Tiam1-regulated osteopontin in senescent fibroblasts contributes to the migration and invasion of associated epithelial cells
Tiam1-regulated osteopontin in senescent fibroblasts contributes to the migration and invasion of associated epithelial cells
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DOI：
10.1242/jcs.089466
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发表时间：
2012-01-15
影响因子：
4
通讯作者：
Buchsbaum, Rachel J.
中科院分区：
文献类型：
--
作者：
Liu, Jiewei;Xu, Kun;Buchsbaum, Rachel J.
肿瘤微环境随着肿瘤的进展而发生变化。癌症发病率随着年龄的增长而增加，并与衰老细胞的组织积累有关。衰老成纤维细胞被认为有助于衰老组织中肿瘤的发展。我们已经证明，缺乏Rac交换因子Tiam1的成纤维细胞促进相关上皮肿瘤细胞的侵袭和转移。在这里，我们使用细胞侵袭性的三维培养模型来概述这种效应背后的几个步骤。我们发现应激诱导的衰老诱导成纤维细胞Tiam1蛋白水平下降和骨桥蛋白水平增加，衰老的成纤维细胞裂解物诱导Tiam1蛋白以钙和钙蛋白酶依赖的方式降解。成纤维细胞Tiam 1蛋白水平的变化诱导骨桥蛋白mRNA和蛋白的反向变化。衰老成纤维细胞诱导共培养乳腺上皮细胞的侵袭和迁移增加。这些作用在上皮细胞中通过增加成纤维细胞Tiam1或减少成纤维细胞骨桥蛋白而得到改善。最后，在种子细胞迁移实验中，我们发现衰老或缺乏tiam1的成纤维细胞诱导上皮细胞迁移增加，这依赖于成纤维细胞分泌骨桥蛋白。这些发现表明，衰老成纤维细胞促进相关肿瘤肿瘤进展的一种机制是通过成纤维细胞Tiam 1蛋白的降解和成纤维细胞骨桥蛋白分泌的增加。
The tumor microenvironment undergoes changes concurrent with neoplastic progression. Cancer incidence increases with aging and is associated with tissue accumulation of senescent cells. Senescent fibroblasts are thought to contribute to tumor development in aging tissues. We have shown that fibroblasts deficient in the Rac exchange factor Tiam1 promote invasion and metastasis of associated epithelial tumor cells. Here, we use a three-dimensional culture model of cellular invasiveness to outline several steps underlying this effect. We find that stress-induced senescence induces decreased fibroblast Tiam 1 protein levels and increased osteopontin levels, and that senescent fibroblast lysates induce Tiam1 protein degradation in a calcium- and calpain-dependent fashion. Changes in fibroblast Tiam 1 protein levels induce converse changes in osteopontin mRNA and protein. Senescent fibroblasts induce increased invasion and migration in co-cultured mammary epithelial cells. These effects in epithelial cells are ameliorated by either increasing fibroblast Tiam1 or decreasing fibroblast osteopontin. Finally, in seeded cell migration assays we find that either senescent or Tiam1-deficient fibroblasts induce increased epithelial cell migration that is dependent on fibroblast secretion of osteopontin. These findings indicate that one mechanism by which senescent fibroblasts promote neoplastic progression in associated tumors is through degradation of fibroblast Tiam 1 protein and the consequent increase in secretion of osteopontin by fibroblasts.