Causes
The incidence of gastric cancer is increasing year by year, which is a serious threat to people’s life and health safety. The causes of gastric cancer have not been fully elucidated so far, and the occurrence of gastric cancer is the result of a combination of many factors.
1.External factors
Certain carcinogenic factors can play a carcinogenic role when the stomach is in contact with the outside world through diet.
(1) N-nitroso compounds: N-nitroso compounds exist widely in nature, and pickled foods and sauerkraut contain N-nitroso compounds. It can enter the body directly with food and is called exogenous. The influence of dietary factors on the development of gastric cancer has been paid attention to by oncology researchers in various countries. The possible dietary carcinogenic factors are frequent consumption of smoked and baked foods (containing benzo(a)pyrene) or pickled foods and sauerkraut (containing N-nitroso compounds). Zhang Bin, Department of General Surgery, Henan Cancer Hospital
Recent studies have proposed additional protective factors, such as milk, animal protein, fresh vegetables and some fruits.
The results of the survey conducted by the Epidemiology Group of China’s Comprehensive Study of Gastric Cancer on the high and low incidence areas of gastric cancer in China show that gastric cancer is closely related to diet. In the experiment of hepatocellular carcinoma induced by heterochromatic mycotoxin in rats, the occurrence of gastric adenocarcinoma was seen. From the survey area of the main food and the patient’s gastric juice can be detected Aspergillus trichiura and Aspergillus oryzae and other fungi, the detection rate of high incidence of gastric cancer areas is obviously higher than the low incidence areas, can suggest that moldy food is a risk factor related to gastric cancer.
High-salt salted food is considered another risk factor for the occurrence of gastric cancer. Comparative survey also found that food varieties in areas with high incidence of gastric cancer are more simple, while the intake of fresh vegetables, beans and animal protein in areas with low incidence of gastric cancer are more varied, which may indicate that gastric cancer is related to the loss of nutrient balance. In addition, survey statistics suggest that the amount of fresh vegetable intake is negatively correlated with the adjusted mortality rate of gastric cancer, which can be considered as a protective factor for fresh vegetables. Fresh vegetables are rich in vitamins A, C and minerals. Vitamin A is associated with epithelial regeneration and maintenance of its normal function, and vitamin C blocks the synthesis of nitroso compounds with secondary amines in the stomach. Iron deficiency has been shown to be associated with Plummer-Vinson syndrome, which is related to the development of esophageal and gastric cancer, so iron deficiency is indirectly related to the development of gastric cancer.
(2) Helicobacter pylori (HP) infection: In recent years, it is generally believed that HP infection is related to the development of gastric cancer. 1994 WHO has listed it as the first category of gastric cancer risk factors. Domestic and foreign epidemiological survey data show that the incidence of gastric cancer is positively correlated with the rate of HP infection, and the risk of gastric cancer is 6 times higher in HP-infected patients than in non-infected patients. It is also found that the age of HP infection is advanced in areas with high incidence of gastric cancer. HP is involved in the occurrence of gastric cancer, and its mechanism is multifaceted. HP metabolism can produce toxic substances such as urea and phospholipase, which can reduce the acidity of local environment and lead to epithelial cell damage, resulting in chronic atrophic gastritis; in addition, HP infection causes inflammatory cell infiltration in gastric mucosa, which increases oxygen free radicals and releases various cytokines, leading to DNA damage and apoptosis. Several studies have shown that the apoptosis index of gastric mucosal epithelial cells is significantly higher in HP-infected patients. Apoptosis stimulates epithelial cell proliferation or leads to gastric mucosal atrophy, which is the main link of gastric carcinogenesis. The rate of HP infection in patients with gastric cancer is reported differently, which may be related to the stage, pathological type and location of the lesion, in addition to the different examination methods and sampling populations.
HP is an important risk factor for the development of gastric cancer, which interacts and influences with host factors and various external factors to cause the development of gastric cancer. eventually lead to the occurrence of gastric cancer
(3) Fungi: fungal toxins can induce gastric adenocarcinoma or precancerous lesions in the stomach of rats. It has been proved that Aspergillus and its metabolites have synergistic carcinogenic effect with N-nitroso compounds. Some fungi can also synthesize N-nitrosamines. Long-term consumption of moldy food may be an important factor in carcinogenesis.
(4) Schistosomiasis: It has been reported that the cancer rate of gastric schistosomiasis can reach 50% to 75%. No carcinogenic substances have been extracted from schistosome eggs, and whether it is related to the mechanical stimulation of the eggs or toxins is yet to be confirmed.
(5) Geographical and environmental factors: Surveys on the epidemiological aspects of gastric cancer in various countries around the world have shown that there are significant differences in the incidence of gastric cancer in different regions and races. These differences may be related to genetic and environmental factors. Some data indicate that gastric cancer mostly occurs in high latitudes, and the more distant countries are from the equator, the higher the incidence of gastric cancer. There is also information that its incidence is related to coastal factors. Here there are factors of different dietary habits, and geochemical factors and the possibility of carcinogenic substances in the environment should also be considered.
(6) Other factors: A lot of investigation data show that social, economic, geographical, psychological and dietary behaviors and habits have a role in the development of stomach cancer. High-salt diet and smoking also have a certain relationship. There are reports of changes in the content and proportion of chromium, cobalt, selenium, copper and manganese in blood, hair and tissues of gastric cancer patients, which may be related to soil, but there is a lack of solid information on the quantitative-effect relationship.
2.Intrinsic factors
(1) Genetic factors and genetic variation: there is a tendency of family gathering in gastric cancer development, and the incidence rate of gastric cancer among patients’ family members is 2 to 4 times higher than that of the general population. There may be differences in the incidence rate of gastric cancer among different groups of people with ANO blood type, and there are also differences among different races, some people have statistics that the incidence rate of gastric cancer among people with A type is 20% higher than that of people with other blood types, but there are also some reports that there is no difference in the incidence rate of gastric cancer among people with different blood types. In recent years, some people have studied the relationship between the incidence of gastric cancer and HLA, but further conclusions have yet to be made. Investigation data indicate that genetic factors play an important role in the development of gastric cancer.
In recent years, chromosomal abnormalities have been found in gastric cancer cells and their precancerous lesions, and in terms of number, chromosomes are mostly heteroploid; in terms of structure, chromosomal rearrangements, breaks, deletions and other abnormalities may occur.
(2) Dysregulation of apoptosis and proliferation: the balance within normal tissues is mainly the balance of cell proliferation and death, and excessive growth is the result of too little cell death and too much reproduction. And the disorder of cell death process is closely related to the formation of tumor. It is known that there are 2 types of cell death: necrosis and apoptosis.
(3) Immune dysfunction: the occurrence, development and metastasis of tumor are closely related to the immune status of the body.
(4) Low non-immune protective factors: It has been experimentally proved that in the presence of carcinogenic substances, the gastric mucosal barrier and the interaction of anti-damaging factors with damaging factors play an important role in the development of gastric cancer. Some antioxidant vitamins such as vitamin A, C, E and β-carotene have anti-cancer effects. Insufficient levels in the body for a long period of time favor tumorigenesis and may be related to increased oxygen free radical activity, reduced cellular immune function and blocked intercellular linkage traffic. In recent years, it has been found that folate deficiency is related to the development of gastric cancer, because folate is the donor of one carbon unit, which is related to DNA methylation, and its deficiency can lead to the reduction of gene methylation level and susceptibility to carcinogenesis.
(5) The role of oxygen free radicals: experiments have confirmed that oxygen free radicals play an important role in cancer induction, cancer promotion and anti-cancer, which can initiate cell division, cause DNA synthesis and damage to the whole cell, and activate oncogenes leading to cancer. The generation of lipid peroxides (LPO) under the action of free radicals can make certain “carcinogens” into carcinogens and promote carcinogenesis. The apparent loss of Mn-superoxide dismutase (Mn-SOD) activity in mitochondria is a cause of carcinogenesis. Oxygen free radicals may be one of the factors that initiate apoptosis.
(6) Role of GI hormones: Seven types of endocrine cells have been found in gastric cancer tissues, which together with gastric cancer cells constitute cancer nests, infiltrate the interstitium and act on the self-growth, differentiation, metabolism, histological type and infiltrative metastasis of cancer tissues by autocrine or paracrine means. Gastrin has been reported to cause cancer and promote cancer cell growth mainly through cAMP and cAMP-dependent protein kinase (PKA). In vitro cell culture revealed that low concentrations of gastrin can promote the growth of malignant cells. In animal experiments, gastrin was found to promote N-nitrosamine carcinogenesis in the stomach, especially in the early stage, mainly causing hard cancer. Gastrin can cause diffuse fibrous tissue hyperplasia in gastric cancer tissues, and the prognosis is extremely poor. The gastrin disruptor ——proglutamine can inhibit the pro-tumor growth effect of gastrin. bennett et al. reported that patients with a transforming growth factor (α-TGF) and growth factor receptor detectable in gastric cancer tissue had an extremely poor prognosis. Certain atypical hyperplasia found to have a high rate of carcinogenesis in the presence of this factor. Most observations indicate that estrogen has a stimulating effect on gastric carcinogenesis and growth, while androgens have an inhibitory effect. marita found that the positive rate of prolactin was positively correlated with the depth of gastric cancer infiltration and the extent of lymphatic metastasis.
(7) Disease factors: It is now recognized that patients with some diseases have increased incidence of gastric cancer, so they are regarded as precancerous lesions, also called precancerous state. Such patients are considered as high-risk group. They include chronic atrophic gastritis, gastric ulcer, gastric polyp, remnant stomach and hypertrophic gastritis, etc.
Chronic atrophic gastritis: Chronic gastritis can be classified as superficial, atrophic and hypertrophic. It is now recognized that atrophic gastritis is a pre-cancerous lesion of the stomach, especially when it coexists with gastric polyps or intestinal glandular hyperplasia. Long-term follow-up at home and abroad has reported that the length and severity of chronic atrophic gastritis are related to the incidence of gastric cancer, with many reports of a 2% to 10% incidence of gastric cancer in this disease. Superficial gastritis can be cured, but there is a possibility of gradual transformation to atrophic gastritis. Hypertrophic gastritis has little relationship with the development of gastric cancer. Atrophic gastritis is difficult to cure, and its tissues tend to regenerate, sometimes forming polyps and sometimes becoming cancerous. Long-term follow-up can reveal that about 10% of atrophic gastritis is cancerous.
Gastric polyps: Any benign gastric tumor has the potential to become malignant, and epithelial adenomas or polyps have a greater chance of malignant transformation. The cancer rate of rare adenomatous and villous gastric polyps can be 15% to 40%, while the most common hyperplastic polyps are only 1%. The incidence of cancer is increased in polyps larger than 2 cm in diameter. Some data reported that 20% of patients diagnosed as gastric polyps by X-ray were accompanied by some kind of malignant changes; in the specimens of gastric polypectomy, 14% of multiple polyps were seen to have malignant changes and 9% of single polyps had malignant changes, which means that the cases diagnosed as gastric polyps should not be let go easily.
③ Gastric ulcer: the problem of cancer of gastric ulcer has not been uniformly recognized. It is generally believed that its cancer rate is about 1%-6%. Nowadays, most of them think that it is related to mucosal intestinalization or heterogeneous hyperplasia at the edge of the ulcer. As to whether gastric ulcer can become cancerous, it is reported that the cancer rate of gastric ulcer is 5%-10%, especially for patients with long history of gastric ulcer and middle-aged or above, the chance of complication of cancer is higher.
(4) Residual stomach: After surgical removal of gastric sinus and part of gastric body for benign lesions, gastric acid secretion decreases, leading to bile reflux, forming neutral and alkaline environment in the stomach, which causes abnormal reproduction of bacteria in the stomach and promotes the synthesis of nitrite and N-nitro compounds to induce cancer, which usually occurs more than 10 years after surgery. The incidence of residual gastric cancer in China is 2% to 5%, but there are reports of more than 10%. It may be related to bile reflux. Many anaerobic bacteria in gastric juice, etc. can also decompose the conjugated primary bile acids that reflux into the stomach, generating free secondary bile acids that can both damage the gastric mucosal barrier and cause cancer, while deoxycholic acid in secondary bile acids is a cancer initiating factor and stone bile acids are cancer initiating factors and mutagens. These may lead to the development of residual gastric cancer later on. Residual gastric cancer mostly occurs 15 to 20 years after surgery, and the relative risk increases 3 to 6 times thereafter.
⑤ Giant gastric mucosal crepitations (Menetrier’s disease): the cancer rate of this disease is about 10%.
(6) Bile reflux: animal experiments have confirmed that bile reflux can induce gastric cancer. Epidemiological investigation also found that bile reflux gastritis is positively correlated with gastric cancer, and the mechanism is the same as above.
3.Intestinal epithelial metaplasia and heterotypic hyperplasia
The development of gastric cancer from normal gastric mucosa is a long and gradual process, and certain transitional lesions appearing in this process are called precancerous lesions. Studying the conditions and rules of formation, development and transformation of these lesions is one of the important aspects in studying the etiology, pathogenesis and prevention of gastric cancer. It is now believed that intestinal epithelial hyperplasia and heteroglandular hyperplasia of gastric mucosa have precancerous significance, while the latter is more significant. Recently, it has been proposed that heterogeneous glandular cystic dilatation also has the nature of precancerous lesions.
(1) Heterogeneous hyperplasia: also known as atypical hyperplasia. It refers to pathological changes in the epithelium of the gastric mucosa that deviate from normal growth and differentiation, including cellular heterotypes, structural disorders and abnormal differentiation. It is commonly seen in atrophic gastritis, gastric ulcer margins and gastric paracancer tissue. It is a recognized precancerous lesion of the stomach.
(2) Intestinal epithelial metaplasia: intestinal epithelial metaplasia of gastric mucosa (intestinal metaplasia) refers to the appearance of intestinal glandular epithelium on gastric mucosa with absorptive cells, cup cells and Pan cells, which no longer secrete neutral mucin but acidic mucin, with relative immaturity and bi-directional differentiation to intestine and stomach. Intestinalization begins with stem cells in the neck of the pyloric gland, turning the epithelium of the pyloric duct into intestinalized epithelium. Intestinalization tends to occur in the pyloric gland area of the gastric sinus and gradually expands to the migrating part and the body, which is the same as that of gastric cancer, and tends to expand with age. Intestinalization is common in chronic gastritis, especially atrophic gastritis, gastric ulcer margin and paracancerous tissue. There are 3 levels of lesions: mild, with occasional entericized glandular ducts within the gastric cell; moderate, with about 1/2; and severe, with most of the gastric cell replaced by entericized glandular ducts.
(3) Glandular heterogeneous dilatation: Gastric mucosal glandular dilatation can be divided into simple and heterogeneous, the former glandular dilatation is slight, no atrophy and heterogeneity, focal or isolated distribution, and can be normalized by treatment. In the former, the glandular dilatation is mild, without atrophy and heterogeneity, focal or isolated, and can return to normal after treatment. A few of them are transformed into heterogeneous dilatation, also called cystic heterogeneous dilatation. The domestic reported cancer rate is 9.9%, which may be an important precancerous lesion.
It is a malignant disease formed by a variety of external carcinogenic factors acting on the defective organism or a specific response to carcinogens on a certain genetic background over a long period of time and multiple steps. It is believed that although the age of onset of gastric cancer is in middle age, the carcinogenic effect has already occurred during youthful development. At present, the general tendency is to develop in a pattern of chronic gastritis-entericization-anomalous hyperplasia-gastric cancer.