Gastric cancer is one of the common malignant tumors with high morbidity. According to statistics in 2018, there were 1.034 million new cases worldwide, and about 783,000 patients died, accounting for 8.2% of the total deaths12. However, the prognosis of advanced gastric cancer and early gastric cancer are completely different. Due to the lack of specificity symptoms of early gastric cancer and insufficient screening methods, more than two-thirds of patients have been at the middle and advanced stages of gastric cancer at the first diagnosis, resulting in only 30% of 5-year survival rate 13. However, the 5-year overall survival rate after accurate diagnosis at an early stage and timely radical resection of gastric cancer exceeds 90%. At present, the diagnosis of gastric cancer mainly relies on imaging examination, gastrointestinal endoscopy, and histopathology. However, early gastric cancer has no obvious symptoms or signs. Conventional ultrasound, CT and other imaging detection methods cannot accurately diagnose. Besides, there are no obvious general changes in the early gastric cancer lesions. Therefore, conventional endoscopy is less sensitive to early gastric cancer, with a detection rate of about 7.3% 14. At the same time, endoscopy is invasive, prone to cross-infection and relatively expensive. Due to its high limitations, it cannot be used as a tool for large-scale gastric cancer screening. Therefore, it is imperative to find more sensitive early gastric cancer diagnostic markers. Metabolomics is an important method for the screening of biomarkers. Compared with the problems of gene complexity and post-transcriptional modification faced by other omics research, metabolomics can directly and comprehensively reflect the body's endogenous metabolic information15,16. Many studies have reported the application of metabolomics in the discovery of early biomarkers for breast cancer, liver cancer, rectal cancer, and other tumors. For example, Xu et al. (show) adopted Mendelian randomized method to perform 27 case-control studies on the relationship between blood homocysteine levels and the risk of gastric cancer, which proved that the blood homocysteine level has a significant impact on the risk of gastric cancer. The purpose of this experiment is to use liquid chromatography-mass spectrometry (LC-MS) to detect serum samples of advanced gastric cancer, early gastric cancer, and healthy people. Spermine, enterostatin, Heparan sulfate and 2,3-Diacetoxypropyl stearate have good diagnostic ability for early gastric cancer, and the verification group have proved that the results are reliable and sensitive.
Spermine is a more common type of polyamines (PAs). It is widely involved in many cell activities, including cell growth, proliferation, differentiation, amino acid and protein synthesis, and DNA damage 17,18. Studies have found that changes in the content of polyamines are accompanied by the occurrence and development of tumors, which proved that polyamines are involved in tumor transformation and the regulation of tumor microenvironment 19. The content of polyamines in proliferating cells is significantly higher than that in slow proliferation. Therefore, the content of polyamines is higher in many tumor tissues than that in corresponding normal tissues 20,21. Besides, the biosynthesis, catabolism, and membrane transport of polyamines in cells are strictly regulated. Therefore, changes in polyamine content also represent abnormal cell membrane functions. Rupesh haturvedi found that Helicobacter pylori strains increase the level of spermine oxidase, which decomposes spermine to increase the level of its metabolite hydrogen peroxide, resulting in DNA damage, and ultimately leads to gastric cancer occur22. In his study, we found significant different levels of spermine in blood samples between early gastric cancer and healthy people. The results are the same as previous studies, providing a new scientific basis for biomarker screening and drug targets for early gastric cancer.
Heparan sulfate, also called heparan sulfate, is composed of glucosamine (GLcN) and glucuronic acid (GLcA) or iduronic acid (IdocA). Its function is modified by some enzymatic reactions in the synthesis process23. Heparan sulfate combines with the core protein on the cell membrane to form the heparan sulfate proteoglycan (HSPG) in the tumor extracellular matrix and basement membrane. It plays an important role in the regulation of inflammation, cell growth, apoptosis, infection, tumor development and other different pathophysiological processes 24. At the same time, heparin sulfate can also be used as a carrier of cell nutrition and growth factors, which can transport cellular nutrients into cells, and can also transport growth factors without membrane receptors, thereby affecting the signal activation of downstream transduction pathways 25, Barbara Bartolini systematically described the role of heparin sulfate in the cancer occurrence and development26. Other studies have shown that heparin sulfate plays an important role in the embryonic development of the stomach: HS is necessary for the differentiation of the front stomach squamous epithelium and the basal cells. HS activates the FGF in epithelial cells by promoting the combination of FGF and FGFR, which controls the development of glands. HS can also limit the proliferation of gastric interstitial smooth muscle27–29. This shows that heparin sulfate is involved in the embryonic development of the stomach and has a potential connection with gastric diseases, which supports the results of this study. In this study, it was found that the level of heparin sulfate in patients with gastric cancer first decreased and then significantly increased, which is consistent with previous studies. There is also evidence that heparin sulfate as a carrier can participate in the process of transporting polyamines from outside of the cell to the inside of the cell30. Whether it is related to the change in spermine content is worthy of our further study.
Triacylglycerol is a component of lipids, which is a lipid formed by glycerol and 3 fatty acids. Under normal circumstances, the triglycerides in the plasma maintain a dynamic balance. However, the lipid consumption and lipid metabolite levels of gastric cancer patients increase. Therefore, the plasma lipid level of gastric cancer patients decreases and the lipid level can be used as a diagnostic biomarker of gastric cancer31,32. In this study, we found that the decrease of lipid metabolites such as triacylglycerol in patients with gastric cancer indicates that the lipid metabolism of patients with early gastric cancer has changed significantly. Although there are no reports about the relationship between gastric cancer and triacylglycerol, triacylglycerol serves as a kind of Important ester compounds, may involved in life metabolism, and are likely to have some potential connection with gastric cancer. Therefore, the results of this study provide new insights in this regard. In addition, studies have found that the lipid metabolism process of tumor cells affects the oncogenic signal transduction pathway. And lipids participate in the immune regulation of tumor cells, preventing tumor cells from the destruction of the body's immune system33. All the above need to be further studied.
Enterostatin is a pentapeptide released by proenzyme during fat digestion. In addition to the pancreas, intestinal statin immune response cells are also present in the gastric antrum and the proximal small intestine. Enterostatin can selectively reduce fat intake, reduce insulin secretion, and increase energy expenditure by activating brown adipose tissue during high-fat feeding. At present, there are many studies about enterostatin in the treatment of diabetes, but there are few reports related to the relationship between enterostatin and gastric cancer34,35. Enterostatin is an important part of the normal metabolism of the human body. In this study, we found that enterostatin in patients with gastric cancer is lower than that in healthy people, indicating that enterostatin may affect gastric cancer occurrence and development, which providing a new way for the diagnosis and therapy of gastric cancer.
This study has discovered and verified the different expressions of the four statistically significant metabolites in blood samples of early gastric cancer. The changes in their content may be related to the cancer occurrence and development. And the metabolic mechanism can be continued to be explored. However, to obtain more ideal results, a larger sample size is required. Metabolomics is a research that requires high-throughput support. If the sample size is sufficient, more different metabolites may be screened. At the same time, metabolomics can find the differences between compounds. To fully understand the mechanism of disease occurrence and development, it is necessary to combine genomics and proteomics to conduct research from multiple perspectives.