Extracellular DNA in pancreatic cancer promotes cell invasion and metastasis.
Extracellular DNA in pancreatic cancer promotes cell invasion and metastasis.
复制标题
胰腺癌的细胞外DNA促进细胞侵袭和转移。
DOI：
10.1158/0008-5472.can-12-3287
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发表时间：
2013-07-15
期刊：
影响因子：
11.2
通讯作者：
Shi J
中科院分区：
文献类型：
--
作者：
Wen F;Shen A;Choi A;Gerner EW;Shi J
侵袭性转移是胰腺癌高发病率和死亡率的主要原因，但其侵袭性行为的基础仍不明确。细胞外DNA （exDNA）是最近发现的炎症组织状态的组成部分。在这里，我们报告了exDNA存在于胰腺癌细胞表面，它对驱动转移行为至关重要。ExDNA在培养的胰腺癌细胞表面和周围丰富，但在正常胰腺细胞中缺失。引人注目的是，用DNase I来降解DNA的癌细胞培养物非特异性地减少了与基质附着、迁移和侵袭相关的转移特征。我们通过植入表达萤火虫荧光素酶的胰腺癌细胞建立原位异种移植模型，进一步评估了exDNA在体内胰腺癌转移中的作用。无创生物发光成像证实DNase I治疗足以抑制肿瘤转移。机制研究表明存在一个正反馈回路，其中exDNA促进炎症趋化因子CXCL8的表达，导致胰腺癌细胞产生更高的exDNA，并通过DNase I治疗显著降低CXCL8水平。综上所述，我们的研究结果强烈表明exDNA与胰腺癌的高度侵袭性和转移性有关。
Aggressive metastasis is the chief cause of the high morbidity and mortality associated with pancreatic cancer, yet the basis for its aggressive behavior remains elusive. Extracellular DNA (exDNA) is a recently discovered component of inflammatory tissue states. Here we report that exDNA is present on the surface of pancreatic cancer cells where it is critical for driving metastatic behavior. ExDNA was abundant on the surface and vicinity of cultured pancreatic cancer cells, but absent from normal pancreas cells. Strikingly, treatment of cancer cell cultures with DNase I to degrade DNA non-specifically reduced metastatic characters associated with matrix attachment, migration and invasion. We further assessed the role of exDNA in pancreatic cancer metastasis in vivo using an orthotopic xenograft model established by implantation of pancreatic cancer cells expressing firefly luciferase. Non-invasive bioluminescent imaging confirmed that DNase I treatment was sufficient to suppress tumor metastasis. Mechanistic investigations suggested the existence of a positive feedback loop in which exDNA promotes expression of the inflammatory chemokine CXCL8 which leads to higher production of exDNA by pancreatic cancer cells, with a significant reduction in CXCL8 levels achieved by DNase I treatment. Taken together, our results strongly suggest that exDNA contributes to the highly invasive and metastatic character of pancreatic cancer.