Maspin expression in prostate tumor elicits host anti-tumor immunity
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Sijana H. Dzinic1,2, Kang Chen2,3,4,5,6,7, Archana Thakur2,5, Alexander Kaplun1,2,12, R. Daniel Bonfil1,2,8, Xiaohua Li1,2, Jason Liu1,2, M. Margarida Bernardo1,2, Allen Saliganan2,8, Jessica B. Back2,5, Hiroshi Yano2,5, Dana L. Schalk2,5, Elyse N. Tomaszewski2,5, Ahmed S. Beydoun1,2, Gregory Dyson2,5, Adelina Mujagic1,2, David Krass1,2, Ivory Dean1,2, Qing-Sheng Mi2,4,9, Elisabeth Heath8,11, Wael Sakr1,2, Lawrence G. Lum2,4,5,10 and Shijie Sheng1,2,5
1 Department of Pathology, Wayne State University School of Medicine, Detroit, Michigan
2 Tumor Biology and Microenvironment Program, Barbara Ann Karmanos Cancer Institute, Detroit, Michigan
3 Department of Obstetrics and Gynecology, Wayne State University School of Medicine, Detroit, Michigan
4 Department of Immunology and Microbiology, Wayne State University School of Medicine, Detroit, Michigan
5 Department of Oncology, Wayne State University School of Medicine, Detroit, Michigan
6 Department of Perinatology Research Branch, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health (NIH), Detroit, Michigan
7 Mucosal Immunology Studies Team, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, Maryland
8 Department of Urology, Wayne State University School of Medicine, Detroit, Michigan
9 Henry Ford Health Systems, Detroit, Michigan
10 Department of Medicine, Wayne State University School of Medicine, Detroit, Michigan
11 Molecular Therapeutics Program, Barbara Ann Karmanos Cancer Institute, Detroit, Michigan
12 Current address: BIOBASE Corporation, Beverly, Massachusetts
Shijie Sheng, email:
Keywords: prostate tumor xenograft, tumorigenicity, flow cytometry, CD11b+Ly6Ghigh neutrophils, neutrophil maturation and chemotaxis, B-cell antibody response, 51Cr-release assay, antibody-dependent cellular cytotoxicity, lymphangiogenesis, intratumoral fibrosis, angiogenesis, leukocyte-filled lytic and necrotic centers
Received: September 14, 2014 Accepted: October 21, 2014 Published: October 21, 2014
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.
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