Abstract
37 Background: Despite being a leading cause of cancer-related death world wide, gastric adenocarcinoma (GA) lacks distinctive biomarkers and targeted therapies. Underexpression of the E-cadherin gene in GA is associated with an aggressive phenotype and a poor prognosis but the mechanisms of this difference are poorly understood. Developing effective therapies for GA requires identification of critical functional markers and deeper understanding of its pathophysiology. Methods: Unsupervised hierarchical clustering analysis of a publicly available 230-sample GA microarray dataset identified a prominent cluster (21.7%) associated with underexpression of E-cadherin and overexpression of a Wnt-family protein: secreted frizzled-related protein 1 (sFRP-1). Archival GA specimens were then assessed for the expression of sFRP-1 by immunohistochemistry. Prognostic significance was assessed using univariate and multivariate analyses. GA cell lines transfected with sFRP-1 were used to determine the role of sFRP-1 in gastric cancer. Results: 85 patients with GA underwent surgery with curative intent; 39 stained positive for sFRP-1 (46%). In this positive group, sFRP-1 staining was focal; was commonly found on the leading edge of the infiltrating tumor mass; and was not restricted to one histopathologic group, grade, or clinical stage. On univariate analysis T stage, nodal involvement, pathologic stage, nuclear grade, E-cadherin status and sFRP-1 status were predictive of overall survival. In a multivariate model, T stage (p < 0.001), nuclear grade (p < 0.001), E-cadherin status (p = 0.031) and sFRP-1 status (p = 0.0097) were predictive of overall survival. Overexpression of sFRP-1 in GA cell lines induced mesenchymal phenotype, enhanced growth and stem cell-like properties. sFRP-1 also attenuated Wnt signaling and E-cadherin expression, but potentiated Notch and Hedgehog signaling known to be involved in GA progression. These findings suggest a Wnt-independent mechanism mediated by sFRP-1. Conclusions: The aggressive biological subtype of gastric cancer may be linked to overexpression of sFRP-1. Our findings identify sFRP-1 as a functional prognostic biomarker for gastric cancer, which may serve as a potential therapeutic target. No significant financial relationships to disclose.
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