The cathepsins that have already shown an increased expression in the presence of gastric cancer are B, E, K, L, S, X, and Z. To date, there are only a few studies that sought to assess the relation between CTTS and gastric cancer [7, 8]. This enzyme appears to play an important role in the tumor invasion process through the degradation of the extracellular matrix, modulation of the immune response, and regulation of several cell signaling pathways, including the activation of tyrosine kinase receptors, especially c-Met, matrix metalloproteinases, IL-11, CXCL16, and Integrin alpha-6-beta-4 [2, 7, 9]. Still, specifically for gastric adenocarcinoma, CTTS appears to have an activating effect on the MKN7 and MKN45 cancer cell lines .
Liu et al.  evaluated the serum dosage of CTTS in patients with gastric cancer by comparing the results with healthy patients and with benign gastric lesions. They observed that the serum CTTS values of patients with gastric cancer were significantly higher than those of non-tumor gastric tissue controls (P < 0.001). Still in this study, the authors investigated the diagnostic power of CTTS in their sample of 496 patients, finding sensitivity and specificity values of 60.7% and 90%, respectively. Additionally, in this study, there was a significant decrease in serum CTTS levels after surgical resection of the tumor, suggesting an intimate relation between this enzyme and the tumor microenvironment. In our study, we found similar results, with CTTS expression significantly higher in the group of patients with gastric adenocarcinoma compared to those of controls. The results of these studies suggest that CTTS may be a potential biomarker for the diagnosis of gastric cancer.
Yang et al.  studied the expression of cathepsins through a proteomic analysis of cultures of normal cells and gastric cancer. We observed a higher protein expression and a positive regulation of cathepsin S in gastric cancer cell secretome. There were no statistically significant differences in CTSS expression between the intestinal, diffuse, and mixed subtypes.
Researchers have shown a correlation between CTTS and disease characteristics, such as tumor size, lymph node invasion, distant metastases, and overall survival, noting that higher CTTS expressions were related to more advanced TNM stages and worse survival rates . In the present study, there was no statistically significant association between CTTS expression and tumor staging or survival rates. A possible explanation for such a difference between the studies is the number of patients included, which was noticeably lower in our analysis.
Infection of the gastric mucosa by H. pylori is known to be an important risk factor for the development of gastric adenocarcinoma. However, the exact mechanisms of activation of carcinogenesis are not yet fully elucidated . One of the possible mechanisms pointed out in this process is the pro-inflammatory response orchestrated by Th17 cells in the infected gastric mucosa [11, 12]. Previous studies have shown an association between infection by H. pylori and increased levels of expression of cathepsins D and X. However, there are no studies determining the behavior of CTTS in the presence of an infection by H. pylori [13, 14]. In the present study, we evaluated the expression of CTTS in samples of gastric mucosa infected by H. pylori. We observed that 87.5% of the samples in the gastritis group with H. pylori showed positive expression for CTTS, contrasting with only 12.5% of the gastritis group without H. pylori. These results reinforce the hypothesis that CTTS is involved in the process of carcinogenesis of gastric adenocarcinoma, since it also has a higher expression.
This study has some limitations that deserve attention. First is the sample size, which, as a result of the single-center character of this study, was limited, with a sample power of 72.7%. As the sample was non-probabilistic, and selected by convenience, we did not calculate the sample size since we included in the analysis all patients operated on during the study period. Another limitation that is worth mentioning is in relation to the observational and cross-sectional nature of this study. A longitudinal analysis could provide more accurate information about the relationship between CTTS expression and patient survival. However, for our primary result, the methodology applied was adequate.
In contrast to the limitations discussed above, the present study reports important data that provide robustness and authenticity to the analysis. It is one of the few studies to study the expression of CTTS in samples of gastric adenocarcinoma in humans and the first to attest a possible relationship between the expression of this enzyme and infection by H. pylori, an important risk factor for the development of gastric adenocarcinoma.