some studies have reported a twofold increased risk of ESCC with colonization of H. pylori in the stomach, while others have found no association or even reduced risk with H. pylori colonization.71 , 72

Human Papilloma Virus

Human papilloma virus (HPV) plays an important role in the etiology of epithelial cancers of the cervix, vulva, anus, penis, and oropharyngeal cavity.73 , 74 However, despite numerous studies, the role of HPV in the etiology of ESCC remains controversial.73 While many studies have found no evidence of HPV in esophageal tumors,75 – 81 others have found HPV in up to 75% of cancers.82 The inconsistency of these results could be differences in the study design, geographic variation, or lack of appropriate adjustment for tobacco use and alcohol consumption. Because of these conflicting results, the IARC concluded that “there is inadequate evidence in humans for carcinogenicity of HPV in the esophagus”.73

Other

Low Intake of Fruits and Vegetables

A low intake of fruits and vegetables has long been considered a possible risk factor for ESCC, and a majority of studies conducted worldwide have found inverse associations between intake of fruits (especially citrus fruits) and the risk of developing esophageal cancer. Recently new cohort studies, carried out in Europe and the USA, have provided additional support for a protective association of both fruit and vegetable intake with esophageal cancer.83 – 85 By analyzing the evidence from various studies, the World Cancer Research Fund–American Institute for Cancer Research (WCRF–AICR) concluded that the high intake of fruits and vegetables probably decreases esophageal cancer risk by approximately 20% per 50 g of fruit or vegetable intake per day.86 , 87

Dietary Zinc Deficiency

Dietary zinc deficiency is typically found in those who consume relatively little meat and large quantities of whole grain.88 This dietary pattern is seen in regions with high rates of ESCC, such as Linzhou, China, which has one of the highest rates in the world with more than 100 cases per 100,000 people annually.89 Studies of endoscopic biopsy samples demonstrate an inverse relationship between esophageal tissue zinc concentration and ESCC.90

Molecular Alterations in Esophageal Squamous Cell Carcinoma

Numerous molecular alterations are associated with the development of ESCC such as altered expression of p53, p16, cyclin D1, EGFR, E-cadherin, p27, p21, and others.5 , 36 , 91 – 95 These changes in gene expression are often correlated with known risk factors in esophageal cancer. In this section, we discuss common genetic and epigenetic alterations in ESCC (see Table 4.2) and their role in the development of ESCC in more detail.

Table 4.2 Molecular alterations prevalent in esophageal squamous cell carcinoma
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p53

The tumor suppressor p53 maintains genetic stability and DNA repair capacity.96 , 97 p53 promotes cell cycle arrest through induction of p21 WAF1 98 and induces apoptosis by downregulating bcl-2 and upregulating Bax. 99 , 100 Wild-type p53 protein plays a crucial role in cell proliferation by arresting the cell cycle in G1 phase, regulating apoptosis, and suppressing angiogenesis.101 However, the function of p53 is lost through mutations, as well as by other factors, including overexpression of MDM2 (murine double minute gene 2), which results in increased degradation of p53 or inactivation of p14ARF, leading to inhibition of cell cycle arrest, DNA repair, and apoptosis.102 p53 gene mutations, frequently as point mutations, have been reported in over half of all human cancers96 and appear to occur at an early stage during esophageal squamous cell carcinogenesis and correlate with tumor progression.101 , 103 , 104 The reported frequency of p53 gene mutation in esophageal cancer varies widely from 17% to 84%,105 – 113 perhaps due to differences in the analytical methods that have been used.31 , 101 Dietary carcinogens and habits such as alcohol and tobacco appear to promote p53 mutations in ESCC, particularly in studies of high risk areas such as China, Southern Brazil, and Taiwan.96 , 101 , 108 , 114 , 115 The mutational spectrum of p53 in esophageal and lung cancers is consistent with the mutation pattern induced by certain polyaromatic hydrocarbons such as benzo-a-pyrene in cigarette smoke.35 , 44 , 116 For example, 40–50% of p53 gene mutations in Japanese individuals with ESCC are G-to-T transversions, a phenomenon associated with DNA adduct formation by benzo-a-pyrene.101 , 117 Among 48 p53 mutations identified in surgically resected ESCC in Japan between 1995 and 2005 (Table 4.3), transversions are found in 24 (50%), followed by transitions in 14 (29.2%), and frameshifts in 10 (20.8%); similar results are seen in additional studies from China.108 , 113 Taken together, these data suggest that p53 mutation, perhaps as a result of environmental factors, plays a critical role in the multistep process of ESCC.

Table 4.3 The mutation spectrum of p53 in ESCC in Japan (adapted from Egashira et al101)
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p16

p16, a tumor suppressor gene located at chromosome 9p21, inhibits the cyclin-dependent kinases Cdk 4 and 6 that bind to cyclin D1 and downregulate the pRb pathway, thereby blocking cell cycle progression from G1 to S phase.118 Inactivation of p16 in human cancers is a frequent event and is associated with homozygous deletion, genetic mutation, or aberrant DNA methylation.119 – 121 Loss of the p16 gene and decreased protein expression occur in the early stage of esophageal carcinogenesis, either by promoter methylation or loss of heterozygosity.5 , 36 , 122 Interestingly, p16 promoter hypermethylation seems to occur more frequently in heavy drinkers and smokers.123 While the impact of p16 on patient prognosis is unclear, loss of p16 expression could result in poor pro­gnosis by inactivation of pRb,124 and hypermethylation of CpG islands on p16 may then be a useful biological marker.

cyclin D1

Cyclin D1 is the protein product of the CCND1 gene located on chromosome 11q13 and controls cell cycle progression through the G1–S checkpoint.125 Cyclin D1 enhances esophageal squamous cell transformation,126 and overexpression of cyclin D1 is a common feature of esophageal carcinogenesis, including dysplasia and early cancers, with 23–73% of human ESCC tumor samples exhibiting overexpression of cyclin D1.127 – 132 Increased levels of cyclin D1 result from amplification at 11q13, which is observed in several cancers including ESCC.127 – 131 , 133 , 134 Cyclin D1 overexpression and gene amplification appear to predict poor prognosis in human ESCC patients.124 , 131 , 135 – 137 A causal relationship between carcinogens found in tobacco smoke and upregulation of cyclin D1 has been reported in both lung cancer and ESCC,132 and cigarette smoke extract stimulates cell proliferation and upregulates cyclin D1 expression in various human ESCC cell lines.138

EGFR

Epidermal derived growth factor (EGFR), a tyrosine kinase receptor, plays an important role in regulating cell growth and tumorigenesis. Binding of ligands such as epidermal growth factor (EGF) to EGFR triggers a cascade of phosphorylation events in the cytoplasm leading to the activation of downstream targets such as MAPK (mitogen-activated protein kinase) and AP-1 (activator protein 1), nuclear translocation of ERK1/2, and expression of genes like JUN, FOS, and COX2. 139 The net effect is generally induction of cell proliferation, and upregulation of EGFR has been reported in premalignant lesions and ESCC.5 , 36 , 91 , 94 , 95 Amplification of EGFR is a major mechanism of upregulation and is correlated with the depth of invasion of the tumor, lymph node metastases, and unfavorable prognosis.140 , 141 Mutations in EGFR exist but are rare.142

MAPK Signaling

Mitogen-activated protein kinases (MAPK) are crucial ­components of signaling cascades that regulate numerous physiological processes in normal tissues and during pathogenesis.143 There are three major subfamilies of MAPK, the classical extracellular signal-regulated kinases (ERK) and two types of stress-activated MAPK, the c-Jun N-terminal or stress-activated protein kinases (JNK/SAPK) and p38/MAPK14.144 , 145 The classical MAPK pathway involves a catalytic series of events triggered by RAS and RAF activation and is important for cell proliferation.146 Many cancer-associated mutations are found in RAS and the serine–threonine kinase BRAF, 147 , 148 and activation of the ERK–MAPK pathway is involved in the progression of various cancers.149 Mutations in KRAS have been reported in various tumors including colon and lung cancers,150 with approximately 50% of colon cancers containing KRAS mutations.151 Moreover, mutation of KRAS is an early event in tumor development.152 Mutations in BRAF are associated with increased kinase activity and may result in constitutive KRAS and ERK activation.153 MAPK is a key downstream mediator of EGFR activation in ESCC,154 and pharmacologic inhibition of MAPK signaling results in decreased cell proliferation.154 , 155

TGF-β Signaling

Transforming growth factor (TGF-β; TGFB) is a multipotent cytokine that plays an important role in the regulation of apoptosis, differentiation, and cell growth.156 TGFB is typically anti-inflammatory with a suppressive effect on carcinogenesis under normal conditions. However, many cancers originate from uncontrolled cell growth and differentiation through dysregulation of TGFB signaling.156 Resistance to TGFB-induced growth inhibition is found in many tumor cells,157 and, once cellular transformation has occurred, TGFB may promote tumor invasion and metastasis and inhibit immune surveillance.158 Altered expression of the TGFB mediators SMAD2 and SMAD4 is correlated with tumor progression and poor prognosis in ESCC,159 – 162 and, in patients with ESCC, high expression of SMURF2 (a ubiquitin ligase targeting SMAD7163) is correlated with ESCC development and poor prognosis.161

Retinoic acid and Retinoic Acid Receptors

Retinoids, a group of synthetic vitamin A analogs, can modulate cell growth and differentiation by binding to specific nuclear retinoioic acid receptors (RAR), members of the steroid hormone receptor superfamily.164 RAR are ligand-activated DNA-binding proteins that modulate gene transcription and are divided into 3 subtypes, α, β, and γ.165 Retinoic acid (RA) is growth inhibitory in ESCC cells, and RAR-β is lost early and progressively during esophageal squamous cell carcinogenesis.53 , 166 – 170 Thus many esophageal, lung, and breast cancer cell lines that do not express RAR-β are resistant to retinoid treatment,53 and restoration of RAR-β2 suppresses ESCC growth, induces apoptosis, and inhibits tumor formation.52 , 139 , 171 In addition, RAR-β 2 is methylated in human cancers, leading to the suggestion that it functions as a tumor suppressor.53 However, the function of RAR-β is complex, since reduced RAR-β 2 expression correlates with increased RAR-β 4 expression in ESCC,172 and induction of RAR-β 4 enhances growth of cancer cells that do not express RAR-β 2. 173 While the molecular mechanisms of antitumor effects by RA in ESCC are not fully understood, restored sensitivity to RA is associated with suppression of EGFR, ERK1/2, AP-1, and COX-2. 139 Interestingly, the induction of cytochrome CYP2E1 by ethanol enhances the degradation of RA which in turn increases the expression of EGFR, ERK1/2, AP-1, and COX-2. 53

Wnt/β-Catenin Signaling

Wnt/β-catenin signaling plays an important role in normal development and stem cell maintenance, whereas its aberrant upregulation is involved in tumorigenesis.174 In the absence of the Wnt ligand, a large multicomponent complex that includes adenomatous polyposis coli protein (APC), axin, casein kinase 1 (CK1), and glycogen synthase kinase 3β (GSK3β) facilitates the degradation of β-catenin, while binding of Wnt ligand leads to the accumulation of free β-catenin in the cytoplasm, its nuclear translocation, and transcriptional activation of target genes.175 , 176 Overexpression of Wnt ligands, mutations in APC, and/or stabilizing β-catenin mutations are commonly associated with constitutively upregulated Wnt signaling and tumor development.177 , 178 While studies of Wnt/β-catenin signaling in ESCC are limited, reduced expression of Axin is seen in 47% of ESCC tumor specimens and correlates with tumor progression.179 Moreover, Wnt/β-catenin signaling may be activated in ESCC,180 and alterations in β-catenin expression have been identified in ESCC.181 – 183

Cadherins and Catenins

Cadherins are transmembrane glycoproteins that mediate adhesion at intercellular adherens junctions; the intracellular regions of cadherins bind to proteins called catenins.184 E-cadherin, found mainly in epithelial cells, acts as a mediator for intercellular adhesion, cell polarity, and tissue architecture maintenance,185 and altered expression and localization of E-cadherin is seen in ESCC, with loss or reduced expression in 43% of patients.186 Reduction and loss of E-cadherin expression by gene mutation, loss of heterozygosity, and promoter hypermethylation, interrupt intercellular adhesion and correlate with decreased tumor differentiation and increased infiltration and metastasis.182 , 183 , 187 , 188 Expression of α-catenin, γ-catenin, and p120-catenin is also dysregulated in human ESCC,183 , 186 and recently, loss of p120-catenin resulted in ESCC in mice, establishing p120 as a tumor suppressor in ESCC.189

Krüppel-Like Factors

Members of the Krüppel-like factor (KLF) family of transcription factors are critical regulators of cell proliferation and differentiation during development and tissue homeostasis, as well as in many disease states.190 , 191 KLF4, KLF5, and KLF6 have all been shown to have functional roles in proliferation, differentiation, and/or squamous cell carcinogenesis in the esophagus.192 – 198 In normal esophageal epithelia, KLF4 is expressed as cells differentiate, with highest levels in the suprabasal layers.199 , 200 KLF4 expression is downregulated in ESCC,201 and in ESCC cells, KLF4 promotes apoptosis and inhibits invasion and represses transcription of the survivin gene.194 Interestingly, microRNA-10b promotes migration and invasion in ESCC cells by directly downregulating KLF4. These findings suggest that KLF4 may function as a tumor suppressor in esophagus, as in stomach and colon.202 , 203 KLF5 is expressed predominantly in the proliferative compartments of gastrointestinal epithelia, including in the basal layer of the esophagus.193 , 204 , 205 KLF5 promotes proliferation and migration in nontransformed esophageal keratinocytes,193 , 195 , 196 but in ESCC cells, KLF5 inhibits proliferation and invasion and promotes apoptosis.194 KLF6, which unlike KLF4 and KLF5 is ubiquitously expressed, coactivates the differentiation marker keratin 4 with KLF4 in esophageal epithelial cells.192

microRNAs

microRNAs (miRNAs) are small endogenous, noncoding RNAs which regulate protein expression by repressing gene translation or degrading target mRNAs.206 , 207 microRNAs function as both oncogenes or tumor suppressor genes and are involved in a wide variety of biological and pathological processes including cell differentiation, proliferation, apoptosis, and metabolism.208 Aberrant miRNA levels, specifically an overall downregulation, are observed in many cancers, including ESCC,209 and the miRNA expression profile of ESCC is distinct from that of EAC. For example, miR-194, miR-192, and miR-200 are significantly upregulated in EAC but not in ESCC,210 while miR-342 is aberrantly expressed in ESCC but not EAC.211 High expression of miR-103, miR-107, and miR-129 in patients with ESCC is associated with poor survival,210 , 212 while low expression of miR-21 in ESCC patients correlates with a worse prognosis and poor survival rate.213 In addition, expression of RNASEN, which encodes a key miRNA processing enzyme, correlates with poor prognosis of ESCC.214 The recent discovery of tumor-derived circulating miRNAs suggests the potential utility for miRNAs as biomarkers or prognostic markers for ESCC.215 , 216

Animal Models to Study ESCC

Animal models are invaluable to understand the molecular pathogenesis of ESCC, from normal to dysplastic states and ultimately cancer. ESCC has been modeled in mice and rats by treatment with N-nitroso compounds, such as N-nitrosomethylbenzylamine (NMBA), or a zinc-deficient diet; in these models, the presence of p53 deficiency or cyclin D1 overexpression enhances esophageal squamous cell carcinogenesis.217 – 222 The quinoline derivative 4-nitroquinoline-1-oxide (4-NQO) also causes premalignant and malignant squamous lesions of the oral cavity and esophagus, which are increased by cyclin D1 overexpression.223 , 224 Recently, several genetic animal models of ESCC have emerged that recapitulate the human disease process without addition of carcinogen.189 , 197 , 198 , 225 Cyclin D1 overexpression in mice produces squamous cell dysplasia of the tongue, esophagus, and forestomach,226 and in combination with loss of p53, null mice produces invasive oral and esophageal squamous cell cancer.225 Esophageal-specific deletion of KLF4 results in squamous cell dysplasia and delayed keratinocyte differentiation.198 Many risk factors for ESCC produce chronic irritation,5 , 227 and two recent mouse models, with KLF4 overexpression or p120-catenin deletion, yielded ESCC in the context of chronic inflammation, implicating microenvironment and, possibly, disruption of the esophageal epithelial barrier in the development of ESCC.189 , 197 In the case of KLF4 overexpression, inflammation appears to be mediated by IκB and NFKB activation.

Prevention of Esophageal Squamous Cell Carcinoma

The most obvious approach to the prevention of ESCC is through changes in lifestyle, especially avoiding alcohol and tobacco use, which are the predominant risk factors for ESCC in most parts of the world.5 , 228 Additional benefits may be realized by the elimination of high salt foods that may be contaminated with toxins and nitrosamines and the increased consumption of fruits and vegetables, especially in high risk areas for ESCC.16 Zinc supplementation also be considered, especially in populations at risk for dietary zinc deficiency,88 as it has been shown to reduce premalignant and malignant lesions in animal models229 , 230; however, the benefits of this zinc supplementation in humans are unclear.231

Chemoprevention may have particular relevance in areas of the world where exposure to carcinogens is high. An important component in the chemoprevention of ESCC is that of blocking the progression of premalignant lesions to malignant squamous cell carcinoma.232 Mechanistically, chemopreventive agents can be either “blocking” or “suppressing”.233 Blocking agents act at the initiation stage of carcinogenesis to influence the metabolism of carcinogens, thereby reducing damage to cellular DNA. Suppressing agents act during tumor promotion or progression to alter cellular processes such as proliferation, apoptosis, differentiation, and invasion.16 Dietary administration of ellagic acid, a naturally occurring polyphenol, or diallyl sulfide, a component of garlic, inhibits NMBA-mediated ESCC in rats by stimulating Phase II detoxifying enzymes.234 – 237 Curcumin, a polyphenol derived from the roots of Curcumin longa, inhibits both the initiation and postinitiation stages of NMBA-induced esophageal tumorigenesis by reducing cytochrome CYP2B1 in the rat esophagus to inhibit NMBA activation238 , 239; curcumin also inhibits protein kinase C, EGFR, and IκB.240 Isothiocyanates are an effective group of anti-initiating agents.241 , 242 Phenyl isothiocyanide (PEITC), found in many cruciferous vegetables like cauliflower, cabbage, Brussel sprouts, watercress, is a potent inhibitor of the metabolic activation of nitrosamine carcinogens and DNA methylation both in vitro and in vivo243; dietary administration of PEITC can completely inhibit NMBA-induced esophageal tumorigenesis in rats.244

Individuals who possess dysplastic lesions that can progress to ESCC are a major subject population for chemoprevention5 , 16; thus an effective chemopreventive agent for human ESCC should possess significant inhibitory activity when administered after tumor initiation. However, few single compounds have been found to effectively inhibit promotion and progression stages following NMBA-mediated tumorigenesis in rat esophagus. PEITC and EA are highly effective anti-initiation agents but have only a modest effect on esophageal tumorigenesis when administered postinitiation.245 , 246 Decaffeinated green tea and black tea are effective after tumor initiation by NMBA but only when given at very high concentrations.247 When given in the diet, the synthetic, selective iNOS inhibitor 1,4-phenylene-bis-(1,2-ethanediyl)bis-isothiourea (PBIT) and the COX2 selective inhibitor L-748706 reduce tumor incidence and multiplicity in the rat esophagus; L-748706 was effective only when it reduced PGE2 levels in preneoplastic esophageal tissues to levels found in normal esophagus.248 Both the COX2 inhibitor ­JTE-522 and the natural phenol resveratrol also inhibit tumor development in NMBA-treated rat esophagus by reducing PGE2 levels.249 , 250 CPT-11 (irinotecan hydrochloride), a potent anticancer drug for gastric and colorectal cancers, exhibits antiprogression effects by reducing cell proliferation rate in NMBA-exposed squamous epithelium and preneoplastic lesions.251 Finally, treatment of cyclin D1 overexpressing, p53-deficient mice with a nonsteroidal anti-inflammatory drug sulindac markedly decreased progression of esophageal lesions to severe dysplasia.225

Conclusions/Future Directions

Esophageal cancer remains an aggressive and lethal disease and, despite advances in surgical techniques, radiotherapy and chemotherapy, the 5-year survival rate for ESCC has not improved substantially in the past several decades.252 , 253 Several preventive approaches can be easily implemented, such as lifestyle changes (avoidance of tobacco and alcohol use) and improved nutrition (consumption of fresh fruits and vegetables, decreased intake of salty foods, and elimination of pickled vegetables). The advent of new animal models should aid in understanding the molecular mechanisms, pathogenesis, prevention, and treatment of ESCC. Still, there remains an urgent need to better define the signaling pathways dysregulated in ESCC and to discover novel biomarkers for malignant progression and patient prognosis. Identification of additional risk factors for ESCC will provide further insights into esophageal cancer development. With the use of effective molecular biomarkers, a more ­precise risk prediction will be available to detect early and curable lesions, and new targeted therapies may then be implemented to reduce the incidence and mortality of ESCC.