MIS5-4 - Stromal Cell-Derived Factor-1α is Associated with Gallbladder Carcinoma Progression and is a Novel Independent Poor Prognostic Factor

Abstract

ABSTRACT Background Although recent studies have suggested that stromal cell-derived factor-1α (SDF-1α) is important in the progression of various malignancies, its role in gallbladder carcinoma (GBC) remains unknown. We investigated SDF-1α expression in GBC, and its biological and prognostic role in GBC tumorigenesis. Methods We examined SDF-1α expression in tumor specimens from 72 GBC patients by immunohistochemistry and analyzed the correlation between SDF-1α expression and clinicopathologic factors or survival. The functional significance of SDF-1α expression was investigated by SDF-1α treatment; suppression of CXCR4, which is a major receptor of SDF-1α; and SDF-1α overexpression in both in vitro and in vivo studies. Results SDF-1α was differentially expressed in GBC tissues. The expression of SDF-1α was significantly associated with a high histologic grade (P = 0.042) and nodal metastasis (P = 0.015). Multivariate analyses showed that SDF-1α expression (hazard ratio [HR] 8.675; P = 0.014) was an independent risk factor for patient survival. SDF-1α significantly increased anchorage-dependent and -independent growth, migration, invasion, adhesiveness, and survival of GBC cells in vitro, and these effects were dependent on CXCR4. Consistent with these results, overexpression of SDF-1α significantly promoted tumorigenicity of GBCs in a xenograft model. Conclusions Our results indicate that GBC cells express both SDF-1α and its receptor, and SDF-1α may have a role in GBC progression through an autocrine mechanism. In addition, SDF-1α is a novel independent poor prognostic factor in patients with GBC. Thus, targeting SDF-1α and the SDF-1α receptor CXCR4 may provide a novel therapeutic strategy for GBC treatment.