In this study, immunohistochemistry confirmed that the high expression rate of c-Met in GC tissues was significantly higher than that in adjacent tissues (64.95% vs 28.92%). Secondly, the study also found that the mean H-score expression of c-Met in patients with high and low expression of c-Met in cancer tissues was higher than that in adjacent tissues (P<0.05). It indicates that c-Met is highly expressed in most GCs and exerts a vital function. Many studies have also confirmed that c-Met promotes the development, proliferation, invasion, metastasis and angiogenesis of solid tumor cells through downstream signaling pathways, and even promotes chemotherapy resistance[25-28]. This study also found that the high expression of c-Met was associated with poor postoperative survival and was positively correlated with the preoperative blood CA125 level of patients, suggesting that c-Met is a promising molecule in the treatment of GC, which can be used for targeted therapy and also conducive to the monitoring of tumor progression.
C-Met-targeted therapy in GC mainly includes tyrosine kinase inhibitors, monoclonal antibodies and c-Met-targeted adoptive immunotherapy. Tyrosine kinase inhibitors and monoclonal antibodies have shown obvious antitumor activity in cell and xenograft tumor models [12, 29-32], while most tumors have not achieved prominent antitumor activity in clinical trials [7, 33]. Currently, only a few tumors have shown encouraging antitumor activity, especially in the treatment of NSCLC (non-small-cell lung cancer) [34, 35]. Furthermore, c-Met-targeted CAR-T cells have shown good antitumor activity in preclinical studies of GC[36, 37]. Since adoptive immunotherapy mainly relies on the particular expression of c-Met on the cell membrane of GC, it is not limited to the carcinogenic mechanism of c-Met. This study also found that c-Met expression was significantly increased in high-grade clinicopathological stages of GC. Therefore, the above indicated that targeted c-Met adoptive immunotherapy in the middle and late stages of GC might be a new direction for the treatment. Currently, two clinical studies on c-Met CAR-T cells in the treatment of liver cancer, GC and other solid tumors of the digestive system are being implemented in China (NCT03672305, NCT03638206) to evaluate the efficacy and safety of c-Met CAR T cells in solid tumors of the digestive system and expect to achieve good results.
Chuan Xie et al.[38] found that c-Met expression was significantly increased in GC specimens with H pylori infection, and in vitro experiments also confirmed that H pylori infection may activate the HGF/c-MET signaling pathway, which may be involved in the occurrence of GC. Secondly, Xiaojun Huang et al.[39] carried out an in-depth study and found that c-Met expression increased significantly in GC tissues with positive cytotoxin-related gene A (CagA) and H pylori infection. Meanwhile, it was also found that the activation of the c-Met signaling pathway was associated with inhibiting autophagy and promoting tumor cell invasion and metastasis in patients. However, our study found no significant increase in c-Met expression in the H pylori-positive group. H pylori infection is only one of the pathogenic causes of GC, and cancer progression and metastasis are a process of multiple oncogenes[40]. Studies have also confirmed that c-Met interacts with multiple molecules in promoting cancer progression[15, 41, 42]. The results of these studies may also be caused by the interaction between c-Met and downstream carcinogens of H pylori infection in the progression of GC. However, the occurrence and progression of GC caused by H pylori infection is also the result of the action of multiple oncogenes. Therefore, the correlation between H pylori infection and c-Met high expression requires more studies in the future to verify and explore its molecular mechanism.
As is known to all, AFP, CEA, CA199, CA153, CA125 and CA50 are common tumor markers of the digestive system. Exploring the correlation between these markers and c-Met may provide a new idea for optimizing c-Met targeting therapy strategies for GC. This study found that the correlation test between c-Met and serum CA125 level of patients was statistically significant, showing a positive correlation. Thus, it is possible to predict the expression of c-Met in tumors by detecting preoperative CA125 levels better to guide postoperative monitoring and prognosis assessment of patients. Recently, Can Hu [43] conducted a study on CA125 and its prognosis in GC patients undergoing neoadjuvant chemotherapy, and found that the level of CA125 before neoadjuvant chemotherapy was correlated with the prognosis of patients. The OS after chemotherapy decreased with the increase of CA125 levels. The study suggests that patients with serum CA125 normalization after neoadjuvant chemotherapy may benefit from survival. In addition, Hongbo Zhou et al.[44] explored the relationship between serum CA19-9, CA125 levels and HER2 expression in patients with GC, and confirmed their correlation with the risk of recurrence and metastasis. GC patients with CA19-9, CA125 and HER2 positive had a significantly higher recurrence and metastasis than those with negative GC. There was also no correlation between serum CA19-9 and CA125 and HER2 positive expression. These studies confirmed the correlation between serum CA125 level and prognosis of GC patients and the possibility of the theory of correlation between c-Met and CA125. This finding is expected to help clinicians assess the role of c-Met in GC progression by monitoring peripheral blood CA125, and thus better guide clinicians to choose c-Met inhibitors or c-Met-CAR-T cell therapy. Therefore, it provides ideas for targeting c-Met in treating of GC and other solid tumors.
This study revealed that patients with high c-Met expression had a higher clinicopathological stage and a higher likelihood of tumor metastasis. High c-Met expression was also found to be associated with poor 5-year OS. In order to research the function of c-Met in different clinicopathological stages, subgroup analysis was also conducted according to different clinicopathological stages of the tumor. The results demonstrated that the high expression of c-Met in stage Ⅰ-Ⅱ was associated with poor 5-year OS, while there was no correlation in stage Ⅲ-Ⅳ patients. ZHANG Q and Ya'nan Yang et al.[17, 45] also found that the high expression of c-Met correlated with poor prognosis in GC patients, and the results were consistent with our study. However, their research for the patient was not for a more detailed analysis. Our study innovatively stratified patients according to clinicopathological stage. Results show that the c-Met at stage Ⅰ-Ⅱ tumor tissue plays a more critical role in promoting tumor proliferation and metastasis, while this effect in stage Ⅲ-Ⅳ perhaps be weakened by other molecular mechanisms of cancer. After all, the molecular mechanism and regulation of promoting tumor proliferation and metastasis in advanced cancer are more complex. These studies suggest that inhibitors and mAb of c-Met may achieve more significant benefits in patients with early-stage GC.
Univariate and multivariate COX regression analyses were performed to investigate further the risk factors associated with 5-year survival after surgery. The results revealed that age, clinicopathological stage, high expression of c-Met and preoperative serum AFP might be independent risk factors for survival 5 years. Tobias Jagomast et al.[19] studied the prognostic value of c-Met in patients undergoing radical gastrectomy in Canada. The results demonstrated that c-Met high expression was correlative with poor OS. Multivariate analysis showed that the co-expression of EGFR and c-Met was an independent risk factor for postoperative survival of GC. However, Marina Alessandra Pereira et al.[18] recently reported that c-Met was associated with postoperative survival, but not an independent risk factor for prognosis. These studies confirmed the role of c-Met in the progression of GC and demonstrated the important role of the interaction between EGFR and c-Met in GC progression. Therefore, this molecular interaction may account for the negative or positive results of c-Met being an independent risk factor for GC.
In addition, our study found that increased preoperative AFP may be an independent risk factor for postoperative survival of GC in our included population. Xiang Xu et al.[46] conducted a meta-analysis on the effect of serum AFP level on prognosis in patients with GC before treatment. Thirteen studies involving 9,099 patients with GC was entered in the analysis. The results revealed that a high serum AFP level before treatment correlated with poor prognosis in GC patients. The above studies are consistent with our conclusions, suggesting that serum AFP level before treatment can act as a prognostic indicator of GC patients, and AFP can be used to assess the disease condition and prognosis of GC patients. However, AFP is a specific tumor marker of liver cancer, and its serum expression level in GC patients may be significantly lower than that in liver cancer patients. Therefore, more studies are needed to confirm whether AFP can be used as a specific tumor marker for GC to guide clinical practice.
This study also has some limitations. On the one hand, the sample size included in the study is limited, resulting in bias. Secondly, there is a lack of clinical data to monitor postoperative serum tumor markers in patients, leading to the failure of the correlation study between the above indicators and c-Met. However, the pathological data, clinical indicators and preoperative blood tumor markers of patients in this study were relatively complete. Therefore, the conclusion of this study is detailed and reliable.