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

Overview

Journal J Cancer Sci Ther

Publisher Omics Publishing Group

Date 2015 Mar 24

PMID 25798214

Citations 9

Authors

Donghang Zheng

Hao Chen

Mee Y Bartee

Jennifer Williams

Jennifer A Davids

David A Lomas

Grant McFadden

Alexandra R Lucas

Affiliations

Soon will be listed here.

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.

Citing Articles

Urokinase-Type Plasminogen Activator Receptor (uPAR) in Inflammation and Disease: A Unique Inflammatory Pathway Activator.

Hamada M, Varkoly K, Riyadh O, Beladi R, Munuswamy-Ramanujam G, Rawls A Biomedicines. 2024; 12(6).

PMID: 38927374 PMC: 11201033. DOI: 10.3390/biomedicines12061167.

Viral SERPINS-A Family of Highly Potent Immune-Modulating Therapeutic Proteins.

Varkoly K, Beladi R, Hamada M, McFadden G, Irving J, Lucas A Biomolecules. 2023; 13(9).

PMID: 37759793 PMC: 10526531. DOI: 10.3390/biom13091393.

TNFSF15 and MIA Variant Associated with Immunotherapy and Prognostic Evaluation in Esophageal Cancer.

You J, Bian J, Chen J, Xia T, Deng A, Zhang M J Oncol. 2023; 2023:1248024.

PMID: 36936375 PMC: 10023233. DOI: 10.1155/2023/1248024.

The Role of Myeloid-Derived Suppressor Cells in the Treatment of Pancreatic Cancer.

Dong P, Yan Y, Fan Y, Wang H, Wu D, Yang L Technol Cancer Res Treat. 2022; 21:15330338221142472.

PMID: 36573015 PMC: 9806441. DOI: 10.1177/15330338221142472.

Neuroserpin, a crucial regulator for axogenesis, synaptic modelling and cell-cell interactions in the pathophysiology of neurological disease.

Godinez A, Rajput R, Chitranshi N, Gupta V, Basavarajappa D, Sharma S Cell Mol Life Sci. 2022; 79(3):172.

PMID: 35244780 PMC: 8897380. DOI: 10.1007/s00018-022-04185-6.

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