Gastric cancer, despite its decreasing incidence, represents one of the major health problem worldwide and the fifth most common type of cancer [1]. Gastric cancer is a silent disease frequently diagnosed in advanced stages, which is responsible for its elevated mortality especially among the elderly population where the incidence is significantly higher [2, 3]. Advances in technology have allowed the development of several methods to understand the mechanisms underlying gastric carcinogenesis, resulting in the identification of a large number of molecular targets that can be used as biomarkers with diagnostic and prognostic potentials. Recent studies have identified CD26/ dipeptidyl peptidase 4 (DPP4) as a gene that affects the invasiveness of many tumor cells [4–8] and it is consistently associated with cancer. CD26/dipeptidyl peptidase 4 is a widely expressed cell surface peptidase that exhibits a complex biology with three different functions: adenosine deaminase (ADA) binding, serine peptidase activity, and extracellular matrix (ECM) binding. CD26 may be cell membrane-anchored or in a soluble form, occurring in the serum (sCD26). Cell-associated CD26 is widely expressed on T cells, B cells, natural killer cells, endothelial cells and epithelial cells. The different biological activities of CD26 and its ubiquitous expression may reflect its diverse, sometimes opposing functions in physiological and pathological settings [9].

A deficiency in solubilized CD26 was reported in total homogenates of tumors of colon, kidney, lung and liver. On the contrary, cell-surface CD26 expression has been correlated with disease aggressiveness of T and B cell lymphomas and leukaemias, follicular cell-derived thyroid carcinomas and basal cell carcinomas [10]. In addition, serum DPP4 levels is increased in patients with hepatic cancer and decreased in patients with blood, solid and oral cancer [10, 11]. Recently, CD26 has been identified as a serum marker for colorectal cancer detection [11–13] as well as a prognostic factor able to promote human colorectal cancer metastasis [14], while to best of our knowledge no study investigated the role of serum CD26 in gastric cancer. Only a previous study suggested that CD26 expression level in surgical samples may be considered a reliable biomarker of malignant GISTs of the stomach characterized by distinct clinical, genetic, and histopathological features [15]. Considering that non-invasive biological serum markers would be of great benefit for screening, we aimed at investigating the potential role of CD26 serum levels as a diagnostic marker for gastric cancer detection.

The major findings of our investigation are: i) patients affected by gastric cancer have significantly lower serum CD26 levels compared with healthy subjects ii) CD26 serum levels are associated with gastric cancer presence iii) CD26 measurement shows higher diagnostic efficiency compared CEA and CA19.9 in gastric cancer iiii) patients with HER2 positive tumors have significantly lower serum CD26 levels compared with the HER2 negative counterpart.

Gastric cancer represents the third most common cause of cancer-related death in the world and most patients present advanced disease at diagnosis making its treatment very intricate [1–3]. It is widely accepted that early diagnosis and treatment are keys for better clinical outcome in patients with gastric cancer [2, 3].

CD26 is a multifunctional cell surface glycoprotein with intrinsic dipeptidyl peptidase 4 activity particularly expressed on epithelial cells and lymphocytes [9, 17, 18]. However, CD26 also exists as a soluble circulating form in plasma and its role it is still unknown. Cell surface proteases participate in malignant transformation and cancer progression by promoting invasion and metastasis. Sometimes they can also gave an opposite effect, this is the case of CD26 [11, 17]. In fact, surface CD26 expression is lost or altered in melanoma, hepatocellular carcinoma and colon cancer cells [10]. It has been suggested that CD26 with its enzymatic activity is able to degrade growth factors required for survival and invasiveness of tumor cells [12]. Also serum CD26 is substantially dysregulated in various cancers: serum CD26 levels are increased in patients with hepatic cancer and decreased in patients with blood, thyroid and oral cancers [10, 11]. Recently, CD26 has been identified as a serum marker for colorectal cancer detection and prognostic factor [12–14] while to best of our knowledge no study investigated the role of serum CD26 in presence of gastric cancer.

With this preliminary study we found that patients affected by gastric cancer have lower levels of circulating serum CD26 compared with healthy controls, thus representing a powerful biomarkers of gastric cancer. We found a lack of any association of sCD26 levels with tumor localization, size, type, differentiation, TNM, stage or lymph node metastases. Accordingly Cordero and colleagues [12, 13] did not found any relationship between the levels of sCD26 and the Dukes’ stage classification in patients affected by colorectal cancer. These data collectively suggest the potential usefulness of this molecule for early diagnosis of gastric cancer. The regression analysis showed that lower sCD26 levels were associated to gastric cancer presence independent of age, gender and others tumors biomarkers (CA19.9 and CEA). This findings further support the relevance of CD26 as a new diagnostic marker for gastric cancer with higher efficiency compared with other available biomarkers as shown by the ROC curve. Whether lower CD26 serum levels are associated with lower or higher tumor surface expression is unknown and may represent a limitation of this study. However, previous evidence are showing that impairment in sCD26 in colorectal cancer does not seem to be originated by alteration of CD26 on tumour cells [11–13]. Thus, we can speculate that the drop in serum CD26 levels may be related to a dysfunction in the immune system status in patients with gastric cancer. In fact, a cross-talk between the lymphoid lineage and malignant tumors in vivo have been long discussed and some data about the immune defective antitumor response in many cancers, such as colonic, have been described before, including a defect in IL-12 production [19], which is a well-known CD26 up-regulator on T cells [20]. Again in oral cancer patients, in which around a 50 % decrease in serum CD26 activity has been reported, a correlation between sCD26 and CD26+ T was found, and the mount of CD26 in T lymphocyte plasma membranes were significantly lower than in healthy subjects [21]. Thus, even in the gastric cancer, the hypothetic role of sCD26 in crosstalk between the immune system and carcinogenesis, cannot be ruled out. Further studied are needed to test such an hypothesis and to collect the lymphocyte count, subset distribution and other immune parameters in patients with gastric cancer. Interestingly recent studies are showing that sCD26 therapy enhances the immune function in some pathological conditions such as AIDS [22] and it might be interesting to analyze if gastric cancer patients may well benefit from exogenous sCD26 treatment.

Our most important finding is that lower serum CD26 levels were found particularly in sera of patients with HER2 positive tumors. Upon the increased knowledge of breast cancer cells molecular pathways, the biological feature of gastric cancer is becoming more clear and particular attention should be paid to the identification of the human epidermal growth factor receptor-2 (HER2) amplified gastric cancer subtype. This latter accounts for 10–38 % of all gastric cancers, with an higher prevalence in tumors from the upper third of the stomach than in those located in more distal areas, as well as in Lauren’s intestinal type than in diffuse-type gastric cancer [23]. HER2 protein overexpression on the gastric cancer cells’ surface with its enhanced and prolonged signals influence particularly the carcinogenesis processes determining distinctive clinic-pathological phenotype characterized by acquisition of advantageous properties for excessive and uncontrolled cell growth, identifying a distinctive gastric cancer entity [24]. From a prognostic perspective, even though the negative prognostic effect of HER2 positivity in breast cancer is well assessed, the relationship between HER2 status and prognosis of gastric cancer patients remains controversial [25]. Nevertheless the administration of standard chemotherapy with Trastuzumab, a monoclonal antibody that binds to the extracellular domain of the HER2 receptor blocking its downstream signaling, shows a clinically meaningful improvement in overall survival for patients with HER2-positive advanced gastric cancer [26]. The lower serum CD26 levels in patients with HER2 positive tumors suggests an attractive linking mechanism between innate effector cells/T-cells immunity and the anti-tumoral effects. Supporting this, it has been demonstrated that CD26 is a potential target for amino boronic dipeptide PT-100, a dipeptidyl peptidase (DPP) inhibitor, which is able to augment the effect of trastuzumab on the growth inhibition of HER2 positive carcinoma cell lines in animal models [27].

Indeed, establishing the diagnosis at an early stage in gastric cancer, with a simple biochemical index, is a current subject of research in clinical oncology. The CEA levels are the marker of reference in this neoplasia, although not recommended as diagnostic test [28]. Our results revealed that sensitivities of sCD26 were higher at different specificity levels than those of CEA or CA 19.9 as well as efficiency. Indeed, the fact the CD26 levels significantly increase after surgery may indicate that the sCD26 serum level may be used also as prognostic marker. However further studies are needed to validate such an hypothesis.

Using novel biomarkers to early gastric cancer detection may potentially decrease mortality and medical costs. Preoperative sCD26 level may represent an useful and easy biomarker for early detection of gastric cancer. Indeed the finding that patients with HER2 positive tumors have lower sCD26 levels may have clinical potential in gastric cancer management improving the effect of drugs on the growth inhibition of HER2 positive cancers.