Abstract
The goal of the current study is to examine the biological effects of epithelial-specific tumor suppressor maspin on tumor host immune response. Accumulated evidence demonstrates an anti-tumor effect of maspin on tumor growth, invasion and metastasis. The molecular mechanism underlying these biological functions of maspin is thought to be through histone deacetylase inhibition, key to the maintenance of differentiated epithelial phenotype. Since tumor-driven stromal reactivities co-evolve in tumor progression and metastasis, it is not surprising that maspin expression in tumor cells inhibits extracellular matrix degradation, increases fibrosis and blocks hypoxia-induced angiogenesis. Using the athymic nude mouse model capable of supporting the growth and progression of xenogeneic human prostate cancer cells, we further demonstrate that maspin expression in tumor cells elicits neutrophil- and B cells-dependent host tumor immunogenicity. Specifically, mice bearing maspin-expressing tumors exhibited increased systemic and intratumoral neutrophil maturation, activation and antibody-dependent cytotoxicity, and decreased peritumoral lymphangiogenesis. These results reveal a novel biological function of maspin in directing host immunity towards tumor elimination that helps explain the significant reduction of xenograft tumor incidence in vivo and the clinical correlation of maspin with better prognosis of several types of cancer. Taken together, our data raised the possibility for novel maspin-based cancer immunotherapies.
Highlights
Maspin, an epithelial-specific member of the serine protease inhibitor superfamily, was first discovered in 1994 as a tumor suppressor in breast cancer [1]
Genes commonly regulated by maspin were a subset of histone deacetylase 1 (HDAC1) target genes that were closely associated with epithelial differentiation and transforming growth factor-β (TGF-β) signaling
To directly investigate the effect of maspin expression in tumor cells on tumor growth and interaction with the host environment in vivo, we inoculated athymic nude mice subcutaneously (s.c.) with either DU145 cells stably transfected with human maspin (M7) or those transfected with an empty vector (Neo)
Summary
An epithelial-specific member of the serine protease inhibitor (serpin) superfamily, was first discovered in 1994 as a tumor suppressor in breast cancer [1]. Consistent with clinical data, functional studies revealed tumor suppressive functions of maspin in a range of biological processes in tumor cells, including cell differentiation, apoptosis, and angiogenesis [9,10,11,12,13,14]. Genes commonly regulated by maspin were a subset of histone deacetylase 1 (HDAC1) target genes that were closely associated with epithelial differentiation and transforming growth factor-β (TGF-β) signaling. We have previously shown that maspin can sensitize tumor cells to drug induced apoptosis in vitro [15]. Maspin has been shown to reduce tumor-derived vascular endothelial growth factor (VEGF) expression and angiogenesis [11, 16]
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