Chemoprevention of esophageal squamous cell carcinoma

doi:10.1016/j.taap.2007.01.030

Toxicology and Applied Pharmacology

Volume 224, Issue 3, 1 November 2007, Pages 337-349

https://doi.org/10.1016/j.taap.2007.01.030 Get rights and content

Abstract

Esophageal squamous cell carcinoma (SCC) is responsible for approximately one-sixth of all cancer-related mortality worldwide. This malignancy has a multifactorial etiology involving several environmental, dietary and genetic factors. Since esophageal cancer has often metastasized at the time of diagnosis, current treatment modalities offer poor survival and cure rates. Chemoprevention offers a viable alternative that could well be effective against the disease. Clinical investigations have shown that primary chemoprevention of this disease is feasible if potent inhibitory agents are identified. The Fischer 344 (F-344) rat model of esophageal SCC has been used extensively to investigate the biology of the disease, and to identify chemopreventive agents that could be useful in human trials. Multiple compounds that inhibit tumor initiation by esophageal carcinogens have been identified using this model. These include several isothiocyanates, diallyl sulfide and polyphenolic compounds. These compounds influence the metabolic activation of esophageal carcinogens resulting in reduced genetic (DNA) damage. Recently, a few agents have been shown to inhibit the progression of preneoplastic lesions in the rat esophagus into tumors. These agents include inhibitors of inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2), vascular endothelial growth factor (VEGF) and c-Jun [a component of activator protein-1 (AP-1)]. Using a food-based approach to cancer prevention, we have shown that freeze-dried berry preparations inhibit both the initiation and promotion/progression stages of esophageal SCC in F-344 rats. These observations have led to a clinical trial in China to evaluate the ability of freeze-dried strawberries to influence the progression of esophageal dysplasia to SCC.

Introduction

Esophageal cancer in humans occurs worldwide with a variable geographic distribution and ranks sixth as a cause of cancer mortality (Parkin et al., 2001). There are two main types of esophageal cancer with distinct etiological and pathological characteristics, squamous cell carcinoma (SCC) and adenocarcina. Esophageal SCC is the predominant type of esophageal malignancy worldwide, although adenocarcinomas are more prevalent in the USA (Souza, 2002). Epithelial dysplasia, characterized by an accumulation of atypical cells with nuclear hyperchromasia, abnormally clumped chromatin and loss of polarity, is the principal precursor lesion of esophageal SCC (Krasna and Wolfer, 1996). Esophageal SCC develops through a progressive sequence from mild to severe dysplasia, carcinoma in situ and, finally, invasive carcinoma (Anani et al., 1991, Kuwano et al., 1993, Shu et al., 1981). The tumors present as fungating, ulcerating or infiltrating lesions in the esophageal epithelium. Most esophageal cancer patients present with advanced metastatic disease at the time of diagnosis (Layke and Lopez, 2006). This results in a poor prognosis; only 1 in 5 esophageal cancer patients survives more than 3 years after initial diagnosis (Polednak, 2003, Younes et al., 2002).

Section snippets

Epidemiology of esophageal SCC

The incidence of esophageal SCC shows marked variation in its geographic distribution and occurs at very high frequencies in certain parts of China, Iran, South Africa, Uruguay, France, Italy and Puerto Rico (Krasna and Wolfer, 1996, Rose, 1973, Schottenfeld, 1984, Sons, 1987, Stoner and Gupta, 2001, Yang, 1980). One-half of all esophageal SCC in the world occurs in China. Areas located in the southern parts of the Taihang mountains on the borders of Henan, Shansi and Hopei provinces have among

Etiology of esophageal SCC

There are several factors involved in the etiology of esophageal SCC (Stoner and Gupta, 2001). The excessive use of tobacco is a principal risk factor for this disease (Layke and Lopez, 2006). Several tobacco carcinogens, including certain nitrosamines, polycyclic aromatic hydrocarbons and aromatic amines, and toxins, including aldehydes and phenols, may be causally related to esophageal cancer (Hecht and Stoner, 1996, Tuyns, 1982, Wynder and Bross, 1961). Alcohol consumption has been shown to

Prevention of esophageal SCC

One approach to the prevention of esophageal SCC is through changes in lifestyle, especially the avoidance of alcohol and tobacco use. Additional benefits may be realized by the elimination of high salt foods that may be contaminated with microbial toxins, nitrosamines and their precursors. The increased consumption of vegetables and fruit throughout the world, and especially in the high-risk areas for esophageal SCC, might also be expected to reduce the incidence and mortality from the

Rat esophageal tumor model

Nitrosamine-induced tumorigenesis in the Fischer-344 rat has proven to be a valuable animal model for studies of the molecular biology and chemoprevention of esophageal SCC (Beer and Stoner, 1998, Hecht and Stoner, 1996, Stoner and Gupta, 2001). Several nitrosamines, including the food contaminant, N-nitrosomethylbenzylamine (NMBA), and the tobacco-specific nitrosamine, N-nitrosonornicotine (NNN), induce tumorigenesis in the rat esophagus (Fig. 1) (Stoner and Gupta, 2001). NMBA is by far the

Chemoprevention studies in rat esophagus

Mechanistically, chemopreventive agents have been classified as either “blocking” agents or “suppressing” agents (Wattenberg, 1985). Blocking agents act at the initiation stage of carcinogenesis through their influence on the metabolism of carcinogens leading, ultimately, to reduced damage to cellular DNA. Suppressing agents act on the promotion/progression stages of carcinogenesis by influencing cell proliferation rates, apoptosis, differentiation, angiogenesis, tissue invasion, etc. Several

Chemoprevention of human esophageal squamous cell carcinoma

An important component in chemoprevention of human esophageal SCC is that of blocking the progression of premalignant lesions, such as epithelial dysplasia, to malignant SCC (Wang et al., 2005). With the availability of endoscopic and cytological screening techniques, the identification and follow-up of esophageal dysplasia among high-risk populations have become possible. The use of “balloon cytology” coupled with endoscopy in China has proven useful in identifying individuals with

Conclusions

The 5-year survival rate for esophageal SCC has not improved substantially in the past several decades in spite of advances in surgical techniques, radiotherapy and chemotherapy. Prevention is clearly an important approach to reduce the incidence and mortality from this disease. Lifestyle changes, especially the avoidance of tobacco and alcohol use, and the elimination of high salt and moldy foods, would reduce the incidence and mortality from the disease. In addition, the increased consumption

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Concerns are raised over the risk to digestive system's tumors from the N-nitrosamines (NAs) exposure in drinking water. Albeit considerable studies are conducted to explore the underlying mechanism responsible for NAs-induced esophageal squamous cell carcinoma (ESCC), the exact molecular mechanisms remain largely unknown, especially at the epigenetic regulation level. In this study, it is revealed that the urinary concentration of N-Nitrosodiethylamine is higher in high incidence area of ESCC, and the lncRNA-UCA1(UCA1) is significantly decreased in ESCC tissues. In vitro and in vivo experiments further show that UCA1 is involved in the malignant transformation of Het-1A cells and precancerous lesions of the rat esophagus induced by N-nitrosomethylbenzylamine (NMBzA). Functional gain and loss experiments verify UCA1 can affect the proliferation, migration, and invasion of ESCC cells in vitro and in vivo. Mechanically, through binding to heterogeneous nuclear ribonucleoprotein F (hnRNP F) protein, UCA1 regulates alternative splicing of fibroblast growth factor receptor 2 (FGFR2), which promotes the FGFR2IIIb isoform switching to FGFR2 IIIc isoform, and the latter activates epithelial-mesenchymal transition via PI3K-AKT signaling pathways impacting tumorigenesis. Therefore, NAs-mediated downregulation of UCA1 promotes ESCC progression through targeting hnRNP F/FGFR2/PI3k-AKT axis, which provides a new chemical carcinogenic target and establishes a previously unknown mechanism for NAs-induced ESCC.
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Because of the difficulty in obtaining continuous tumorigenic specimens from human, addressing this issue would be highly dependent on animal models. Fortunately, it has been shown that NMBA can specifically induce tumorigenesis in the esophagus of rats in the same sequence as the progression of human ESCC (Stoner et al., 2007). Numerous abnormalities have been identified in the esophageal cancerization of rats induced by NMBA, such as the p53, cyclooxygenase 2 (COX2), vascular endothelial growth factor (VEGF) (Stoner et al., 2007), nuclear factor kappa B (NF-κB) (Cui et al., 2019), AMP-activated protein kinase (AMPK)/mammalian target of the rapamycin (mTOR) signaling pathway (Fan et al., 2019), and so on.
Esophageal squamous cell carcinoma (ESCC) is an environment-relevant malignancy with a high mortality. Nitrosamines, a class of nitrogen-containing environmental carcinogens, are widely suggested as a risk factor for ESCC. However, how nitrosamines affect metabolic regulation to promote ESCC tumorigenesis is largely unknown. In this study, the transition trajectory of serum metabolism in the course of ESCC induced by N-nitrosomethylbenzylamine (NMBA) in rats was depicted by an untargeted metabolomic analysis, and the potential molecular mechanisms were revealed. The results showed that the metabolic alteration in rats was slight at the basal cell hyperplasia (BCH) stage, while it became apparent when the esophageal lesion developed into dysplasia (DYS) or more serious conditions. Moreover, serum metabolism of severe dysplasia (S-DYS) showed more similar characteristics to that of carcinoma in situ (CIS) and invasive cancer (IC). Aberrant nicotinate (NA) and nicotinamide (NAM) metabolism, tryptophan (TRP) metabolism, and sphingolipid metabolism could be the key players favoring the malignant transformation of esophageal epithelium induced by NMBA. More particularly, NA and NAM metabolism in the precancerous stages and TRP metabolism in the cancerous stages were demonstrated to replenish NAD⁺ in different patterns. Furthermore, both the IDO1-KYN-AHR axis mediated by TRP metabolism and the SPHK1-S1P-S1PR1 axis by sphingolipid metabolism provided an impetus to create the pro-inflammatory yet immune-suppressive microenvironment to facilitate the esophageal tumorigenesis and progression. Together, these suggested that NMBA exerted its carcinogenicity via more than one pathway, which may act together to produce combination effects. Targeting these pathways may open up the possibility to attenuate NMBA-induced esophageal carcinogenesis. However, the interconnection between different metabolic pathways needs to be specified further. And the integrative and multi-level systematic research will be conducive to fully understanding the mechanisms of NMBA-induced ESCC.
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Epidemiological findings have reported that nitrosamines exposure can increase the risks of some gastrointestinal diseases (Fritschi et al., 2015; Gu et al., 2016; Zeng et al., 2015; Zhao et al., 2020). Toxicological assays have demonstrated that nitrosamines can induce tumorigenesis via multiple mechanisms, such as generating adducts, interfering DNA repair, altering epigenetic or genomic stability, activating receptor-mediated signaling, causing immunosuppression, and influencing cell proliferation (Fishbein et al., 2020; Gu et al., 2016; Stoner et al., 2007; Zeng et al., 2015). Traditional approaches, monitoring a small number of pre-designed targets, are often inadequate for fully assessing the hazardous effects of nitrosamines.
Nitrosamines, a group of emerging nitrogenous pollutants, are ubiquitously found in the drinking water system. However, less is known about how systemic biological responses resist or tolerate nitrosamines, especially long-term co-exposure at low concentrations. In this study, untargeted metabolomics was used to investigate the metabolic perturbations in human esophageal epithelial Het-1A cells induced by a mixture of nine common nitrosamines in drinking water at environmentally relevant, human-internal-exposure, and genotoxic concentrations. Generally, the disrupted metabolic spectrum became complicated with nitrosamines dose increasing. Notably, two inflammation-associated pathways, namely, cysteine (Cys) and methionine (MET) metabolism, and nicotinate and nicotinamide metabolism, changed significantly under the action of nitrosamines, even at the environmentally relevant level. Furthermore, targeted metabolomics and molecular biology indicators in cells were identified in mice synchronously. For one thing, the up-regulated Cys and MET metabolism provided methyl donors for histone methylation in the context of pro-inflammatory response. For another, the down-regulated NAD⁺/NADH ratio inhibited the deacetylation of NF-кB p65 and eventually activated the NF-кB signaling pathway. Taken collectively, the metabolomics molecular signatures were important indicative markers for nitrosamines-induced inflammation. The potential crosstalk between the inflammatory cascade and metabolic regulation also requires further studies. These findings suggest that more attention should be paid to long-term co-exposure at low concentrations in the control of nitrosamines pollution in drinking water. Additionally, this study also highlights a good prospect of the combined metabolomic-molecular biology approach in environmental toxicology.
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Among the suspected factors in the environment, N-nitrosamine compounds are a class of the most probable carcinogens concerned with EC. Carcinogenesis of nitrosamines mainly arises from their active electrophilic intermediates which lead to DNA alkylation damage (Stoner et al. 2007). Toxicological data have proven that nitrosamines can induce tumors in the esophagus of experimental animals along with a string of molecular events (Ushida et al. 2000; Stoner et al. 2007; Li et al. 2002).
Esophageal cancer (EC) is a deadly malignancy worldwide with a high incidence and exhibits unevenly geographic prevalence, which suggests that environmental factors are deeply involved in the development of EC. Although the carcinogenesis of nitrosamines in the esophagus has been identified by tremendous toxicological data, the role of nitrosamines in the genesis of human EC has so far proved inconclusive largely due to a lack of convincing evidences. In this study, urinary nitrosamines in population controls and cases with esophageal precancerous lesions, including reflux esophagitis (RE) accompanying with basal cell hyperplasia (BCH) and dysplasia (DYS), and esophageal squamous cell carcinoma (ESCC) were detected by a SPE-LC-MS/MS method and the associated risk was evaluated. Higher excretion concentrations of N-nitrosomethylethylamine (NMEA) in the RE/BCH patients, NMEA and N-nitrosodibutylamine (NDBA) in the DYS patients, and NMEA, NDBA, N-nitrosopyrrolidine (NPyr) and N-nitrosomorpholine (NMor) in the ESCC patients were observed compared with the controls (p < .05). And with the progression of esophageal lesion, the exposure complexity increased in terms of the categories of nitrosamines. Furthermore, the observed positive associations between the hazardous exposure of NMEA, NDBA and NPyr and the increased risk of ESCC, and between NMEA and NDBA and RE/BCH were established. These findings provided direct evidence to support the hypothesis that exposure to nitrosamines are involved in the carcinogenesis of esophageal epithelia in this high incidence area from the perspective of endogenous exposure assessment. However, discoveries in this study need to be confirmed by systematic researches in the future. And the dose-response relationships, the reference ranges or cutoff values to predict the risks of nitrosamines exposure also need to be defined.
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ReviewChemoprevention of esophageal squamous cell carcinoma

Abstract

Introduction

Section snippets

Epidemiology of esophageal SCC

Etiology of esophageal SCC

Prevention of esophageal SCC

Rat esophageal tumor model

Chemoprevention studies in rat esophagus

Chemoprevention of human esophageal squamous cell carcinoma

Conclusions

Loss of heterozygosity in multistage carcinogenesis of esophageal carcinoma at high-incidence area in Henan Province, China

World J. Gastroenterol.

An extensive morphological and comparative study of clinically early and obvious squamous cell carcinoma of the esophagus

Pathol. Res. Pract.

Decreased expression of NDRG1 is correlated with tumor progression and poor prognosis in patients with esophageal squamous cell carcinoma

Dis. Esophagus

Loss of disabled-2 expression is an early event in esophageal squamous tumorigenesis

World J. Gastroenterol.

Transgenic rats carrying human c-Ha-ras proto-oncogene are highly susceptible to N-nitrosomethylbenzylamine induction of esophageal tumorigenesis

Jpn. J. Cancer Res.

Dietary ellagic acid reduces the esophageal microsomal metabolism of methylbenzylnitrosamine

Cancer Lett.

Clinical models of chemoprevention for the esophagus

Hematol. Oncol. Clin. North Am.

Effect of diallyl sulfide on rat liver microsomal nitrosamine metabolism and other monooxygenase activities

Cancer Res.

Glucosinolates in crucifer vegetables: turnips and rutabagas

J. Agric. Food Chem.

Inhibition of N-nitrosomethylbenzylamine-induced tumorigenesis in the rat esophagus by dietary freeze-dried strawberries

Carcinogenesis

Piroxicam is an ineffective inhibitor of N-nitrosomethylbenzylamine-induced tumorigenesis in the rat esophagus

Cancer Res.

Differential protein expression between esophageal squamous cell carcinoma and dysplasia, and prognostic significance of protein markers

Pathol. Res. Pract.

Inducible nitric oxide synthase expression in N-nitrosomethylbenzylamine (NMBA)-induced rat esophageal tumorigenesis

Mol. Carcinog.

Chemopreventive effects of a selective nitric oxide synthase inhibitor on carcinogen-induced rat esophageal tumorigenesis

Cancer Res.

Chemopreventive properties of black raspberries in N-nitrosomethylbenzylamine-induced rat esophageal tumorigenesis: down-regulation of cyclooxygenase-2, inducible nitric oxide synthase, and c-Jun

Cancer Res.

Black raspberries inhibit N-nitrosomethylbenzylamine (NMBA)-induced angiogenesis in rat esophagus parallel to the suppression of COX-2 and iNOS

Carcinogenesis

Protective association of aspirin/NSAIDs and esophageal cancer: a systematic review and meta-analysis

Gastroenterology

The effects of ellagic acid and 13-cis-retinoic-acid on N-nitrosomethylbenzylamine-induced esophageal tumorigenesis in rats

Cancer Lett.

Extraction, stability and quantitation of ellagic acid in various fruits and nuts

J. Food Compos. Anal.

Chemoprotection against N-nitrosomethylbenzylamine-induced mutation in the rat esophagus

Nutr. Cancer

Risk of gastrointestinal malignancies and mechanisms of cancer development with obesity and its treatment

Best Pract. Res. Clin. Gastroenterol.

Suppressive effect of CPT-11 on rat esophageal tumorigenesis induced by N-nitrosomethylbenzylamine

Oncol. Rep.

p53 tumor suppressor gene mutation in early esophageal precancerous lesions and carcinoma among high-risk populations in Henan, China

Cancer Res.

Chemoprevention of N-methyl-N-nitrosourea induced rat mammary carcinogenesis by soy foods or biochanin A

Jpn. J. Cancer Res.

Amplification of int-2 gene in primary esophageal carcinoma and fetal esophageal carcinoma induced by N-methyl-N-benzylnitrosamine

Chin. J. Oncol.

Effects of dietary N-(4-hydroxyphenyl)retinamide on N-nitrosomethylbenzylamine metabolism and esophageal tumorigenesis in the Fischer 344 rat

J. Natl. Cancer Inst.

Improved isolation of glucobrassicin and other glucosinolates

J. Sci. Food Agric.

Lung and esophageal carcinogenesis

Overexpression of human telomerase RNA is an early event in esophageal carcinogenesis

Virchows Arch.

Amplification of EGF receptor gene but no evidence of ras mutations in primary human esophageal cancers

Cancer Res.

Genetic analysis of human esophageal tumors from two high incidence geographic areas: frequent p53 base substitutions and absence of ras mutations

Cancer Res.

Lack of effects of selenium on N-nitrosomethylbenzylamine-induced tumorigenesis, DNA methylation and oncogene expression in rats and mice

Nutr. Cancer

Investigation of the enhancement of NMBA-induced esophageal tumorigenesis by 6-phenylhexyl isothiocyanate

Cancer Lett.

Dry beans inhibit azoxymethane-induced colon carcinogenesis in F344 rats

J. Nutr.

Smoking, alcohol drinking, green tea consumption and the risk of esophageal cancer in Japanese men

J. Epidemiol.

Review
Chemoprevention of esophageal squamous cell carcinoma