Tiam1-regulated osteopontin in senescent fibroblasts contributes to the migration and invasion of associated epithelial cells

Abstract

SummaryThe 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 Tiam1 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 Tiam1 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 Tiam1 protein and the consequent increase in secretion of osteopontin by fibroblasts.

Role of osteopontin in the pathophysiology of cancer

“…Cancer incidence increases with aging and is associated with tissue accumulation of senescent cells. Liu and colleagues have elegantly shown that senescent fibroblasts promote neoplastic progression in associated tumors through degradation of fibroblast Tiam1 protein and the consequent increase in secretion of OPN by fibroblasts (Liu et al, 2012). …”

Epithelial-mesenchymal co-culture model for studying alveolar morphogenesis

“…Three-dimensional co-culture model systems have proven very useful in studying invasion of epithelial cells and epithelial tubes into mesenchymal cell-containing matrices. [35][36][37] In vitro multicellular systems have been useful for studying cell assembly during epithelial cyst formation or branching morphogenesis. 38,39 To model alveolar morphogenesis, we tested multiple 3-D epithelial-mesenchymal co-culture approaches using various matrix compositions, including collagen gels, matrigel, and synthetic hydrogels.…”

Regulation of Cell Behavior by Extracellular Proteins

“…High levels of osteopontin expression are correlated with this activated phenotype [43]. Increased levels of osteopontin secreted by senescent fibroblasts also promote migration of mammary epithelial cells, a process linked to neoplastic progression and tumor development in aging tissues [44]. Thus osteopontin is predicted to be a primary determinant of the activated phenotype characteristic of adventitial fibroblasts in hypertensive lungs.…”