Clinical implications and diagnostic usefulness of correlation between soluble major Histocompatibility Complex Class I Chain-Related Molecule A and Protumorigenic Cytokines in Pancreatic Ductal Adenocarcinoma

Abstract

BACKGROUND: Tumor-derived soluble factors serve as mediators between tumors and surrounding microenvironment to promote tumor growth and metastasis under a complex network. The objective of this study was to evaluate the relationships between soluble major histocompatibility complex class I chain-related molecule A (sMICA) and 4 categories of cytokines (tumor-related proinflammatory, anti-inflammatory, chemotactic/proangiogenic, and growth-stimulatory) in the development and progression of pancreatic ductal adenocarcinoma (PDAC). METHODS: Serum levels of sMICA and 4-categorized cytokines were measured by enzyme-linked immunosorbent assay and chemiluminescent immunoassay, respectively, in 134 individuals (normal, n = 55; chronic pancreatitis, n = 25; PDAC, n = 54). Clinical implications of sMICA and tumor-related cytokines, their correlations, and diagnostic usefulness in PDAC were evaluated. RESULTS: Serum sMICA, which was associated with the development and progression of PDAC, correlated with interferon-γ negatively (P = 0.024), whereas it correlated positively with the anti-inflammatory cytokines interleukin-10 (IL-10) and IL-1 receptor antagonist, and the bifunctional cytokine tumor necrosis factor α, with respect to PDAC development (P < .05). sMICA also correlated positively with the chemotactic/proangiogenic cytokines vascular endothelial growth factor, soluble CD40 ligand, and IL-8, and the tumor growth-stimulatory cytokines epidermal growth factor and transforming growth factor α, with respect to PDAC development and/or progression. Logistic regression analysis validated the diagnostic usefulness of combination use of sMICA and its related cytokines to predict the presence of PDAC and distant metastasis in PDAC, superior to carbohydrate antigen 19-9. CONCLUSIONS: sMICA may be involved in tumor-associated angiogenesis and tumor growth either directly or indirectly by affecting corresponding cytokines as well as causing impairment of natural killer cell cytotoxicity in the development and progression of PDAC. A combination of sMICA and its related cytokines exhibited remarkable diagnostic potential in PDAC.