De Arcangelis A, Lefebvre O, Méchine-Neuville A, Arnold C, Klein A, Rémy L, Kedinger M, Simon-Assmann P
INSERM Unité 381, Ontogénèse et Pathologie du Système Digestif, 3 Avenue Molière, 67200 Strasbourg, France.
Int J Cancer. 2001 Oct 1;94(1):44-53. doi: 10.1002/ijc.1444.
Laminins represent a growing family of glycoproteins constituting the basement membrane. They are known to direct many biological processes. With respect to carcinogenesis, laminins play an important role in cell adhesion, mitogenesis, differentiation and even metastasis. To further study the biological significance of laminin-1 (composed of alpha1, beta1 and gamma1 chains) in intestinal cell differentiation or tumorigenesis, an alpha1-laminin expression vector was introduced into the HT29 colonic cancer cells, in which laminin alpha1 chain is not expressed. Upon transfection of the alpha1 chain, the alpha1beta1gamma1 trimer was found secreted in the media along with free alpha1 chain as assessed by immunoprecipitation. The presence of the laminin alpha1 chain did not significantly modify the levels of the other laminin chains nor the integrins expressed by the HT29 cells. In spite of similar growth properties with the control cells in vitro (plastic dish, soft agar), the laminin alpha1 transfectants showed a significantly increased tumor growth when injected in nude mice. Histologic and immunohistochemic examination of the laminin alpha1-expressing tumors points to an increased recruitment of the host stromal and vascular cells, without modification in the differentiation profile and invasion potential. In parallel, a clear accumulation of laminin-10 (alpha5beta1gamma1) at the carcinoma/stromal interface and a segregation of the integrin beta4 subunit at the basal pole of the cancer cells occurred, compared to control tumors. Overall, our observations emphasize the importance of laminin-1 as a chemoattractant of both stromal and vascular cells and in epithelial/stromal cell interactions for the organization of the basement membrane and segregation of integrins leading to an epithelial cell growth signal. Such a sequence of events is reminiscent of what occurs during development.
层粘连蛋白是构成基底膜的一个不断增加的糖蛋白家族。已知它们能指导许多生物学过程。关于致癌作用，层粘连蛋白在细胞黏附、有丝分裂、分化甚至转移中发挥重要作用。为了进一步研究层粘连蛋白-1（由α1、β1和γ1链组成）在肠道细胞分化或肿瘤发生中的生物学意义，将α1-层粘连蛋白表达载体导入不表达层粘连蛋白α1链的HT29结肠癌细胞中。转染α1链后，通过免疫沉淀评估发现α1β1γ1三聚体与游离α1链一起分泌到培养基中。层粘连蛋白α1链的存在并未显著改变其他层粘连蛋白链的水平，也未改变HT29细胞表达的整合素水平。尽管在体外（塑料培养皿、软琼脂）与对照细胞具有相似的生长特性，但层粘连蛋白α1转染子注射到裸鼠中时肿瘤生长显著增加。对表达层粘连蛋白α1的肿瘤进行组织学和免疫组织化学检查表明，宿主基质和血管细胞的募集增加，而分化特征和侵袭潜能没有改变。同时，与对照肿瘤相比，在癌/基质界面出现了层粘连蛋白-10（α5β1γ1）的明显积聚，并且在癌细胞的基极出现了整合素β4亚基的分离。总体而言，我们的观察结果强调了层粘连蛋白-1作为基质和血管细胞的趋化因子以及在上皮/基质细胞相互作用中对基底膜组织和整合素分离从而导致上皮细胞生长信号的重要性。这样一系列事件让人联想到发育过程中发生的情况。
