Department of Neurology, Washington University, St. Louis, MO.
Department of Neurosurgery, Dayton Children's Hospital, One Children's Plaza, Dayton, OH.
Neoplasia. 2019 Jan;21(1):52-60. doi: 10.1016/j.neo.2018.11.007. Epub 2018 Nov 30.
KIAA1549-BRAF is the most frequently identified genetic mutation in sporadic pilocytic astrocytoma (PA), creating a fusion BRAF (f-BRAF) protein with increased BRAF activity. Fusion-BRAF-expressing neural stem cells (NSCs) exhibit increased cell growth and can generate glioma-like lesions following injection into the cerebella of naïve mice. Increased Iba1 monocyte (microglia) infiltration is associated with murine f-BRAF-expressing NSC-induced glioma-like lesion formation, suggesting that f-BRAF-expressing NSCs attract microglia to establish a microenvironment supportive of tumorigenesis. Herein, we identify Ccl2 as the chemokine produced by f-BRAF-expressing NSCs, which is critical for creating a permissive stroma for gliomagenesis. In addition, f-BRAF regulation of Ccl2 production operates in an ERK- and NFκB-dependent manner in cerebellar NSCs. Finally, Ccr2-mediated microglia recruitment is required for glioma-like lesion formation in vivo, as tumor do not form in Ccr2-deficient mice following f-BRAF-expressing NSC injection. Collectively, these results demonstrate that f-BRAF expression creates a supportive tumor microenvironment through NFκB-mediated Ccl2 production and microglia recruitment.
KIAA1549-BRAF 是散发性毛细胞星形细胞瘤（PA）中最常见的基因突变，产生具有增强 BRAF 活性的融合 BRAF（f-BRAF）蛋白。表达融合 BRAF 的神经干细胞（NSC）表现出增加的细胞生长，并可在向幼稚小鼠的小脑内注射后产生类神经胶质瘤病变。Iba1 单核细胞（小胶质细胞）浸润的增加与小鼠 f-BRAF 表达 NSC 诱导的类神经胶质瘤病变形成有关，这表明 f-BRAF 表达的 NSC 吸引小胶质细胞形成支持肿瘤发生的微环境。在此，我们鉴定出 Ccl2 是由 f-BRAF 表达的 NSC 产生的趋化因子，对于为神经胶质瘤发生创造允许的基质至关重要。此外，小脑 NSC 中 f-BRAF 对 Ccl2 产生的调节以 ERK 和 NFκB 依赖性方式起作用。最后，CCR2 介导的小胶质细胞募集是体内形成类神经胶质瘤病变所必需的，因为在 f-BRAF 表达的 NSC 注射后，CCR2 缺陷型小鼠不会形成肿瘤。总之，这些结果表明 f-BRAF 表达通过 NFκB 介导的 Ccl2 产生和小胶质细胞募集来创建支持性肿瘤微环境。
