Stroma-derived Fibrinogen-like Protein 2 Activates Cancer-associated Fibroblasts to Promote Tumor Growth in Lung Cancer.
Stroma-derived Fibrinogen-like Protein 2 Activates Cancer-associated Fibroblasts to Promote Tumor Growth in Lung Cancer.
复制标题
基质来源的纤维蛋白原样蛋白 2 激活癌症相关成纤维细胞，促进肺癌肿瘤生长。
DOI：
10.7150/ijbs.19398
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发表时间：
2017
影响因子：
9.2
通讯作者：
Zhu B
中科院分区：
文献类型：
--
作者：
Zhu Y;Zhang L;Zha H;Yang F;Hu C;Chen L;Guo B;Zhu B
纤维蛋白原样蛋白2（Fgl 2）是纤维蛋白原超家族的成员，是影响多种细胞功能的多效性细胞因子。先前的研究已经表明，肿瘤细胞来源的Fgl 2促进免疫缺陷小鼠中的肿瘤发生和转移，并且它还在多形性胶质母细胞瘤（GMB）中充当免疫抑制调节剂。本研究旨在评估肿瘤基质来源的Fgl 2是否以及如何影响肿瘤发生和肿瘤进展。我们在Fgl 2基因敲除（Fgl 2-KO）小鼠中建立了同基因可移植性刘易斯肺癌（LLC）模型，并且我们发现宿主Fgl 2的缺陷与同基因LLC肿瘤的生长减少相关。此外，我们证实宿主Fgl 2缺陷通过下调趋化因子（C-X-C基序）配体12（CXCL 12）表达显著降低骨髓源性抑制细胞（MDSC）的积累。更重要的是，我们证明了Fgl 2诱导了癌症相关成纤维细胞（CAF）的活化和促肿瘤发生表型，CAF是肿瘤微环境（TME）中CXCL 12的主要来源。我们的研究结果提出了一个新的作用，基质衍生的Fgl 2在CAF的激活和功能，表明Fgl 2是一个有效的治疗肺癌的治疗靶点。
Fibrinogen-like protein 2 (Fgl2), a member of the fibrinogen super family, is a pleiotropic cytokine that impacts diverse cellular functions. Previous studies have shown that tumor cell-derived Fgl2 promotes tumorigenesis and metastasis in immune-deficient mice, and it also functions as an immune-suppressive modulator in glioblastoma multiform (GMB). This study aimed to evaluate whether and how tumor stroma-derived Fgl2 affects tumorigenesis and tumor progression. We established the syngeneic transplantable Lewis lung carcinoma (LLC) model in Fgl2-knock-out (Fgl2-KO) mice and we found that deficiency of host Fgl2 is associated with reduced growth of syngeneic LLC tumors. Furthermore, we confirmed that host Fgl2 deficiency significantly decreased the accumulation of myeloid-derived suppressor cells (MDSCs) through down-regulation of chemokine (C-X-C motif) ligand 12 (CXCL12) expression. More importantly, we demonstrated that Fgl2 induced an activated and pro-tumorigenic phenotype of cancer-associated fibroblasts (CAFs) which are the principal source of CXCL12 in the tumor microenvironment (TME). Our results present a novel role of stroma-derived Fgl2 in CAF activation and function, suggesting that Fgl2 is an effective therapeutic target for treating lung cancer.