Stromal-epithelial interactions in aging and cancer: Senescent fibroblasts alter epithelial cell differentiation

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Description

Cellular senescence suppresses cancer by arresting cells at risk for 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. Further, we identify MMP-3 as the major factor responsible for the effects of senescent ... continued below

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38 pages

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Parrinello, Simona; Coppe, Jean-Philippe; Krtolica, Ana & Campisi, Judith July 14, 2004.

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Description

Cellular senescence suppresses cancer by arresting cells at risk for 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. Further, 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.

Physical Description

38 pages

Notes

OSTI as DE00838074

Source

  • Journal Name: Journal of Cell Science; Journal Volume: 118; Other Information: Submitted to Journal of Cell Science: Volume 118; Journal Publication Date: 02/01/2005

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  • Report No.: LBNL--56629
  • Grant Number: AC03-76SF00098
  • Office of Scientific & Technical Information Report Number: 838074
  • Archival Resource Key: ark:/67531/metadc788888

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  • July 14, 2004

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  • Dec. 3, 2015, 9:30 a.m.

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  • June 22, 2016, 6:38 p.m.

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Parrinello, Simona; Coppe, Jean-Philippe; Krtolica, Ana & Campisi, Judith. Stromal-epithelial interactions in aging and cancer: Senescent fibroblasts alter epithelial cell differentiation, article, July 14, 2004; Berkeley, California. (digital.library.unt.edu/ark:/67531/metadc788888/: accessed August 22, 2017), University of North Texas Libraries, Digital Library, digital.library.unt.edu; crediting UNT Libraries Government Documents Department.