Lee Jisook, Dang Xitong, Borboa Alexandra, Coimbra Raul, Baird Andrew, Eliceiri Brian P
Department of Surgery, University of California San Diego School of Medicine, San Diego, California (J.L., X.D., A.B., R.C., A.B., B.P.E.).
Neuro Oncol. 2015 May;17(5):685-96. doi: 10.1093/neuonc/nou302. Epub 2014 Nov 5.
Extensive infiltration of brain tumors by microglia and macrophages is a hallmark of tumor progression, and yet the overall tumor microenvironment is characterized by an immunosuppressive phenotype. Here we identify esophageal cancer-related gene 4 (Ecrg4) as a novel thrombin-processed monocyte chemoattractant that recruits myeloid cells, promotes their activation, and leads to a blockade of tumor progression.
Both xenograft glioma and syngeneic glioma models were used to measure orthotopic tumor progression and overall survival. Flow cytometry and immunohistochemical analyses were performed to assess myeloid cell localization, recruitment, and activation.
Ecrg4 promotes monocyte recruitment and activation of microglia in a T-/B-cell-independent mechanism, which leads to a reduction in glioma tumor burden and increased survival. Mutational analysis reveals that the biological activity of Ecrg4 is dependent on a thrombin-processing site at the C-terminus, inducing monocyte invasion in vivo and in vitro. Furthermore, tumor-induced myeloid cell recruitment is impaired in Ecrg4 knockout mice, leading to increased tumor burden and decreased survival.
Together, these results identify Ecrg4 as a paracrine factor that activates microglia and is chemotactic for monocytes, with potential as an antitumor therapeutic.
小胶质细胞和巨噬细胞对脑肿瘤的广泛浸润是肿瘤进展的一个标志，然而肿瘤整体微环境的特征却是免疫抑制表型。在此，我们鉴定出食管癌相关基因4（Ecrg4）是一种新型的经凝血酶处理的单核细胞趋化因子，它可募集髓样细胞，促进其活化，并导致肿瘤进展受阻。
采用异种移植胶质瘤模型和同基因胶质瘤模型来测量原位肿瘤进展和总生存期。进行流式细胞术和免疫组化分析以评估髓样细胞的定位、募集和活化情况。
Ecrg4通过一种不依赖T细胞/B细胞的机制促进单核细胞募集和小胶质细胞活化，从而导致胶质瘤肿瘤负荷降低和生存期延长。突变分析显示，Ecrg4的生物学活性依赖于其C末端的一个凝血酶处理位点，可在体内和体外诱导单核细胞浸润。此外，在Ecrg4基因敲除小鼠中，肿瘤诱导的髓样细胞募集受损，导致肿瘤负荷增加和生存期缩短。
总之，这些结果表明Ecrg4是一种旁分泌因子，可激活小胶质细胞并对单核细胞具有趋化作用，具有作为抗肿瘤治疗药物的潜力。
