alexa Myxomaviral Anti-Inflammatory Serpin Reduces Myeloid-Derived Suppressor Cells and Human Pancreatic Cancer Cell Growth in Mice
ISSN: 1948-5956

Journal of Cancer Science & Therapy
Open Access

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Research Article

Myxomaviral Anti-Inflammatory Serpin Reduces Myeloid-Derived Suppressor Cells and Human Pancreatic Cancer Cell Growth in Mice

Donghang Zheng1, Hao Chen1, Mee Y Bartee1, Jennifer Williams1, Jennifer A Davids1, David A Lomas3, Grant McFadden2 and Alexandra R Lucas1,2*
1Department of Medicine, University of Florida, Gainesville, FL, USA
2Department of Molecular Genetics and Microbiology, University of Florida, Gainesville, FL, USA
3University of Cambridge, Cambridge, UK
Corresponding Author : Alexandra Lucas, MD, FRCP(C)
Ethel Smith Chair Vasculitis Research
Section Head Vascular Research, Professor of Medicine
Divisions of Cardiovascular Medicine and Rheumatology
University of Florida, 1600 SW Archer Rd
PO BOX 100277, Gainesville, FL 32610-0277, USA
Tel: 1-352-672-2301
E-mail: [email protected]
Received June 15, 2013; Accepted August 16, 2013; Published August 19, 2013
Citation: Zheng D, Chen H, Bartee MY, Williams J, Davids JA, et al. (2013) Myxomaviral Anti-Inflammatory Serpin Reduces Myeloid-Derived Suppressor Cells and Human Pancreatic Cancer Cell Growth in Mice. J Cancer Sci Ther 5:291-299. doi:10.4172/1948-5956.1000219
Copyright: © 2013 Zheng D, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
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Abstract

Modification of the tumor microenvironment by inflammatory cells represents a newly recognized driving force in cancer with critical roles in tumor invasion, growth, angiogenesis, and metastasis. Increased thrombolytic cascade serine proteases, specifically urokinase-type plasminogen activator and its receptor, correlate with inflammatory cell migration, pancreatic cancer growth, invasion and unfavorable outcomes. Inflammation in pancreatic cancer is linked with myeloid-derived suppressor cell (MDSC) activity and cancer progression. Myxomavirus is a complex DNA virus encoding highly potent immune modulators. Serp-1 and M-T7 are two such secreted anti-inflammatory myxomaviral proteins. Serp-1 inhibits uPA, plasmin and coagulation factor X while M-T7 inhibits C, CC, and CXC chemokines. We have explored the potential use of these viral proteins for treatment of a range of human cancer isolates engrafted in severe combined immunodeficient (SCID) mice. Engrafted tumors were treated with either Serp-1, neuroserpin, a related mammalian serpin that inhibits thrombolytic proteases, or M-T7. Serp-1 and neuroserpin inhibited growth of the pancreatic cancer cell line Hs766t (P=0.03 and P=0.01, respectively) at 4 weeks after implantation. Serp-1 also inhibited growth of a second pancreatic cancer cell line MIA PaCa-2 in mice (P=0.02). Growth of the human breast cancer line MDA231 was not inhibited by Serp-1. M-T7, in contrast, did not alter growth of any of the cancer cell lines tested after implant into SCID mice. Serpin inhibition of pancreatic tumor growth was associated with a significant decrease in splenocyte MDSC counts by flow cytometry (P=0.009), without detected change in other splenocyte subpopulations. Serp-1 and NSP treatment also significantly reduced macrophage infiltration in tumors (P=0.001). In summary two anti-inflammatory serpins reduced inflammatory macrophage invasion and pancreatic tumor cell growth, suggesting potential therapeutic efficacy.

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