Dietary factors associated with gastric cancer - a review

Abstract

Background

Cancer is considered one of the primary illnesses that cause morbidity and mortality in millions of people worldwide and due to its prevalence, there is undoubtedly an unmet need to discover novel anticancer drugs. As most of the target-specific anticancer drugs failed to achieve the expected result so far, new multi-targeted therapies using natural products have become significant. Natural products are readily applicable, inexpensive, accessible and acceptable therapeutic approaches with minimum cytotoxicity. This review explores the relationship between dietary factors and the probability of development of gastric cancer. Over the years, it has been proven that there are many natural products that have chemo-preventative effects such as vitamins, probiotics and prebiotics, green tea, and resveratrol on gastric cancer. Many investigations have looked into the links between dietary components and the risk of stomach cancer and a variety of protective and deleterious factors have been identified in our diet that is associated with gastric cancer. In this study, we have summarized the preventive and injurious components that affect the incidence of gastric cancer.

Conclusion

Based on the potential of natural products for the discovery of new compounds for the treatment of diseases, the purpose of the present review was to investigate the importance of dietary products mitigating the impacts due to the development of gastric cancer. The current analysis proves the protective as well as harmful roles of many elements which are found in our diet in the development of gastric cancer. Our findings can have significant public health implications in terms of gastric cancer prevention. There is an inherent need to offer an insight into benefits and risks, clinical trial designs future translational and cohort studies before effectively clinically translated.

Introduction

Gastric cancer is a major health concern throughout the world. Its incidence is highly variable by regions, most prevalent being in Eastern Asia. It is the 5th most frequent cancer in the world, accounting for 5.6% of all cancer diagnoses in 2020, and the 4th most deadly cancer, accounting for 7.7% of all cancer-related deaths globally [1]. Gastric cancer develops when cells in the stomach start to grow out of control. The most common type of gastric cancer is adenocarcinoma (about 90 of all gastric cancers) which can be of intestinal type or diffuse type. Other variants are squamous cell carcinomas, small cell carcinomas, gastrointestinal stromal tumors, neuroendocrine tumors, lymphomas and leiomyosarcomas. Gastric cancers are classified as cardia or non-cardia based on the structure of the stomach. Diet and helicobacter pylori infection play an important role in gastric cancer development. Other major etiological factors for gastric cancer include smoking, alcohol use, obesity, previous gastric surgery, pernicious anemia, adenomatous polyps, chronic atrophic gastritis and radiation exposure [2]. Gender, age, ethnicity and geography are also, important risk factors.

Diet is an important modifiable risk factor for gastric cancer. There is adequate epidemiological evidence which suggests links of some nutritional exposures and dietary components with gastric cancer. Adequate diet modification may play a key role in reducing the incidence of gastric cancers. This review updates and summarizes the existing data on diet related factors which are associated with increasing risk of gastric cancer or have role in gastric cancer prevention (Table 1).

Table 1 Dietary factors associated with gastric cancer risk [3]

Dietary factors associated with prevention of stomach cancer

Citrus fruit, flavonoids and vitamin C

Many studies have shown the positive effect of citrus fruit intake on prevention of gastric cancer. One- stage pooled analysis including 6340 cases and 14,490 controls from 15 case–control studies from the stomach cancer pooling (StoP) project consortium by Paola Bertuccio et al. has proved an inverse association between citrus fruits and gastric cancer. This association was similar for all gastric cancer sub-sites and histotypes [4]. Other hospital- and community- based case–control studies have also shown the similar effect with inclusion of citrus fruit in diet [5, 6]. This protective effect is due to flavanones (a type of flavonoids) which are present in citrus fruits and juices. These flavanones prevent human gastric cancer cell proliferation, migration and invasion. Hesperitin and naringenin are the two main protective compounds of flavanones due to their antioxidant potentials [7,8,9]. It was seen that by increasing the amount of fruit in the diet of Finnish women for 5 weeks, the mean plasma concentrations of hesperitin and naringenin were increased by more than 6 times and 20 times respectively [10]. Citrus fruits are also rich in vitamin C which reduces the risk of gastric cancer development [11]. A Korean case control study showed an inverse relationship between vitamin C and gastric cancer with a significant difference for the highestversus lowest intake categories. Also, it was seen that Vitamin C-contributing foods, including cabbage, strawberries, and bananas, were protective factors against the risk of gastric cancer [12]. Though some of the studies done in the \past failed to prove the preventive effect of vitamin C for gastric cancer [13, 14], but most other observational studies and meta-analysis proved its beneficial effects [15,16,17].

Phytochemicals display their anticancer movement through focusing on signaling pathways, advancing apoptosis, controlling cancer prevention agent status and detoxification. Individual flavonoids in food might apply distinctive chemoprotective activities against carcinogenesis and this can be one potential justification behind the conflicting discoveries of epidemiological learns about the relationship between absolute flavonoid intake and the risk of disease. The dietary sources flavonoids, hesperetin and naringenin have been reported as chemopreventive agents [18,19,20]. The benefits of the two flavanones exhibit antioxidant, anticancer and anti-inflammatory properties [21,22,23,24]. Recently, the citrus flavonoids naringenin (NAR) and hesperetin (HSP) have been accounted for to forestall senescence [25]. The likely chemoprotective impacts of flavonoids independently furthermore, later on, designated chemoprevention with explicit plant-determined polyphenolic mixtures could turn into the favored methodology for malignant growth anticipation [26]. At that, flavonoids don’t act through a solitary natural system yet rather regulate molecular events and different intracellular signaling pathways for example, progression of cell cycle stage I and II metabolic enzymes [27, 28].

Vegetables

Many studies have proved the benefit of vegetable intake in lowering the gastric cancer risk. The protective effect increases with portions per day [29, 30]. Cruciferous vegetables have anti-carcinogenic properties [31] and have been associated with reduced risk of various cancers, including stomach, lung, breast, bladder, gastric, colorectal, and prostate. Its cancer prevention properties may be due to vitamin C, folate, dietary fiber, phytoestrogens, selenium, and phytochemicals contained in it. A study by Morrison et al. showed a strong inverse association between gastric cancer and cruciferous vegetable consumption [32]. Diets rich in vegetables and fruits and with low amounts of salty and starchy foods are recommendable for the prevention of gastric cancer [33].

Retinol

Vitamin A plays an important role in controlling cell proliferation and differentiation, hence influences carcinogenesis. A prospective cohort study consisted of 82,002 Swedish adults who were followed from 1997 to June 2005 with a mean follow up of 7.2 years showed that high intakes of vitamin A, retinol, dietary alpha-carotene and beta-carotene were associated with a lower risk of gastric cancer [34].There are other studies which have shown that higher plasma levels of retinol are associated with a reduction in risk of gastric cancer [35, 36].

Wine

Wine intake may decrease the chances of gastric cancer. A pooled database from three population studies conducted in 1964–1992 on a total of 15,236 men and 13,227 women which were followed for a total of 389,051 person-years, showed a significant association between glasses of wine drunk per day and gastric cancer [37].

There seems to be a negative association between wine intake and gastric cancer. The increase in wine intake decreases the risk of developing gastric cancer. The Helicobacter pylori disease has been demonstrated to be related with a twofold expansion in the danger of gastric malignant growth and quite a few studies have shown that wine obstructs the endurance of Helicobacter pylori in the stomach [38,39,40], however, the dynamic substances stay obscure. The connection between wine and gastric malignant growth in this study could likewise be ascribed to the substance of antioxidants in wine, which might have a defensive impact against malignant growth advancement. Resveratrol, a polyphenolic phytoalexin specialist in red wine has been implicated in cancer prevention [41,42,43,44]. These advantages ought to be accomplished by the influence of a therapeutic agent with numerous molecular mechanisms and biochemical pathways for the avoidance of chemoresistance while having little cytotoxic consequences for normal cells [45].

Mediterranean diet

The Mediterranean diet is based on the traditional foods that people used to eat in countries like Italy and Greece back in 1960 which mainly consists of vegetables, legumes and fish. The MD is thought to be protective against gastric cancer. An Italian case-control study with a total of 223 cases and 223 controls proved that higher adherence to MD is associated with a reduced risk of gastric cancer [46]. There are other evidence available in literature which showed similar results with adherence to MD [47, 48].

Dietary factors increasing the risk of gastric cancer

Salt and salty food

Gastric cancer is a common neoplasia, and dietary variables, such as salt consumption, are thought to have a role in its development. A number of experimental investigations found that salt had a co- carcinogenic effect when combined with Helicobacter pylori infection, as well as some independent effects like increased cell proliferation and endogenous mutations. A comprehensive meta-analysis of longitudinal studies found that overall salt intake and salt-rich foods have a strong negative influence on the incidence of stomach cancer in the general population [49].

Pickled foods

Consumption of pickled vegetables in East Asia has been linked to an increased incidence of stomach cancer in experimental investigations. A meta-analysis of epidemiologic observational studies which constituted a total of 60 studies, 50 case-control, and 10 prospective studies compared the risk of stomach cancer in pickled vegetable/food users to nonusers (11 studies) or to those in the lowest stated category of use (49studies). Thirty case-control studies revealed a substantial increase in risk, while one revealed a substantial decrease in risk. Two prospective trials revealed a significant increase in risk, while none revealed a substantial decrease. The findings imply that eating pickled vegetables/foods may increase the risk of stomach cancer by 50%, with larger connections in Korea and China [50].

Smoked foods

Smoking is a well-known source of carcinogenic polycyclic aromatic hydrocarbons-contaminated food. According to epidemiological studies, there is a statistical link between the frequent consumption of smoked foods and the increased risk of intestinal cancer [51]. Smoked meats contain heterocyclic amines which are both mutagens and carcinogenic. People who ate smoked-dried salted beef on a regular basis had a nearly three-fold elevated risk of stomach cancer [52].

Nitrosamines and nitroso compounds

Smoked preserved foods, cured meat products, salted preserved foods, and food dried by additions such as malt in the preparation of beer and whiskey all include preformed nitrosamine. Processed meats contain high levels of nitrates and nitrites. When nitrates and nitrites react with amino acids in the stomach, endogenous N-nitroso compounds are formed. Endogenous synthesis of N-nitro compounds is triggered by haem iron in processed beef. By producing DNA damage and oxidative stress, haem iron accelerates the progression of pylori infection. Endogenously generated N-nitro compounds were reduced by ascorbic acid. By forming N-nitroso compounds, nitrates and nitrates, which are commonly used in processed foods, induce stomach cancer. N-nitroso compounds’ reactive intermediates react with proteins and DNA in cells, causing cancer [53].

Alcohol

A meta-analysis by Ma et al. which included 10 studies implied that consuming alcohol raises the risk of stomach cancer. This could be due to the fact that alcohol can function as a solvent, making it easier for other toxic compounds to reach the cells lining the upper digestive tract. In order to determine the difference between moderate drinking and the risk of gastric cancer and heavy drinking and the risk of gastric cancer, they divided the study participants into three groups: control group (no drinking), moderate drinking group, and heavy drinking group. This meta-analysis confirmed that alcohol consumption can increase the risk of gastric cancer even at lower levels of alcohol consumption [54].

Red and processed meat (non cardia)

There is a scarcity of prospective evidence on red and processed meat and the risk of esophageal and gastric cancer subtypes. In 1986, 120,852 people aged 55 to 69 were recruited, and their meat consumption was examined using a 150-item food frequency questionnaire. A case–cohort analysis was performed on 107 esophageal squamous cell carcinomas, 145 esophageal adenocarcinomas, 163 gastric cardia adenocarcinomas, 489 gastric non-cardia adenocarcinomas, and 3923 subcohort members after 16.3 years of follow-up. In men, both processed and red meat consumption were linked to esophageal squamous cell carcinoma [55].

Haem iron (from fresh meat)

Heme iron can catalyze the endogenous synthesis of N-nitroso compounds, which are strong carcinogens, causing oxidative stress and DNA damage. In animal studies, dietary iron increases the risk of esophageal cancer, and it has been discovered as a growth factor for Helicobacter pylori, a known risk factor for stomach cancer [56].

Chemoprevention with dietary supplements

Chemoprevention of gastric cancer appears to be the most promising approach in reducing the incidence and mortality related to this cancer. As there is enough evidence available now regarding the protective role of diet containing micronutrients such as ascorbic acid, beta-carotene and alpha-tocopherol which have antioxidant properties, these dietary supplements can be explored as chemopreventive measure for gastric cancer. A study from Linxian China which recruited about 30,000 individuals showed a lower incidence and risk of death from, gastric cancer in those receiving b-carotene, vitamin E and selenium [57]. In a prospective randomised study by Zullo et al., the administration of ascorbic acid following H. pylori eradication significantly helps to resolve intestinal metaplasia of the gastric mucosa [58]. A chinese interventional study of high dose folic acid in gastric carcinogenesis in beagles has proved an important role of folic acid as chemopreventive agent for gastric cancer with statistically significant difference between case and control arms [59]. Although there are many studies which have shown promising results for the role of dietary chemoprevention of gastric cancer, there are some studies which have failed to prove its benefit. A Colombian randomised control trial conducted on its high-risk population did not show significant benefit of vitamin C and b-carotene as chemopreventive agents for gastric cancer [60]. In another trial, supplementation with a combination of vitamin C, vitamin E, and selenium did not show any effect on the incidence of gastric cancer at 7 years [61].

The potential role of the various dietary supplements to be used for chemoprevention and in cancer patients need pharmacokinetic studies to determine the therapeutic concentration.

Effect of dietary factors on gastric cancer mortality

Along with effect of dietary changes on gastric cancer incidence, there are studies which have shown a significant effect of diet on gastric cancer mortality also. The Chinese study from Linxian mentioned above have also shown a significant difference in gastric cancer mortality in b-carotene, vitamin E and selenium group even after a longer follow up [57]. An epidemiological study conducted in 24 countries has shown that dietary salt intake is a dose-limiting factor for gastric cancer mortality while the effect of nitrates is mainly associated with high salt concentrations [62]. In a study by Ngoan et al. which enrolled more than 30,000 subjects, the dietary factors showed a significant difference included yellow and green vegetables, processed meat and frequent use of cooking oil. Other factors which were effective but failed to show statistical significances were fresh food, pickled food and traditional soups [63]. The correlation of dietary factors with incidence of gastric cancer is described below (Table 2).

Table 2 Correlation of dietary factors with incidence of gastric cancer

The anticancer activity of capsaicin is attained through several mechanisms including cell cycle arrest, activation of apoptosis, inhibition of metastasis and invasion and dysregulation of significant pathways involved in growth and metabolism. Thus, capsaicin has appeared to modify the outflow of a few qualities associated with malignancy cell survival, development capture, angiogenesis and metastasis [81]. Curcumin is also known to inhibit gastric cancer. Curcumin caused the induction of apoptosis and loss of MMP in SGC-7901 gastric cancer cell line via the inactivation of mito-KTAP. Curcumin is found to play important roles such as suppressing the transition of cells from G (1) to S phase to inhibit invasion and cell proliferation of gastric cancer cells. In addition to suppressing cell proliferation, it has been reported that curcumin is responsible for the down-regulation of mRNA and protein expression of cyclin D1 [22]. Formononetin isolated from red clover has many effects such as antioxidant, vasorelaxant, anti-inflammatory, neuroprotective and also possesses anticancer effects by regulating estrogen receptors and mitogen-activated protein kinase pathway [82]. Based on traditional Chinese Medicine, Jianpi Yangzheng Xiaozheng Decoction (JPYZXZ) is an empirical compound prescription. JPYZXZ, has been found to prolong and improve the quality of gastric cancer patients because it is “Qi-invigorating, spleen-strengthening and stasis-removing.” Nevertheless, it is still unclear how the compound acts specifically as an antitumor agent [83].

Conclusion

The current decade has seen an expanding interest in the trajectory for prognosis of gastric cancer [84]. The inclusion of dietary regimens in cancer prevention for general well being is gaining attention. There is a plethora of literature on the role of diet and dietary habits in the occurrence of gastric cancer [85,86,87]. Recently studies have demonstrated the beneficiary role of dietary intake in prevention of gastric carcinogenesis [88,89,90].

Dietary products have been an unsurpassed source of cancer drugs in the modern era of drug discovery. These natural products, their derivatives and analogues based on these drugs constitute an arsenal against various types of neoplasms. They are capable of modulating cancer microenvironment and diverse cell signaling cascades; thus, playing a major role in combating cancer. These compounds are found to be effective against several signaling pathways, mainly cell death pathways (apoptosis and autophagy) and embryonic developmental pathways (Notch pathway, Wnt pathway and Hedgehog pathway). The historical record is strong, but what is the current impact of natural products in the discovery and development of cancer drugs, and importantly what are the prospects for natural products to be a valuable source of future agents is still a road less traveled. Yet there is a need to elucidate the potential efficacy of outlying mechanisms and other associations/cross-connections to discover amicable and sustainable methods for cancer prevention. However; we consider that a cautiously optimistic approach is required to assess the risk-benefit profile of this medication in the disease progression.

This analysis demonstrates that there are a multitude of potential risk factors and protective elements for stomach cancer that can be established in our diet. Our findings can have significant public health implications in terms of gastric cancer prevention, as well as offer insight into future cohort studies and clinical trial design.