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Chair(s): Barcellos-Hoff, Mary Helen
(SY023) Ionizing radiation disrupts epithelium-stroma interactions, a potential mechanism for IR-induced carcinogenesis.
Yuan, Zhi-Min *,1, 1 Dept. of Genetics and Complex Disease, Boston, MA, USA
ABSTRACT- Ample evidence suggests that the stromal microenvironment in which tumor cells develop profoundly influences many steps of epithelial tumorigenesis. Fibroblasts, a major cell type of the stromal compartment, may function as a stress monitor to interact with nearby epithelial cells and to modulate their response. The molecular details of the epithelium-stroma interaction, however, remain not completely understood. Using protracted low-dose ionizing radiation (IR), we demonstrate that human primary mammary stromal fibroblasts respond to low-dose IR by displaying a senescence-like phenotype in a dose-dependent and accumulative manner. To understand the potential influence of senescent stromal fibroblasts on neighboring mammary epithelial cells (MEC), we adopted a three-dimensional (3D) coculture system to study the epithelial-stromal interactions in a tissue-like context. We provide a direct experimental proof that senescent fibroblasts dysregulate the growth of associated MECs under the 3D setting, resulting in aberrant proliferation, morphogenesis and invasion. Further analysis indicates that these effects are mediated through altered cell-cell and cell-matrix interactions because of impaired cytoskeletal regulations and heightened matrix degradative functions of senescent fibroblasts. Importantly, the outcomes of the senescent fibroblast-derived growth modulation on mammary epithelial cells are dependent upon the genetic status of epithelial cells. Mammary epithelial cells with inactivated cell death pathways or those undergoing epithelial-mesenchymal transition fully display their malignant behaviors in the presence of senescent fibroblast. Furthermore, we demonstrate that the heterotypic interactions between senescent fibroblasts and MECs also influence the stress response of MECs, which display increased radio- and chemo-resistance in both two-dimensional and 3D contexts. Together, our results suggest that low-level environmental stress can foster an oncogenic environment that interacts with permissive genetic traits in epithelial cells to promote breast carcinogenesis.
Key words: epithelium-stroma interaction, 3-dimentional coculture, heterotypic interaction
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