Abstract 524: Myxomaviral Anti-angiogenesis Protein Serp-1 Inhibits Pancreatic Cancer Growth in Mice
Modification of the tumor microenvironment by inflammatory cells represents a newly recognized driving force in cancer with a critical role in tumor invasion, growth, angiogenesis, and metastasis. Increased serine proteases in the thrombolytic cascade, specifically urokinase-type plasminogen activator and its receptor, correlate with inflammatory cell invasion, angiogenesis, cancer growth and invasion. Inflammation in pancreatic cancer is linked with myeloid-derived suppressor cell activity and cancer progression. Myxomavirus is a complex DNA virus encoding highly potent immune modulators such as Serp-1, which inhibits uPA, tPA, plasmin and coagulation factor X. Serp-1 has also been demonstrated to inhibit angiogenesis in a chicken chorioallantoic membrane (CAM) model. To explore the potential use of anti-inflammatory, anti-angiogenesis proteins that target thrombotic and thrombolytic as well as inflammatory pathways, for cancer treatment, severe combined immunodeficient (SCID) mice engrafted with human cancer cells were treated with Serp-1 and neuroserpin, a selective mammalian inhibitor of thrombolytic proteases or control saline. Proteins were tested for efficacy in preventing human pancreatic and breast cancer cell growth in NOD/SCID mice (n=67 total) at 4 weeks after implantation. Serp-1 and neuroserpin inhibited pancreatic cancer Hs766t (n=27; P=0.03 and P=0.01, respectively), but not breast cancer MDA231 growth (n=11) when compared to saline controls (N =5). Serpin inhibition of pancreatic tumor growth was associated with decreased MDSC as shown by flow cytometry analysis of splenocyte (P=0.009). Serpin-mediated anti-inflammatory activity in pancreatic tumor growth was also demonstrated by reduced macrophage infiltration in tumors (P=0.001). Furthermore, RT-PCR array analysis revealed a five-fold decrease in the expression of inducible nitric oxide synthase (iNOS), which has been shown to play important role in tumor angiogenesis.
Conclusions Anti-inflammatory protease inhibitors, virus-derived Serp-1 and mammalian neuroserpin, may provide new treatment approaches by targeting the angiogenesis and inflammatory responses that support cancer cell growth.
- © 2013 by American Heart Association, Inc.