Abstract
Cellular mechanism for IR-induced perturbation of breast tissue microenvironmentZhi-Min Yuan, Harvard University School of Public Health, Boston, MA 02115Much of the research concerning IR-induced carcinogenesis has focused on its DNA damaging effects within the target cells. How IR affects the interactions of cells with their immediate surroundings and its role in IR-induced carcinogenesis are, however, less well understood. We show here that low dose IR can substantially perturb the tissue microenvironment by inducing premature senescence in human mammary fibroblasts (HMF), which is associated with marked morphological changes and upregulation of matrix metalloproteinases (MMPs) in these cells. By use of a 3-dimentional (3D) coculture system to model the critical interactions of different mammary cell types with their neighbors and with their environment, we have demonstrated that diminished pseudopods of senescent fibroblasts result in failure of mammary epithelial cells (MEC) to undergo glandular morphogenesis. MMP-mediated pericellular proteolysis loosens the growth constraint imposed by extracellular matrix (ECM), which enables breast cancer cells to fully express their malignant potential. .Our findings together support a model in which IR-induced senescence in stromal fibroblasts results in the perturbation of the tissue microenvironment, which leads to the dysregulation of cell-cell and cell-ECM interactions and promotion of tumor progression.
