Research progress of metabolomics in cervical cancer

Cervical cancer poses a serious health risk to women because it has a precancerous stage that can last for years and can be reversed [1]. A number of studies have shown that 80–90% of 5-year cure rates are due to early diagnosis and treatment of cervical cancer patients [2]. Therefore, effective screening methods for cervical cancer have become an important tool for detecting, interrupting and reducing the occurrence of cervical cancer. However, the study shows that only 81% of women aged 21–65 are up-to-date on screening [3]. Currently, cervical cancer screening is mainly performed by cervical cytology, colposcopy, cervical biopsy, and high-risk Human Papillomavirus (HPV) [4], that often causes delays in many patients due to problems in obtaining the material. While the specimens used for metabolomic analysis are mainly biological fluids such as serum, plasma, and urine, which are rich in metabolic information, simple to obtain, and more acceptable to patients.

Metabolomics is a discipline proposed by Nicholson [5] in 1999 for studying the "mapping" of the metabolome from a holistic perspective. Metabolomics is a new field developed after genomics and proteomics [6], which focuses on the dynamic changes in the quality and quantity of endogenous metabolites (such as amino acids, fatty acids, sugars, vitamins and lipids) in living organism caused by external stimulation [7]. As serious metabolic disorders are common in tumor patients, scientists have obtained characteristic differential metabolic profiles and identified specific biomarkers through metabolomic studies of cervical cancer patients [8], which provide new ideas for research related to detection, screening, early diagnosis and treatment of cervical cancer.

Tumor tissue requires adequate nutrients and an energy supply during growth and proliferation. In adaptation to tumorigenesis and progression, there are significant changes in many aspects of tumor cell metabolism, such as glycolysis, tricarboxylic acid cycle, oxidative phosphorylation, amino acid metabolism, fatty acid metabolism and nucleic acid metabolism, which is called metabolic reprogramming of tumor cells [9]. Differential metabolite analysis of cervical cancer, cervical intraepithelial neoplasia and control tissues showed higher levels of isoleucine, leucine, valine, glycoprotein, methionine and lower levels of α-glucose and β-glucose in patients with cervical intraepithelial neoplasia compared to normal controls; patients with cervical squamous cell carcinoma had higher levels of lactate, alanine, isoleucine, methylhistidine acid, lipid low density lipoprotein (LDL) was higher and tyrosine, phenylalanine, α-glucose, β-glucose, creatine, shark inositol, and acetic acid were lower. Lactate, alanine, glycine, and LDL were higher in patients with cervical squamous cell carcinoma compared with patients with cervical intraepithelial neoplasia [10]; tyrosine, α-glucose, β-glucose, acetic acid, and phenylalanine were lower [8].

Cervical cancer is a complex disease with multifactorial and multisystemic functional flocculation that can lead to metabolomic changes and pathophysiological alterations of the disease. It has been found that biomarkers of intermediates and end products of abnormal metabolic processes can be used to study tumorigenesis and progression.

Nevertheless, despite significant advancements in metabolomics methods, the identification of metabolite biomarkers that can distinguish cancer patients from healthy controls and many novel findings on altered cancer metabolism, many challenges persist in developing the routine clinical utility of metabolomics for cancer diagnosis. In addition, a major challenge for metabolomics is the interference by contributions from confounding factors such as diet, age, gender, ethnicity, drugs, lifestyle and environment [80]. The sensitivity of metabolism to biological changes means that metabolite levels are affected not only by disease processes, but also by many others. With approximately 5000–8000 small molecule metabolites present in the human body (excluding lipids), the identities of most of these are still unknown or at least difficult to measure. Biological specimens used for study are extremely complex; no single analytical technique is currently capable of detecting all the metabolites in a single step. These challenges are in fact well recognized and there are already major efforts to overcome them. Therefore, this will bring greater difficulties to clinical work, for example, studies have shown that the metabolites between races are different [81]. Secondly, there are 5000–8000 metabolites in the human body, most of these are still unknown, which is one of the main reasons that the existing results cannot be directly applied to the clinical utility. The application of metabolite to the clinic requires more molecular theory support, and when we learn more about the pathway of metabolite production, we will be better able to integrate it with clinical cases. We think that we may not have found the specific numerical range of the changes of metabolites, but their change rules are discernable. According to the above experiments, the trend of these metabolites is similar.

By directly reflecting the changes in the microenvironment of the body, metabolomics research can provide a comprehensive understanding of the patterns of metabolites in the occurrence and development of diseases, thus providing new ideas for disease prevention and diagnosis. Metabolomics testing is less damaging and more acceptable to the patient than doing puncture for pathology. It can reduce the patient's fear and pain, which have a greater advantage in the initial screening, it will be able to detect asymptomatic early-stage patients earlier. In clinical work, pathologic diagnosis is time-consuming and often bring high monetary costs. However, metabolomics is often judged by blood or urine. The acquisition method is less damaging and less costly, and can quickly provide the basis for diagnostic and therapeutic programs.

Metabolomics has an advantage in the field of histological research by analyzing the physicochemical properties of endogenous small-molecule metabolites in the human body with a variety of analytical instruments. By analyzing the total metabolic components of the body and finding specific biomarkers from them, timely, accurate, highly sensitive and highly specific diagnosis of clinical diseases can be made. With the continuous in-depth research on metabolomics research technology, it will bring more benefits in the screening, diagnosis and treatment of cervical cancer with its advantages of holistic and dynamic nature. In future clinical trials we could conduct controlled trials in different populations of different ages, ethnicities, living regions and lifestyles to determine whether there is still variability in their metabolites in the absence of the effects of cancer disease. If there is variability across populations, this will affect the clinical significance of what they represent. Instead of prescribing a certain interval for determining the diagnostic significance of metabolites, we might consider determining the clinical significance of these metabolites by individual trends, which might eliminate the anomalies caused by errors in different populations. We need to do more research on the molecular structure, many machines have been able to analyze the structure of metabolites, but their origin and mechanism of action are still unclear. We can apply C13 and other tracking methods to track the metabolites in the metabolism of the pathway, in order to clarify the significance of its representative. Through the current experiments, we can know that there are differences in metabolite trends in different cancer diseases. In the future, we can select more specific metabolites by comparing the metabolite differences between different cancers. Their expression trends in different tumors will be studied more thoroughly, thus improving the specificity of metabolites in cancer diagnosis. The accuracy of metabolites in cancer diagnosis requires strict identification of other diseases associated with the production of such metabolites, which requires more basic experimental research. As more markers are discovered, the accuracy will be higher. We believe that metabolomics will make great progress in the diagnosis, treatment, and prognosis of cervical cancer with the advancement of various studies.