Stromal SPARC expression and patient survival after chemoradiation for non-resectable pancreatic adenocarcinoma

Abstract

Purpose Pancreatic stellate cells (PSC) drive desmoplasia in pancreatic cancer. Our study analyzed both tumor and PSC, since interaction of these cell types may promote tumor progression. Experimental design Immunohistochemical expression of SPARC, CTGF, TGF-β1, phospho-Akt, survivin and α-SMA was analyzed prior to chemoradiation in 58 locally advanced pancreatic cancer (LAPC) biopsy specimens. Fisher’s exact test served to detect associations between tumor and PSC expression of markers. Kaplan-Meier analysis and multivariate analysis were used to evaluate the association of marker expression with overall survival. SPARC expression was analyzed in human pancreatic cancer cells (Panc-1) and in human PSC (hPSC), and the effect of SPARC on the invasion of Panc-1 cells was measured in monoculture or in coculture with hPSC. Results SPARC was expressed predominantly in the peritumoral and distal stroma. SPARC in distal stroma correlated inversely with overall survival of the patients with LAPC (p=0.013) with a relative hazard of 2.23 (95% CI, 1.05 to 4.72; P=0.036). TGF-β1 in the tumor was also a negative prognostic factor (P=0.03). Within the tumor cells, phospho-Akt correlated with TGF-β1, SPARC and survivin. Tumor phospho-Akt correlated with stroma phospho-Akt, tumor TGF-β1 correlated with stroma TGF-β1 and α-SMA, tumor survivin correlated with stroma survivin and distal SPARC. Within the stroma, SPARC and TGF-β1 correlated with α-SMA. Peritumoral SPARC correlated with distal SPARC. In vitro, SPARC was highly expressed in hPSC but not in Panc-1 cells. Exogenous SPARC did not change radiation resistance but increased the invasion of Panc-1 cells both in monoculture and in coculture with hPSC. Conclusions Our hypothesis of a detrimental effect of PSC on patient survival in LAPC after chemoradiation is supported by the inverse correlation of SPARC in distal stromal cells with patients survival. Furthermore in vitro data indicate that paracrine SPARC from PSC increases the invasion of pancreatic cancer cells.