Paracrine Activation of Chemokine Receptor CCR9 Enhances The Invasiveness of Pancreatic Cancer Cells
Paracrine Activation of Chemokine Receptor CCR9 Enhances The Invasiveness of Pancreatic Cancer Cells
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DOI：
10.1007/s12307-013-0130-6
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发表时间：
2013-12-01
影响因子：
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通讯作者：
Kim, Joseph
中科院分区：
文献类型：
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作者：
Heinrich, Eileen L.;Arrington, Amanda K.;Kim, Joseph
趋化因子受体介导癌症进展和转移。我们以前研究过趋化因子受体CCR 9在胰腺癌中的表达。在这里，我们的目的是评估胰腺星状细胞（PSC）作为CCL 25（CCR 9配体）的来源，以及作为胰腺癌细胞中CCL 25-CCR 9信号传导的激活剂。采用免疫组化法检测人胰腺癌组织和正常胰腺组织中CCL 25和CCR 9的表达水平。通过酶联免疫吸附试验验证PSC和PANC-1细胞中CCL 25的体外分泌。使用改良的Boyden室测定法，用CCL 25、PSC分泌蛋白和PANC-1分泌蛋白作为化学引诱物测量胰腺癌细胞侵袭。CCR 9在胰腺癌组织中有表达，而在正常胰腺组织中无表达。在正常胰腺组织样品中不存在CCL 25表达，但在癌细胞和肿瘤周围的基质细胞中观察到CCL 25表达。在体外，PANC-1细胞和PSC都分泌CCL 25。在侵袭测定中，暴露于CCL 25、PSC和PANC-1条件培养基显著增加了PANC-1细胞的侵袭性。在侵袭测定中包括CCR 9中和抗体阻断了由化学引诱物引起的侵袭细胞的增加。我们的研究表明胰腺癌的侵袭性通过CCR 9的自分泌和旁分泌刺激而增强。肿瘤微环境中的PSC似乎有助于CCR 9的旁分泌激活。对CCR 9作为胰腺癌潜在治疗靶点的研究必须考虑癌细胞自分泌信号和来自肿瘤微环境相互作用的旁分泌信号。
Chemokine receptors mediate cancer progression and metastasis. We have previously examined chemokine receptor CCR9 expression in pancreatic cancer. Here, our objective was to evaluate pancreatic stellate cells (PSCs) as a source of CCL25, the CCR9 ligand, and as an activator of CCL25-CCR9 signaling in pancreatic cancer cells. CCL25 and CCR9 expression levels in human pancreatic cancer tissues and normal human pancreas were assessed by immunohistochemsitry. In vitro secretion of CCL25 in PSCs and PANC-1 cells was verified by enzyme-linked immunosorbent assay. Pancreatic cancer cell invasion was measured using a modified Boyden chamber assay with CCL25, PSC secreted proteins, and PANC-1 secreted proteins as the chemoattractant. There was immunostaining for CCR9 expression in human pancreatic tumor tissues, but not in normal pancreatic tissue. CCL25 expression was absent in the normal pancreatic tissue sample, but was observed in cancer cells and in the stromal cells surrounding the tumor. In vitro, both PANC-1 cells and PSCs secreted CCL25. In an invasion assay, exposure to CCL25, PSC- and PANC-1-conditioned media significantly increased the invasiveness of PANC-1 cells. Inclusion of a CCR9-neutralizing antibody in the invasion assay blocked the increase in invading cells elicited by the chemoattractants. Our studies show that pancreatic cancer invasiveness is enhanced by autocrine and paracrine stimulation of CCR9. PSCs in the tumor microenvironment appear to contribute to paracrine activation of CCR9. Investigations into CCR9 as a potential therapeutic target in pancreatic cancer must consider cancer cell autocrine signaling and also paracrine signaling from interactions in the tumor microenvironment.