Tumor-Derived GM-CSF Promotes Inflammatory Colon Carcinogenesis via Stimulating Epithelial Release of VEGF
Tumor-Derived GM-CSF Promotes Inflammatory Colon Carcinogenesis via Stimulating Epithelial Release of VEGF
复制标题
肿瘤源性 GM-CSF 通过刺激上皮释放 VEGF 促进炎症性结肠癌发生
DOI：
10.1158/0008-5472.can-13-1459
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发表时间：
2014-02-01
期刊：
影响因子：
11.2
通讯作者：
Chen, Guojiang
中科院分区：
文献类型：
--
作者：
Wang, Yi;Han, Gencheng;Chen, Guojiang
慢性炎症是结肠炎相关癌症（CAC）发展的主要驱动力。在炎症性肠病患者的粘膜中观察到粒细胞巨噬细胞集落刺激因子（GM-CSF）的产生升高。然而，人们对它在从结肠炎到癌症的进展中的作用仍然知之甚少。在此，我们证明，结肠上皮细胞（CEC）是一个主要的细胞来源的GM-CSF和它的生产显着增加时，CAC模型建立的氧化偶氮甲烷和葡聚糖硫酸钠。此外，我们发现GM-CSF是CEC通过细胞外信号调节激酶（ERK）依赖性途径以自分泌和/或旁分泌方式释放VEGF的驱动因素。在体内阻断GM-CSF活性显著降低了VEGF的上皮释放，从而消除了CAC的形成。在体外治疗转化CEC与重组GM-CSF显着增强其侵袭潜力，主要是在VEGF依赖的方式。此外，由于抗生素治疗或Toll样受体4消融显著损害了其上皮表达，因此将肠道微生物群衍生的脂多糖鉴定为CEC中GM-CSF表达的触发物。总之，这些发现可能对了解CAC发病机制以及临床上靶向GM-CSF或VEGF的治疗方案的治疗潜力具有重要意义。Cancer Res; 74（3）; 716-26.（C）2013年AACR。
Chronic inflammation is a major driving force for the development of colitis-associated cancer (CAC). Elevated production of granulocyte macrophage colony-stimulating factor (GM-CSF) has been observed in mucosa of patients with inflammatory bowel disease. Its actions in the progression from colitis to cancer, however, remain poorly understood. Herein, we demonstrated that colonic epithelial cells (CEC) were a major cellular source of GM-CSF and its production was significantly augmented when CAC model was established by administration of azoxymethane and dextran sulfate sodium. Furthermore, we showed that GM-CSF was a driver for VEGF release by CEC in autocrine and/or paracrine manners through the extracellular signal-regulated kinase (ERK)-dependent pathway. Blocking GM-CSF activity in vivo significantly decreased epithelial release of VEGF, thereby abrogating CAC formation. In vitro treatment of transformed CEC with recombinant GM-CSF dramatically augmented its invasive potentials, largely in VEGF-dependent fashion. Furthermore, commensal microbiota-derived lipopolysaccharides were identified as a trigger for GM-CSF expression in CEC, as antibiotics treatment or Toll-like receptor 4 ablation considerably impaired its epithelial expression. Overall, these findings may have important implications for the understanding of mechanisms underlying CAC pathogenesis and the therapeutic potentials of regimens targeting GM-CSF or VEGF in clinic. Cancer Res; 74(3); 716-26. (C)2013 AACR.