Pancreatic stellate cell secreted IL-6 stimulates STAT3 dependent invasiveness of pancreatic intraepithelial neoplasia and cancer cells.
Pancreatic stellate cell secreted IL-6 stimulates STAT3 dependent invasiveness of pancreatic intraepithelial neoplasia and cancer cells.
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DOI：
10.18632/oncotarget.11786
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发表时间：
2016-10-04
期刊：
影响因子：
--
通讯作者：
Merchant NB
中科院分区：
文献类型：
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作者：
Nagathihalli NS;Castellanos JA;VanSaun MN;Dai X;Ambrose M;Guo Q;Xiong Y;Merchant NB
胰腺导管腺癌（PDAC）是一种由几种基质成分（如胰腺星状细胞（PSC））支持的动态肿瘤。PSC和肿瘤细胞之间存在显著的串扰，以刺激致癌信号传导和PDAC的恶性进展。然而，PSC如何激活PDAC细胞中的细胞间信号传导仍有待阐明。我们以前已经表明，激活的信号转导和转录激活因子3（STAT 3）信号转导是胰腺肿瘤进展的关键组成部分。我们假设PSC分泌的IL-6激活STAT 3信号传导以促进PanIN进展为PDAC。用PSC条件培养基（PSC-CM）处理人PDAC和小鼠PanIN细胞，并通过免疫印迹分析测定磷酸化和总STAT 3水平。在PSC-CM中定量IL-6，并在存在或不存在中和IL-6抗体和JAK/STAT 3抑制剂AZD 1480的情况下进行细胞侵袭和集落形成测定。Ptf 1aCre/+血清; LSL-KrasG12D/+; Tgfbr 2flox/flox+（PKT）和LSL-KrasG 12 D/+; Trp 53 R172 H/+; Pdx 1Cre/+（KPC）小鼠与来自非携带PDAC的KC和PK小鼠的血清相比显示IL-6水平增加。PSC分泌的IL-6激活了非侵入性前体PanIN细胞以及PDAC细胞中的STAT 3信号传导，导致两种细胞类型中的细胞侵袭和集落形成增强。IL-6浓度与磷酸化STAT 3/总STAT 3比值呈显著正相关。IL-6中和或STAT 3抑制减弱PSC-CM诱导的STAT 3信号传导和致瘤性的活化。这些数据提供了PSC直接参与促进PanIN向浸润性癌进展的证据。这项研究证明了PSC分泌的IL-6在通过激活STAT 3信号传导将非侵袭性胰腺前体细胞转变为侵袭性PDAC中的新作用。
Pancreatic ductal adenocarcinoma (PDAC) is a dynamic tumor supported by several stromal elements such as pancreatic stellate cells (PSC). Significant crosstalk exists between PSCs and tumor cells to stimulate oncogenic signaling and malignant progression of PDAC. However, how PSCs activate intercellular signaling in PDAC cells remains to be elucidated. We have previously shown that activated signal transducer and activator of transcription 3 (STAT3) signaling is a key component in the progression of pancreatic neoplasia. We hypothesize that PSC secreted IL-6 activates STAT3 signaling to promote PanIN progression to PDAC. Human PDAC and mouse PanIN cells were treated with PSC-conditioned media (PSC-CM), and phospho- and total-STAT3 levels by immunoblot analysis were determined. IL-6 was quantified in PSC-CM and cell invasion and colony formation assays were performed in the presence or absence of a neutralizing IL-6 antibody and the JAK/STAT3 inhibitor AZD1480. Serum from Ptf1aCre/+;LSL-KrasG12D/+;Tgfbr2flox/flox' (PKT) and LSL-KrasG12D/+; Trp53R172H/+; Pdx1Cre/+ (KPC) mice demonstrated increased levels of IL-6 compared to serum from non-PDAC bearing KC and PK mice. PSC secreted IL-6 activated STAT3 signaling in noninvasive, precursor PanIN cells as well as PDAC cells, resulting in enhanced cell invasion and colony formation in both cell types. There was a significant positive linear correlation between IL-6 concentration and the ratio of phosphorylated STAT3/total STAT3. IL-6 neutralization or STAT3 inhibition attenuated PSC-CM induced activation of STAT3 signaling and tumorigenicity. These data provide evidence that PSCs are directly involved in promoting the progression of PanINs towards invasive carcinoma. This study demonstrates a novel role of PSC secreted IL-6 in transitioning noninvasive pancreatic precursor cells into invasive PDAC through the activation of STAT3 signaling.