Interaction between cancer cells and stromnal fibroblasts is required for activation of the uPAR-uPA-NMP-2 cascade in pancreatic cancer metastasis
Interaction between cancer cells and stromnal fibroblasts is required for activation of the uPAR-uPA-NMP-2 cascade in pancreatic cancer metastasis
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DOI：
10.1158/1078-0432.ccr-06-2088
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发表时间：
2007-06-01
影响因子：
11.5
通讯作者：
Li, Xiaowu
中科院分区：
文献类型：
--
作者：
He, Yu;Liu, Xiang-de;Li, Xiaowu
目的：肿瘤细胞与周围间质成纤维细胞之间的相互作用在肿瘤的生长和侵袭过程中起着重要作用。本研究旨在通过评价SF激活尿激酶型纤溶酶原激活物(UPA)-纤溶酶-基质金属蛋白酶-2(uPA-MMP2)级联反应的方式，探讨SF对胰腺癌侵袭行为的调节作用。实验设计：采用免疫组织化学方法分析uPA、MMP2及uPA受体(UPAR)在人转移性胰腺癌组织中的表达模式，并通过与SF共培养胰腺癌细胞，探讨SF在激活uPA-纤溶酶-MMP2级联反应中的作用。结果：uPA表达及成纤维细胞uPAR表达与人胰腺癌肝转移相关。在转移性胰腺癌中，MMP2而不是MMP9被激活。在体外培养体系中，瘤周成纤维细胞与转移性胰腺癌BxPc3细胞共培养后，可激活基质金属蛋白酶-2，上调uPAR的表达。在该共培养体系中，uPA-纤溶酶原级联参与了基质金属蛋白酶-2的激活。这种激活需要SF和癌细胞之间的直接相互作用。在共培养体系中，整合素α(6)β(1)在BxPc3细胞中表达增加，阻断整合素α(6)β(1)的功能，降低uPA和MMP2的活性。提示癌细胞整合素与SF的uRARs之间的相互作用可能参与了uPAR-MMP2级联的激活。结论：SF可能通过激活uPA-纤溶酶原-MMP2级联途径促进胰腺癌的转移。
Purpose: Interaction between tumor cells and surrounding stromal fibroblast (SF) plays a critical role in tumor growth and invasion. The aim of the study is to determine the role of SF in regulating the invasive behaviors of pancreatic cancer by evaluating the mode of SF activating the urokinase plasminogen activator (uPA) - plasmin-matrix metalloproteinase (MMP)-2 cascade.Experimental Design: The expression patterns of uPA, MMP-2, and uPA receptor (uPAR) in human metastatic pancreatic cancer were analyzed by immunohistochemistry and the roles of SF in activation of the uPA-plasmin-MMP-2 cascade were evaluated by coculturing pancreatic cancer cell lines with SF.Results: uPA expression and fibroblastic uPAR expression were correlated with liver metastasis of human pancreatic cancer. MMP-2 rather than MMP-9 was activated in the metastatic pancreatic cancer. In the in vitro culture system, the coculture of peritumor fibroblasts with metastatic pancreatic cancer BxPc3 cells resulted in activation of MMP-2 and up-regulation of uPAR expression. In this coculture system, the uPA-plasminogen cascade was involved in MMP-2 activation. This activation required a direct interaction between SF and cancer cells. In the coculture system, intergrin alpha(6)beta(1) expression was increased in BxPc3 cells, and blocking the function of integrin alpha(6)beta(1), decreased the activation of uPA and MMP-2. This suggests that interaction between integrins of cancer cells and the uRARs of the SF might be involved in the activation of the uPAR-uPA-MMP-2 cascade.Conclusion: Our results suggest that SF plays a role in promoting pancreatic cancer metastasis via activation of the uPA-plasminogen-MMP-2 cascade.