To our best knowledge, this is the first meta-analysis study assessing the concentrations of serum C3 levels in cancer patients with the objective of assessment of the role of C3 in the development and progression of cancer. Our results showed that the serum C3 concentrations in cancer patients were significantly higher than that of healthy people in the control group. Additionally, we made an analysis of the serum C3 concentrations in 84 lung cancer patients and 30 healthy people, which could be merged into our meta-analysis and support the conclusions.
The function of complement is to detect, mark and eliminate the invasion of microorganism with almost immediate reaction but with enough specificity, so as to prevent damage to the host cell [30, 31]. Complement is generally thought to prevent tumor formation, but it is often affected by certain conditions and is currently considered to be a major obstacle to the success of antibody immunotherapy [16]. The complement system suppresses tumorigenesis by promoting the acute inflammation and tumor cell lysis; Instead, it promotes tumor growth by stimulating chronic inflammation, immuno-suppression, and angiogenesis [32].
Day after another, more research is providing a strong evidence that C3 can affect the occurrence and development of cancer. For instance, it is reported that the increase of plasma C3 level in patients with lung cancer is a function of the shortening of the survival period of patients with cancer [33, 34]. Interestingly, studies have found that the growth and metastasis of primary tumors in mice lacking C3 are strongly inhibited. This is evident by increasing the number of IFN-γ+/TNF-α+/IL-10 + CD4 + and CD8 + T cells and that C3-deficient mice have a T cell and IL-10 dependence on tumor development [35, 36]. In a mouse model of epithelial ovarian cancer, a genetic C3 deficiency can also impair tumor vascularization by altering the function of endothelial cells [37]. It is hypothesized that cancer metastasis is the cause of death in approximately 90% of cancer patients [38]. Moreover, the neoplastic transformation is enhanced by the ability of malignant cells to activate the complement C3, which may be involved in the process of cancer metastasis [38]. What’s more, study showed that C3 plays an important role in the immunosurveillance and earlier cancer metastasis [39].
Some attempts have been made to determine whether serum C3 levels are closely related to the rapeutic effect and prognosis of cancer. A number of researchers have reported that multiple tumors can significantly improve C3/C3a levels in the cell experiments or animal models, including cases with breast cancer, lung cancer, ovarian cancer, rectal cancer and liver cancer [40];[41]; [36, 42, 43]. Experimentally, it was reported that complement C3 can be considered as an early diagnostic marker for some type of cancers [40, 44, 45]. The above described research supports the results of our meta-analysis from different angles, indicating that our analytical results are reliable.
We made an analysis of the serum C3 concentrations in 84 lung cancer patients and 30 healthy people, which not only could be merged into our meta-analysis as an advanced research but also support the conclusions of our meta-analysis. Then, we carried out a meta-analysis of 19 studies regarding the serum C3 concentrations of cancer patients. Our analysis suggested that there is a significantly increased concentration of C3 in the cancer patient’s serum or plasma compared to healthy controls. This phenomenon may suggest that C3 concentration of complement may be a marker of cancer patients at a certain period, or C3 may be considered as a new guideline for cancer prevention and treatment. Therefore, it is necessary for researchers to carry out experiments, further exploration and discovery.
As mentioned earlier, numerous studies support the results of our meta-analysis revealing that our research is well founded. We had to admit that our research is heterogeneous. Hence, we performed subgroup analysis and sensitivity analysis in details to explore and discuss the potential sources of heterogeneity as far as possible. Fortunately, the results showed that our research results are relatively stable.
The presented data of meta-analysis are originating from previous studies, which measured the C3 concentrations clinically starting with the original assay and raw data in order to provide support, reference and comparison for C3 concentration data from various bodies of scientific research. Since the systematic clinical study of serum C3 in cancer patients is more inclined to mass spectrometry and proteomics, or to animal experiments and cell models, the data are relatively difficult to collect, and relatively old.
The reported meta-analysis in our study has several advantages. Firstly, to our best knowledge, this is the first meta-analysis study assessing the concentrations of serum C3 levels in cancer patients with the objective of assessment of the role of C3 in the development and progression of cancer, which can provide more data for the clinic. More importantly, it can provide a comparison and reference for data analysis and experimental conclusions about cancer patients C3. Secondly, we measured and compared the serum C3 concentrations of lung cancer patients and healthy people in clinical and also included its serum data into meta-analysis. Fortunately, our clinical data analysis results and our meta-analysis results support and confirm each other. What’s more, among the data collected by the meta-analysis, there is not any study on the determination of C3 by ELISA so our clinical study increased the stability of the conclusion. Next, in our meta-analysis, we conducted a detailed subgroup analysis to explain the source of heterogeneity and its possible impact on the results. Finally, in our meta-analysis, there is no positive evidence of publication bias and the sensitivity analyses were performed which results did not achieve statistical significance.
On the other side, our study has inherent limitations. First, the number of articles and studies involved in our meta-analysis is insufficient, and the publication year is old. The reason for this limit is related to the human method of studying the serum C3 level of cancer patients and the individual method of searching for literature, which may lead to an insufficient sample size and amount of data (the type of cancer is not comprehensive enough; the numbers in the control and experimental groups is not large enough). Therefore, if we want to obtain more accurate and reliable conclusions, it is necessary to analyze the data of others and undertake large-scale retrospective research. Secondly, in addition to the concentrations of serum C3 in cancer patients, there are indicators (such as CH50) cannot be included in our meta-analysis due to the different units of concentration. Finally, the quality evaluation is not particularly satisfactory, which should be improved in future studies.