Benbow U, Schoenermark M P, Orndorff K A, Givan A L, Brinckerhoff C E
Department of Medicine, Dartmouth Medical School, Hanover, NH 03755, USA.
Clin Exp Metastasis. 1999 May;17(3):231-8. doi: 10.1023/a:1006639214618.
Matrix metalloproteinases (MMPs) play an important role in tumor cell invasion and metastasis. These processes require the dissolution of the basement membrane and invasion of the stromal matrix (ECM), and are mediated by MMPs. Consequently, MMP inhibitors may be attractive as new anticancer agents. To examine the potential contribution of collagenase-1 (MMP-1) in invasion of stromal matrix, we used the highly invasive and metastatic breast cancer cell line MDA-MB-231 as a model system. These cells express procollagenase-1 constitutively and this expression can be repressed by all-trans retinoic acid. Invasion of these cells into a collagen type I matrix was assessed by scanning electron microscopy (SEM), and was quantitated with a computer program and confocal laser scanning microscopy (CLSM). We found that MDA-MB-231 cells freely invaded the collagen type I matrix, suggesting that these cells possess a mechanism for activating the latent collagenase-1. In contrast, down-regulation of collagenase-1 expression by all-trans retinoic acid caused these cells to become less invasive. To confirm a role for collagenase-1 in mediating collagen type I invasion, assays were carried out in the presence of FN-439, an inhibitor of collagenase-1 enzyme activity. We found that in the presence of the proteinase inhibitor, invasion of type I collagen by MDA-MB-231 cells was also reduced. These results indicate that collagenase-1 produced by the breast tumor cells may enhance stromal matrix degradation by enabling the tumor cells to modulate their own invasive behavior, and suggest that decreasing collagenase-1 levels may be effective in breast cancer therapy.
基质金属蛋白酶（MMPs）在肿瘤细胞侵袭和转移中起重要作用。这些过程需要基底膜的溶解和基质（ECM）的侵袭，且由MMPs介导。因此，MMP抑制剂作为新型抗癌药物可能具有吸引力。为了研究胶原酶-1（MMP-1）在基质侵袭中的潜在作用，我们使用高侵袭性和转移性乳腺癌细胞系MDA-MB-231作为模型系统。这些细胞组成性表达前胶原酶-1，且这种表达可被全反式维甲酸抑制。通过扫描电子显微镜（SEM）评估这些细胞对I型胶原基质的侵袭，并使用计算机程序和共聚焦激光扫描显微镜（CLSM）进行定量分析。我们发现MDA-MB-231细胞可自由侵袭I型胶原基质，表明这些细胞具有激活潜在胶原酶-1的机制。相反，全反式维甲酸下调胶原酶-1表达导致这些细胞的侵袭性降低。为了证实胶原酶-1在介导I型胶原侵袭中的作用，在胶原酶-1酶活性抑制剂FN-439存在的情况下进行了实验。我们发现，在蛋白酶抑制剂存在的情况下，MDA-MB-231细胞对I型胶原的侵袭也减少。这些结果表明，乳腺肿瘤细胞产生的胶原酶-1可能通过使肿瘤细胞调节自身侵袭行为来增强基质降解，并提示降低胶原酶-1水平可能对乳腺癌治疗有效。
