SR-A Inhibits Glioma Progression Through Regulation Of TAM Polarization

Gliomas are the most frequent primary tumors of the central nervous system and there is no effective therapy to inhibit its invasion and proliferation.As an important component of glioma stroma cells,macrophage/microglia plays critical roles in promoting glioma initiation,malignant progression and the suppression of antitumor immunity by creating a favoring microenvironment for glioma.But different types of macrophage/microglia may have different functions during the distinct periods of glioma progression,such as the M1-like macrophage/microglia participate in the early stage of glioma to create an inflammation environment and the M2-like macrophage/microglia act more like hypertrophic macrophage during development in the advanced stage of glioma.However,detailed mechanisms underlying regulation of tumor-associated macrophages(TAM)or microglia in it still remain poorly understood.Here,we demonstrated that class A scavenger receptor(SR-A),an important pattern recognition receptor,may act as a suppressor for glioma growth,invasion and angiogenesis through regulating the polarization of TAM and the production of multiple cytokines such as MMP-9 and VEGF.In the absence of SR-A,more M2-like TAMs were recruited to the glioma microenvironment.and increasing the production of several kinds of pro-tumorgenesis activity cytokines such as MMP-9,VEGF and finally cause the results of more stronger tumor proliferation and angiogenesis in SR-A^-/-murine orthotopic glioma.Further more we also found that the bone marrow derived macrophage play a more important role in the glioma progression,and act as major source of SR-A in glioma microenvironment.Specific restore of SR-A in bone marrow could cause observably decrease of glioma volume,and ablation of SR-A in bone marrow would reverse the phenotype.Those above results indicated us that the bone marrow derived macrophages are the main component of glioma microenvironment stroma cells,and SR-A negatively regulate its polarization towards M2-like macrophage to inhibit glioma progression.And in vitro experiments also suggested us that the absence of SR-A in bone marrow derived macrophage would cause more M2-like polarization through activation of STAT3?6.And as a results induce more proliferation and invasion ability in glioma cell due to the change of macrophage phenotype and multiple overexpression of protumorigenesis cytokines such as VEGF,MMP-9,TGF-b.Therefore,from clinical trials to murine models,our study proved that SR-A may become a key factor in glioma progression through regulation of macrophages/microglia polarization,and as a important pattern recognition receptor with several kinds of ligand,using special ligand to activate the ability of SR-A may become a possible drug target for glioma treatment in future.