Development of Aggressive Pancreatic Ductal Adenocarcinomas Depends on Granulocyte Colony Stimulating Factor Secretion in Carcinoma Cells.
Development of Aggressive Pancreatic Ductal Adenocarcinomas Depends on Granulocyte Colony Stimulating Factor Secretion in Carcinoma Cells.
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DOI：
10.1158/2326-6066.cir-16-0311
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发表时间：
2017-09
影响因子：
10.1
通讯作者：
Novitskiy SV
中科院分区：
文献类型：
--
作者：
Pickup MW;Owens P;Gorska AE;Chytil A;Ye F;Shi C;Weaver VM;Kalluri R;Moses HL;Novitskiy SV
胰腺导管腺癌（PDAC）的生存率仍然很低。需要更多的治疗选择来治疗这种疾病，因为目前的护理标准是无效的。利用侵袭性PDAC（Kras/p48 TGF βRIIKO）动物模型，我们发现TGFβ信号在胰腺上皮G-CSF分泌的调节中的作用。PDAC中升高浓度的G-CSF促进Ly 6 G+细胞从祖细胞分化，刺激髓样细胞分泌IL 10，并通过上调CD 11b+细胞的Arg、iNOS、VEGF、IL 6、IL 1b降低T细胞增殖。PDAC细胞中csf 3的缺失或G-CSF阻断抗体的使用降低了肿瘤生长。抗G-CSF治疗与DNA合成抑制剂吉西他滨联合治疗比单独使用吉西他滨更有效地减小肿瘤大小，增加浸润T细胞的数量，并减少Ly 6 G+细胞的数量。来自癌症基因组图谱和组织微阵列（TMA）的人类数据集的分析与我们的小鼠模型实验的观察结果相关，特别是在I级、II期疾病患者中。我们认为，在侵袭性PDAC中，升高的G-CSF通过促进具有高免疫抑制活性的嗜中性粒细胞样细胞浸润的增加而促进肿瘤进展。这种机制为这种毁灭性疾病的新辅助治疗方法提供了途径。
The survival rate for pancreatic ductal adenocarcinoma (PDAC) remains low. More therapeutic options to treat this disease are needed, for the current standard of care is ineffective. Using an animal model of aggressive PDAC (Kras/p48TGFβRIIKO), we discovered an effect of TGFβ signaling in regulation of G-CSF secretion in pancreatic epithelium. Elevated concentrations of G-CSF in PDAC promoted differentiation of Ly6G+ cells from progenitors, stimulated IL10 secretion from myeloid cells, and decreased T-cell proliferation via upregulation of Arg, iNOS, VEGF, IL6, IL1b from CD11b+ cells. Deletion of csf3 in PDAC cells or use of a G-CSF blocking antibody decreased tumor growth. Anti G-CSF treatment in combination with the DNA synthesis inhibitor gemcitabine reduced tumor size, increased the number of infiltrating T cells, and decreased the number of Ly6G+ cells more effectively than gemcitabine alone. Human Analysis of human datasets from The Cancer Genome Atlas and tissue microarrays (TMAs) correlated with observations from our mouse model experiments, especially in patients with grade I, stage II disease. We propose that in aggressive PDAC, elevated G-CSF contributes to tumor progression through promoting increases in infiltration of neutrophil-like cells with high immunosuppressive activity. Such a mechanism provides an avenue for a neoadjuvant therapeutic approach for this devastating disease.