Inhibition of tumor invasion of smooth muscle cell layers by recombinant human metalloproteinase inhibitor.
Inhibition of tumor invasion of smooth muscle cell layers by recombinant human metalloproteinase inhibitor.
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发表时间：
1991-04
期刊：
影响因子：
11.2
通讯作者：
Y. DeClerck;T. Yean;D. Chan;Hiroyuki Shimada;K. Langley
中科院分区：
文献类型：
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作者：
Y. DeClerck;T. Yean;D. Chan;Hiroyuki Shimada;K. Langley
肿瘤细胞分泌的基质金属蛋白酶在侵袭过程中对细胞外基质的蛋白降解起着重要作用。在之前的研究中，我们发现人HT1080纤维肉瘤细胞对细胞外基质的降解受到内皮细胞的抑制。对内皮细胞分泌的金属蛋白酶抑制物的鉴定使我们假设这些抑制物对抑制作用起作用(癌症研究，46：3580-3586,1986)。在本研究中，我们研究了金属蛋白酶抑制物(MI)/金属蛋白酶组织抑制物(TIMP)-2对c-Ha-ras-1转基因大鼠胚胎细胞4R和HT1080人纤维肉瘤细胞系两种侵袭性肿瘤细胞系降解和侵袭的抑制作用。从转人MI互补DNA的中国仓鼠卵巢细胞培养液中以重组形式获得该抑制物。重组MI/TIMP-2抑制肿瘤细胞系培养上清液中的几种基质金属蛋白酶，包括间质胶原酶。MR 72,000明胶酶(IV型胶原酶)和MR 92,000明胶酶。当重组抑制物与培养细胞一起存在时，当浓度为10微克/毫升时，对平滑肌细胞基质的降解抑制约70%。类似地，对多层生长的平滑肌细胞及其周围基质的穿透也有抑制作用。该抑制剂对细胞生长和附着无影响。因此，重组MI/TIMP-2和TIMP一样，是一种有效的肿瘤侵袭抑制因子。因为这两种抑制物都是由内皮细胞分泌的(J.Biol.化学，264：17445-17453,1989)，它们可能在保护大血管免受入侵方面发挥重要作用。
Matrix metalloproteinases secreted by tumor cells play an important role in the proteolytic degradation of the extracellular matrix during invasion. In a previous study, we showed that the degradation of extra-cellular matrices by human HT 1080 fibrosarcoma cells is suppressed by endothelial cells. The identification of inhibitors of metalloproteinases secreted by endothelial cells led us to postulate that these inhibitors were responsible for the suppressive effect (Cancer Res., 46: 3580-3586, 1986). In the present study, we have investigated the inhibitory activity of one of these inhibitors designated metalloproteinase inhibitor (MI)/tissue inhibitor of metalloproteinases (TIMP)-2 on the degradation and invasion of rat smooth muscle cell matrices by two invasive tumor cell lines, the c-Ha-ras-1 transfected rat embryo cell line 4R and the HT 1080 human fibrosarcoma cell line. The inhibitor was obtained in recombinant form from the culture medium of Chinese hamster ovary cells transfected with a human MI complementary DNA. Recombinant MI/TIMP-2 inhibited several matrix metalloproteinases identified in the culture medium of the tumor cell lines including interstitial collagenase. Mr 72,000 gelatinase (type IV collagenase), and Mr 92,000 gelatinase. Approximately 70% inhibition of the degradation of smooth muscle cell matrices was observed when the recombinant inhibitor was present along with cultured cells at a concentration of 10 micrograms/ml. Similarly, inhibition of the penetration of a multilayer of growing smooth muscle cells and their surrounding matrix was demonstrated. The inhibitor had no effect on cell growth or attachment. Thus, recombinant MI/TIMP-2, like TIMP, is a potent inhibitor of tumor invasion. Since both inhibitors are secreted by endothelial cells (J. Biol. Chem., 264: 17445-17453, 1989), they may play an important role in protecting large blood vessels from invasion.