In situ detection of matrix metalloproteinase-2 (MMP2) and the metalloproteinase inhibitor TIMP2 transcripts in human primary hepatocellular carcinoma and in liver metastasis
In situ detection of matrix metalloproteinase-2 (MMP2) and the metalloproteinase inhibitor TIMP2 transcripts in human primary hepatocellular carcinoma and in liver metastasis
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DOI：
10.1016/s0168-8278(97)80425-4
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发表时间：
1997-03-01
影响因子：
25.7
通讯作者：
Clement, B
中科院分区：
文献类型：
--
作者：
Musso, O;Theret, N;Clement, B
背景/目标：金属蛋白酶（MMP）-2和金属蛋白酶抑制剂TIMP 2，在肿瘤的侵袭中起着至关重要的作用，我们研究了MMP 2和TIMP 2在原发性和继发性人类肝癌中的细胞来源。方法：采用原位杂交和酶谱法，我们分析了手术活检的匹配对肿瘤和非肿瘤肝从6个肝细胞癌和7个肝转移瘤和4个肝供体。使用抗α-平滑肌肌动蛋白抗体在连续切片上进一步表征MMP 2和TIMP 2的细胞来源。原位杂交结果显示，肝癌和肝转移灶中，MMP 2和TIMP 2 mRNA均由抗α-平滑肌肌动蛋白阳性细胞表达于Slender成纤维细胞前包埋，基质为MMP 2（+）/TIMP 2（+）/抗α-平滑肌肌动蛋白（+），肿瘤内微血管MMP 2表达强，TIMP 2 mRNA表达弱，而非肿瘤区中央静脉内皮呈MMP 2（+）/TIMP 2（+）。对照组MMP 2和TIMP 2 mRNA仅分布于汇管区内的成纤维细胞和内皮细胞及散在的肝窦细胞，直接酶谱分析的样本，包括侵入前揭示变量的proMMP 2和它的活性形式在肝细胞癌，而强带相应的活性和潜伏形式的MMP 2检测到肝转移。在肝肿瘤窦周隙中MMP 2（+）/TIMP 2（+）/anti-alpha SM（+）星形细胞的显著密度提示肝星状细胞在分化为肌成纤维细胞后，可能有助于肝转移瘤通过窦状隙网络的传播。
Background/Aims: Metalloproteinase (MMP)-2 and the metalloproteinase inhibitor TIMP2, play a critical role in tumor invasion, We have investigated the cellular sources of MMP2 and TIMP2 in primary and secondary human liver cancers.Methods: Using in situ hybridization and zymography, we analyzed surgical biopsies from matching pairs of tumoral and non-tumoral liver from six hepatocellular carcinomas and seven liver metastases and from four liver donors. The cellular sources of MMP2 and TIMP2 were further characterized using an anti-alpha-smooth muscle actin antibody on contiguous sections.Results: In hepatocellular carcinoma and liver metastases, in situ hybridization showed that MMP2 and TIMP2 mRNA were expressed by anti-alpha-smooth muscle actin-positive cells at the Slender fibroblasts embedded in a front, matrix were MMP2(+)/TIMP2(+)/anti-alpha-smooth muscle actin(+), Intratumor microvessels showed a strong labeling for MMP2 but weak for TIMP2 mRNA, In contrast, the endothelial lining of the central veins was MMP2(+)/TIMP2(+) in non-tumoral areas with signs of blood-flow obstruction, In control livers, MMP2 and TIMP2 mRNA distribution was restricted to fibroblasts and endothelial cells within portal tracts and scattered sinusoidal cells, Direct zymography of samples comprising the invasive front revealed variable amounts of both proMMP2 and its active form in hepatocellular carcinoma, whereas strong bands corresponding to both active and latent forms of MMP2 were detected in liver metastases.Conclusions: The striking density of MMP2(+)/TIMP2(+)/anti-alpha SM(+) stellate-shaped cells in the perisinusoidal space adjacent to liver tumors suggests that hepatic stellate cells, upon differentiation to myofibroblasts, may contribute to the dissemination of liver metastases through the sinusoidal network.