He Yu, Liu Xiang-de, Chen Zhi-yu, Zhu Jin, Xiong Yan, Li Kun, Dong Jia-hong, Li Xiaowu
Hepatobiliary Surgery Institute, Southwest Hospital, Third Military Medical University, Chongqing, P.R. China.
Clin Cancer Res. 2007 Jun 1;13(11):3115-24. doi: 10.1158/1078-0432.CCR-06-2088.
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.
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.
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 uPARs of the SF might be involved in the activation of the uPAR-uPA-MMP-2 cascade.
Our results suggest that SF plays a role in promoting pancreatic cancer metastasis via activation of the uPA-plasminogen-MMP-2 cascade.
肿瘤细胞与周围基质成纤维细胞（SF）之间的相互作用在肿瘤生长和侵袭中起关键作用。本研究旨在通过评估SF激活尿激酶型纤溶酶原激活剂（uPA）-纤溶酶-基质金属蛋白酶（MMP）-2级联反应的方式，确定SF在调节胰腺癌侵袭行为中的作用。
采用免疫组织化学分析人转移性胰腺癌中uPA、MMP-2和uPA受体（uPAR）的表达模式，并通过将胰腺癌细胞系与SF共培养来评估SF在激活uPA-纤溶酶-MMP-2级联反应中的作用。
uPA表达和纤维母细胞uPAR表达与人胰腺癌肝转移相关。转移性胰腺癌中激活的是MMP-2而非MMP-9。在体外培养系统中，肿瘤周围成纤维细胞与转移性胰腺癌BxPc3细胞共培养导致MMP-2激活和uPAR表达上调。在该共培养系统中，uPA-纤溶酶原级联反应参与了MMP-2的激活。这种激活需要SF与癌细胞之间的直接相互作用。在共培养系统中，BxPc3细胞中整合素α(6)β(1)表达增加，阻断整合素α(6)β(1)的功能可降低uPA和MMP-2的激活。这表明癌细胞整合素与SF的uPAR之间的相互作用可能参与了uPAR-uPA-MMP-2级联反应的激活。
我们的结果表明，SF通过激活uPA-纤溶酶原-MMP-2级联反应在促进胰腺癌转移中发挥作用。
