Human cancer is a chronic disease that originates from transformed cells harboring genetic as well as epigenetic alterations. However, cancer is not composed merely of cancer cells. Cancer tissue contains other cell types, including fibroblasts and epithelial cells, immune cells, and cells forming blood vessels and lymphatic vasculature [27
]. In this complex tumor microenvironment, inflammatory mediators regulate different stages of tumor development, including initiation, promotion, invasion, and metastasis [28
S100A9, a member of S100 family, is abundant in granulocytes, monocytes and activated keratinocytes during various inflammatory conditions. In this study, we found that S100A9 was specifically located in inflammatory cells infiltrating gastric cancer tissues and chronic gastritis tissues, while all gastric cancer cells or adjacent cells of gastric mucosa did not express S100A9. Our results agree with previous studies demonstrating high expression of S100A9 in infiltrating immune cells in various cancer types including colorectal cancer [21
] and pancreatic cancer [29
]. At the same time, in other cancer types, such as lung cancer [16
], prostate cancer [17
], and breast cancer [19
], S100A9 is expressed mainly by neoplastic tumor cells themselves. It has been suggested that tumor cells of glandular origin can express S100A9 when they are poor differentiated [18
] or under pathological stress conditions [31
]. However, we did not find any S100A9-positive gastric cancer cell including poorly differentiated ones. High expression of S100A9 in the inflammatory cells in gastric cancer tissues may indicate that S100A9 plays an important role in gastric cancer development.
Correlation among S100A9 expression, clinicopathological features and patient prognosis varies in different cancer types. In lung cancer [16
] and invasive ductal carcinoma of the breast [19
], overexpression of S100A9 in cancer cells has been shown to contribute to the development and progression of cancer. In thyroid carcinoma [34
], expression of S100A8 and S100A9 in cancer cells is crucial for dedifferentiation. In bladder tumors, overexpression of S100A4, S100A8 or S100A11, but not S100A9 in cancer tissues is associated with stage progression, invasion, metastasis and poor survival [35
]. So far studies of S100A protein expression in inflammatory cells infiltrating cancer have been rare due to lack of appropriate way to quantify the S100A expression by inflammatory cells. Only two studies evaluated S100A9 expression in a cancer-associated environment [21
]. The results in colorectal cancer showed that high S100A9 cell count was not associated with patient survival but instead positively correlated with tumor size [21
]. The other study revealed that the ratio of S100A9- and S100A8- positive cells in the stroma was affected by the status of tumor suppressor protein Smad4 in corresponding pancreatic cancer cells [29
]. Our results showed that high S100A9 cell count in gastric cancer tissues was negatively correlated with advanced pathological cancer stages, lymph node metastasis, and tumor invasion. Importantly, presence of S100A9-positive inflammatory cells in cancer tissues also correlated with a better prognosis in patients with gastric cancer. In addition, the cell count of S100A8, a dimerization partner of S100A9, was not correlated with the clinicopathological features or overall survival in patients with gastric cancer. Remarkably, expression of S100A8/A9 heterodimerization complex was apparently absent in gastric cancer tissues, while it was detected in gastritis and control inflammation tissues such as appendicitis. The differential expression and subcellular localization of S100A9 and S100A8/A9 in various tissues may indicate that only S100A9 plays a role in gastric cancer development.
The association of S100A9 expression with different clinicopathological features and patient prognosis among a variety of cancer types suggests that the function of this molecule can be diverse. Growing evidence suggests that S100A9 and its close partner S100A8 and the heterodimer of S100A8/A9 can exhibit both pro- and anti-tumorigenic functions during tumorigenesis [36
]. On one side, the up-regulation of calprotectin is a characteristic feature in pathological conditions of hyperproliferative carcinomas [38
]. On the other side, several in vitro studies have demonstrated that these proteins exhibit growth-inhibitory properties as well as promote cytotoxicity and apoptosis in many cancer types [36
]. Numerous studies have demonstrated the dichotomic effects of these molecules in vitro. In this study, the exogenous S100A9 recombinant protein plays a role in inhibiting the gastric cancer cell line BGC-823 migration and invasion.
The inconsistent association of S100A expression with clinicopathological features and patient prognosis among cancers may be caused by the complexity of the cancer microenvironment. Immune mediators such as S100A9 can play both anti-tumor and tumor promoting roles depending on the cancer types [39
]. Studies have suggested that tumor promoting inflammation and anti-tumor immunity co-exist at different points along the path of tumor progression, and that environmental and microenvironmental conditions dictate the balance between the two [41
]. Since direct in vivo models for evaluating the effects of these phenomena on cancer progression are lacking, further studies are warranted.