Loss Of Sparc In P53-Null Astrocytes Alters Collagen Deposition And Promotes Macrophage Activation And Tumor Phagocytosis

Proceedings: AACR 106th Annual Meeting 2015; April 18-22, 2015; Philadelphia, PABoth the induction of SPARC expression and the loss of the p53 tumor suppressor gene are changes that occur early in glioma development. Therefore, the upregulation of SPARC may cooperate with the loss of p53 to enhance cell survival and inhibit apoptosis during glioma formation. This study determined whether the loss of Sparc in astrocytes that are null for p53 (p53-null/Sparc-null) would result in reduced cell survival and tumor formation and increased tumor immunogenicity in an in vivo xenograft brain tumor model. In vitro, the loss of Sparc in p53-null astrocytes resulted in an increase in cell proliferation (15-33%, pu003c0.01); however, there was an inhibition of growth in soft agar. Intracranial xenografts of p53-null/Sparc-wt and p53-null/Sparc-null astrocytes were assessed for tumor size, proliferation rate, and SPARC expression. At 7 days post-implantation, Sparc-null astrocytes produced significantly smaller tumors (Wilcoxon rank-sum test p = 0.0091, median = 0.709mm2 for Sparc-wt and 0.240mm2 for Sparc-null) with a significantly lower MIB-1 proliferation index (Wilcoxon rank-sum test p = 0.0345, median = 8.6% for Sparc-wt and 0.4% for Sparc-null). By CD68 and periodic acid Schiff +/- diastase staining of xenograft tumors, it was found that Sparc-null tumors had a massive infiltration of microglia/macrophages with a phagocytic appearance compared to the activated, but non-phagocytic, microglia/macrophages present within the Sparc-wt tumors. The loss of Sparc in astrocytes and the resulting increase in microglia/macrophage activation lead to an alteration in the tumor microenvironment with increased collagen deposition and altered collagen structure at both 7 and 50 days post-implantation as assessed by picrosirius red and polarized light microscopy. Sparc-null tumors had increased collagen deposition with a long fiber structure compared to the small bundles of collagen present in Sparc-wt tumors. Our results indicate that the loss of p53 by deletion/mutation in the early stages of glioma formation may cooperate with the induction of SPARC to potentiate cancer cell survival and escape from immune surveillance.Citation Format: Stacey L. Thomas, Chad R. Schultz, Ezekiell Mouzon, William A. Golembieski, Nancy Lemke, Laila M. Poisson, Jorge A. Gutierrez, Sandra Cottingham, Sandra A. Rempel. Loss of Sparc in p53-null astrocytes alters collagen deposition and promotes macrophage activation and tumor phagocytosis. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2363. doi:10.1158/1538-7445.AM2015-2363