Ablation of Neuropilin 1 from glioma-associated microglia and macrophages slows tumor progression
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Jeremy T. Miyauchi1, Danling Chen1, Matthew Choi1, Jillian C. Nissen1, Kenneth R. Shroyer2, Snezana Djordevic3, Ian C. Zachary4, David Selwood5 and Stella E. Tsirka1
1 Department of Pharmacology, Stony Brook University, Stony Brook, NY, USA
2 Department of Pathology, Stony Brook University, Stony Brook, NY, USA
3 Institute of Structural and Molecular Biology, University College London, London, UK
4 Centre for Cardiovascular Biology and Medicine, Division of Medicine, University College London, London, UK
5 Wolfson Institute for Biomedical Research, University College London, London, UK
Stella E. Tsirka, email:
Keywords: glioma, Neuropilin 1, microglia, immunomodulation, macrophage
Received: September 01, 2015 Accepted: January 03, 2016 Published: January 10, 2016
Gliomas are the most commonly diagnosed primary tumors of the central nervous system (CNS). Median times of survival are dismal regardless of the treatment approach, underlying the need to develop more effective therapies. Modulation of the immune system is a promising strategy as innate and adaptive immunity play important roles in cancer progression. Glioma associated microglia and macrophages (GAMs) can comprise over 30% of the cells in glioma biopsies. Gliomas secrete cytokines that suppress the anti-tumorigenic properties of GAMs, causing them to secrete factors that support the tumor’s spread and growth. Neuropilin 1 (Nrp1) is a transmembrane receptor that in mice both amplifies pro-angiogenic signaling in the tumor microenvironment and affects behavior of innate immune cells. Using a Cre-lox system, we generated mice that lack expression of Nrp1 in GAMs. We demonstrate, using an in vivo orthotopic glioma model, that tumors in mice with Nrp1-deficient GAMs exhibit less vascularity, grow at a slower pace, and are populated by increased numbers of anti-tumorigenic GAMs. Moreover, glioma survival times in mice with Nrp1-deficient GAMs were significantly longer. Treating wild-type mice with a small molecule inhibitor of Nrp1’s b1 domain, EG00229, which we show here is selective for Nrp1 over Nrp2, yielded an identical outcome. Nrp1-deficient or EG00229-treated wild-type microglia exhibited a shift towards anti-tumorigenicity as evident by altered inflammatory marker profiles in vivo and decreased SMAD2/3 activation when conditioned in the presence of glioma-derived factors. These results provide support for the proposal that pharmacological inhibition of Nrp1 constitutes a potential strategy for suppressing glioma progression.
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