S100A8 and S100A9 proteins form part of a paracrine feedback loop between pancreatic cancer cells and monocytes
S100A8 and S100A9 proteins form part of a paracrine feedback loop between pancreatic cancer cells and monocytes
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DOI：
10.1186/s12885-018-5161-4
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发表时间：
2018-12-17
期刊：
影响因子：
3.8
通讯作者：
Costello, Eithne
中科院分区：
文献类型：
--
作者：
Nedjadi, Taoufik;Evans, Anthony;Costello, Eithne
研究背景可溶性因子的分泌使肿瘤细胞与周围微环境之间的信息交流成为可能，在肿瘤发生中起着重要作用。胰腺导管腺癌（PDAC）的特征是高度反应性的微环境，含有多种细胞类型，包括表达S100 A8/S100 A9的单核细胞。S100 A8/S100 A9蛋白通过诱导与癌症扩散相关的转移前级联反应来调节癌细胞的行为。本研究的目的是研究如何S100 A8/A9蛋白介导的肿瘤基质串扰PDAC.MethodsCytokine分析胰腺癌细胞衍生的条件培养基进行使用Bio-Pro27 μ M人细胞因子测定。蛋白质表达和激活的下游信号转导效应和NF-B进行了评估，通过Western印迹分析和记者assays.ResultsS100A8和S100 A9培养的胰腺癌细胞的刺激增加的促炎细胞因子IL-8，TNF-α，和FGF的分泌。S100 A8而不是S100 A9诱导PDGF分泌。相反，胰腺癌细胞衍生的条件培养基和单个细胞因子TNF-α和TGF-β诱导HL-60单核细胞系和原代人单核细胞中S100 A8和S100 A9蛋白的表达，而FGF和IL-8仅诱导S100 A9的表达。S100 A8和S100 A9在胰腺癌中激活MAPK和NF-B信号传导。结论S100 A8和S100 A9蛋白可诱导PDAC细胞分泌特异性细胞因子，从而促进S100 A8/A9蛋白的表达。这种旁分泌串扰可能与PDAC的侵袭性和转移潜力有关。
BackgroundThe secretion of soluble factors enables communication between tumour cells and the surrounding microenvironment and plays an important role in oncogenesis. Pancreatic ductal adenocarcinoma (PDAC) is characterised by a highly reactive microenvironment, harbouring a variety of cell types, including S100A8/S100A9-expressing monocytes. S100A8/S100A9 proteins regulate the behaviour of cancer cells by inducing pre-metastatic cascades associated with cancer spread. The aim of this study was to examine how S100A8/A9 proteins mediate tumour-stroma crosstalk in PDAC.MethodsCytokine profiling of pancreatic cancer cell-derived conditioned media was performed using Bio-Plex Pro 27 Plex Human Cytokine assays. Protein expression and activation of downstream signalling effectors and NF-B were assessed by western blotting analysis and reporter assays respectively.ResultsStimulation of cultured pancreatic cancer cells with S100A8 and S100A9 increased the secretion of the pro-inflammatory cytokines IL-8, TNF-, and FGF. S100A8, but not S100A9 induced PDGF secretion. Conversely, pancreatic cancer cell-derived conditioned media and the individual cytokines, TNF- and TGF- induced the expression of S100A8 and S100A9 proteins in the HL-60 monocytic cell line and primary human monocytes, while FGF and IL-8 induced the expression of S100A9 only. S100A8 and S100A9 activated MAPK and NF-B signalling in pancreatic cancer. This was partially mediated via activation of the receptor of advanced glycosylation end-product (RAGE).ConclusionS100A8 and S100A9 proteins induce specific cytokine secretion from PDAC cells, which in turn enhances the expression of S100A8/A9. This paracrine crosstalk could have implications for PDAC invasiveness and metastatic potential.