CSF-1R inhibition alters macrophage polarization and blocks glioma progression

Pyonteck, S.M., et al. Nature medicine 19, 1264-1272 (2013)

Speaker: Dong-Jer Shiao (蕭東哲)                                   Time: 15:00~16:00, Dec. 25, 2013

Commentator: Dr. Pin ling (凌斌 老師)                  Place: Room 601

Abstract:

Glioma is a primary tumor in the brain. Glioblastoma multiforme (GBM) is the most aggressive type of glioma. Currently used therapies include surgery, radiation and chemotherapy. However, most therapeutic approaches targeting glioma cells have failed.  Previous studies have found that noncancerous stromal cells in the tumor microenvironment are a genetically stable therapeutic target. Tumor-associated macrophages (TAM) have been linked with the progression of cancer by favoring tumor angiogenesis, growth and metastasis [1]. Therefore the authors used a drug BLZ945, which can block tumor-associated macrophage proliferation by inhibiting Colony stimulating factor-1 receptor (CSF-1R), and indirectly to inhibit progression of glioma. In this study, PDGF-B-driven glioma (PDG) mice is an animal model of GBM, which when treated with BLZ945, substantially reduced glioma cell progression, apoptosis and improved mice survival. However, the authors found that number of TAMs in PDG mice treated with BLZ945 did not change, since the glioma cells secreted some cytokines such as GM-CSF protecting TAMs in PDG mice against CSF-1R inhibitor-induced death. Glioma conditioned medium (GCM) also triggered macrophage polarization into M2 macrophages, expression marker of M2 macrophages and suppressed phagocytosis in vivo. Surprisingly, when macrophages were treated with CSF-1R inhibitor, macrophages reduced expression of the M2 macrophages associated genes, Arg-1, Mrc1, Adm. Macrophage were able to engulf apoptotic glioma cells. In summary, BLZ945 can alter macrophage polarization and block glioma progression. Therefore BLZ945 may be a potential antitumor drug in the future.

Reference

1.     Mancino, A. & Lawrence, T. Nuclear factor-kappaB and tumor-associated macrophages. Clinical cancer research : an official journal of the American Association for Cancer Research 16, 784-789 (2010)