Stromal-epithelial interactions in aging and cancer: senescent fibroblasts alter epithelial cell differentiation.
Cellular senescence suppresses cancer by arresting cells at risk of malignant tumorigenesis. However, senescent cells also secrete molecules that can stimulate premalignant cells to proliferate and form tumors, suggesting the senescence response is antagonistically pleiotropic. We show that premalignant mammary epithelial cells exposed to senescent human fibroblasts in mice irreversibly lose differentiated properties, become invasive and undergo full malignant transformation. Moreover, using cultured mouse or human fibroblasts and non-malignant breast epithelial cells, we show that senescent fibroblasts disrupt epithelial alveolar morphogenesis, functional differentiation and branching morphogenesis. Furthermore, we identify MMP-3 as the major factor responsible for the effects of senescent fibroblasts on branching morphogenesis. Our findings support the idea that senescent cells contribute to age-related pathology, including cancer, and describe a new property of senescent fibroblasts - the ability to alter epithelial differentiation - that might also explain the loss of tissue function and organization that is a hallmark of aging.
Parrinello
Simona
S
Life Sciences Division, Lawrence Berkeley National Laboratory, Berkeley, CA 94720, USA.
Coppe
Jean-Philippe
JP
Krtolica
Ana
A
Campisi
Judith
J
D000818:Animals; D002450:Cell Communication / Q000502:physiology*; D002454:Cell Differentiation / Q000502:physiology*; D002460:Cell Line; D022081:Cell Surface Extensions / Q000473:pathology; D002471:Cell Transformation, Neoplastic / Q000473:pathology*; D017690:Cell Transplantation; D016922:Cellular Senescence / Q000502:physiology*; D018920:Coculture Techniques; D017077:Culture Media, Conditioned / Q000494:pharmacology; D004847:Epithelial Cells / Q000187:drug effects / Q000473:pathology*; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism / Q000502:physiology*; D006801:Humans; D008321:Mammary Glands, Animal / Q000473:pathology; D019278:Matrix Metalloproteinase 3 / Q000378:metabolism / Q000502:physiology; D051379:Mice; D009361:Neoplasm Invasiveness / Q000473:pathology; D009369:Neoplasms / Q000209:etiology / Q000473:pathology; D009940:Organoids / Q000187:drug effects / Q000473:pathology; D017154:Stromal Cells / Q000502:physiology
D017077:Culture Media, Conditioned; D019278:Matrix Metalloproteinase 3