Circulating blood levels of IL-6, IFN-γ, and IL-10 as potential diagnostic biomarkers in gastric cancer: a controlled study

Abstract

Background: Gastric adenocarcinoma is the third most common cause of cancer-associated death worldwide. Helicobacter pylori infection activates a signaling cascade that induces production of cytokines and chemokines involved in the chronic inflammatory response that drives carcinogenesis. We evaluated circulating cytokines and chemokines as potential diagnostic biomarkers for gastric cancer.

Methods: We included 201 healthy controls and 162 patients with distal gastric cancer who underwent primary surgical resection between 2009 and 2012 in Mexico City. The clinical and pathological data of patients were recorded by questionnaire, and the cancer subtype was classified as intestinal or diffuse. Pathological staging of cancer was based on the tumor-node-metastasis staging system of the International Union Against Cancer. Concentrations of IL-1β, IL-6, TNF-α, IL-10, and MCP-1 in serum were measured using multiplex analyte profiling technology and concentrations of IL-8, IFN-γ, and TGF-β in plasma were measured using enzyme-linked immunosorbent assay.

Results: Levels of IL-1β, IL-6, IFN-γ, and IL-10 were significantly higher and that of MCP-1 was lower in gastric cancer patients compared with controls. No differences in IL-8 or TNF-α levels were observed between gastric cancer and controls. IFN-γ and IL-10 were significantly higher in both intestinal and diffuse gastric cancer, whereas IL-1β and IL-6 were higher and TGF-β lower only in intestinal gastric cancer; MCP-1 was lower only in diffuse gastric cancer. IFN-γ and IL-10 levels were significantly higher in early (I/II) and late stage (III/IV) gastric cancer; IL-1β and IL-8 were higher and MCP-1 was lower only in late stage (IV) patients. Receiver-operating characteristic analysis showed that for diagnosis of GC, IL-6 had high specificity (0.97) and low sensitivity (0.39), IL-10 had moderate specificity (0.82) and low sensitivity (0.48), and IL-1β and IFN-γ showed low specificity (0.43 and 0.53, respectively) and moderate sensitivity (0.76 and 0.71, respectively).

Conclusions: Increased levels of IL-6, IFN-γ, and IL-10 might be useful as diagnostic biomarkers for GC; however, this needs to be confirmed with larger number of patients and with control groups other than blood donors, properly age paired. IL-1β, IL-6, MCP-1, and TGF-β differentiate intestinal from diffuse GC. IFN-γ and IL-10 might be useful for diagnosis of early stage GC, and IL-1β, IL-8, and MCP-1 for late stages of the disease.

Keywords: Biomarker; Gastric cancer; Helicobacter pylori; Immunosuppressive mediators; Inflammatory cytokines.

Fig. 1

The circulating concentrations of IL-1β, IL-6, IFN-γ, IL-10, MCP-1, and TGF-β differ between healthy controls and gastric cancer patients. Circulating concentrations of IL-1β (a), IL-6 (b), IFN-γ (c), IL-10 (d), MCP-1 (e), and TGF-β (f) in healthy controls and patients with gastric cancer were measured by ELISA or xMAP. The gastric cancer group was divided into diffuse (DGC) and intestinal (IGC) types. All measurements were made in duplicate. The statistical analysis was performed by Mann–Whitney U test and the results for each group are presented as median with interquartile range

Fig. 2

Analyses of circulating cytokines by TNM stage of GC show important differences between different stages of GC and healthy controls. Circulating levels of IL-1β (a), IL-6 (b), IFN-γ (c), IL-10 (d), IL-8 (e), MCP-1 (f), TNF-α (g), and TGF-β (h) in healthy controls and gastric cancer patients classified according to the TNM staging as stage I/II, III, or IV were measured by ELISA or xMAP. All measurements were made in duplicate. The statistical analysis was performed by Mann–Whitney U test and results for each group are presented as median with interquartile range