Li F, Strange R, Friis R R, Djonov V, Altermatt H J, Saurer S, Niemann H, Andres A C
Laboratory for Clinical and Experimental Research, Berne, Switzerland.
Int J Cancer. 1994 Nov 15;59(4):560-8. doi: 10.1002/ijc.2910590421.
The mammary gland, during post-lactational involution, is subjected to extensive tissue reconstruction. This process is governed by the concerted expression of extracellular-matrix-degrading enzymes and their inhibitors. During carcinogenesis, the invasive growth of tumor cells is characterized by the penetration of the basement membrane and stromal invasion. We compared the expression of the tissue-remodeling enzymes stromelysin-1, a matrix metalloproteinase, and its inhibitor, tissue inhibitor of metalloproteinase-1 (TIMP-1), during mammary gland involution and carcinogenesis in mouse. In involuting mammary glands, stromelysin-1 was expressed in myoepithelial cells, whereas TIMP-1 was confined to the stromal tissue. To analyze the involvement of these tissue-remodeling genes in tumor development, we examined mammary tumors of transgenic mice expressing either the activated Ha-ras or c-myc oncogene under the control of a milk-protein gene promoter. In the undifferentiated and metastasizing Ha-ras-induced tumors, stromelysin-1 expression was comparable to that seen in involution, whereas TIMP-1 expression was greatly elevated. During Ha-ras-induced carcinogenesis, stromelysin-1 expression was first detected in the myo-epithelial cells surrounding preneoplastic lesions. In contrast, in the well-differentiated and non-metastatic mammary tumors induced by c-myc, no expression of either gene was observed. Thus, expression of stromelysin-1 and TIMP-1 is confined to the aggressively growing tumors and is induced in the earliest stages of carcinogenesis.
在哺乳期后的乳腺退化过程中，乳腺会经历广泛的组织重塑。这个过程由细胞外基质降解酶及其抑制剂的协同表达所调控。在致癌过程中，肿瘤细胞的侵袭性生长表现为基底膜的穿透和间质浸润。我们比较了基质溶解素-1（一种基质金属蛋白酶）及其抑制剂金属蛋白酶组织抑制剂-1（TIMP-1）在小鼠乳腺退化和致癌过程中组织重塑酶的表达。在退化的乳腺中，基质溶解素-1在肌上皮细胞中表达，而TIMP-1局限于间质组织。为了分析这些组织重塑基因在肿瘤发展中的作用，我们检查了在乳蛋白基因启动子控制下表达活化的Ha-ras或c-myc癌基因的转基因小鼠的乳腺肿瘤。在未分化和转移的Ha-ras诱导的肿瘤中，基质溶解素-1的表达与退化过程中所见相当，而TIMP-1的表达则大大升高。在Ha-ras诱导的致癌过程中，基质溶解素-1的表达首先在肿瘤前病变周围的肌上皮细胞中检测到。相比之下，在c-myc诱导的分化良好且无转移的乳腺肿瘤中，未观察到这两种基因的表达。因此，基质溶解素-1和TIMP-1的表达局限于侵袭性生长的肿瘤，并在致癌的最早阶段被诱导。
