1、Cellular senescence, cancer and aging,Buck Institute for Age Research,Lawrence Berkeley National Laboratory,September 10, 2005 SENS2, Cambridge,Suppressing cancer costs - aging,Deplete proliferating/ stem cell pools - Tissue atrophy/degeneration,Deplete proliferating/stem pools Cell dysfunction - lo
2、ss of tissue function/homeostasis,Cellular Senescence Suppresses Cancer, Cancer cells acquire mutations that abrogate the senescence response, Mutations that dampen cellular senescence greatly increase susceptibility to cancer, Cellular senescence is controlled by two powerful gatekeeper tumor suppr
3、essor pathways (p53 and pRB), Mouse model, human tumor data - importance of cell senescence for limiting cancer progression,The senescent phenotype: Altered pattern of gene expression,Cell cycle regulation,Cell structure,Metabolism,Biologically active secreted molecules Proteinases Cytokines Growth
4、factors,Do senescent cells disrupt normal and/or neoplastic tissue structure/function?(effects of senescent stromal fibroblasts on epithelial cells),Jean-Philippe Coppe, Pierre Desprez, Ana Krtolica, Simona Parrinello, Christopher Patil,Senescent fibroblasts disrupt morphology and function of mammar
5、y epithelial cells,BM + PreS Fb BM + Sen Fb,b-casein DAPI,Pre-S Fb Sen Fb,b-casein,E-cadherin,Parrinello et al., J Cell Sci, 2005,Presenescent fibroblasts,Senescent fibroblasts,Core Area,Number,PRIMARY,SECONDARY,TERTIARY,Senescent fibroblasts disrupt ductal morphogenesis of normal mammary epithelial
6、 cells,Parrinello et al., J Cell Sci, 2005,Senescent fibroblasts stimulate proliferation of premalignant and malignant epithelial cells,Krtolica A et al., Proc Natl Acad Sci, 2001,Senescent Fibroblasts Stimulate Tumorigenesis of Premalignant Epithelial Cells In Vivo,Days,40,80,120,Tumor size (mm3 x
7、10),100,0,100,0,200,100,0,200,SCp2 cells alone,+ PresenescentFibroblasts,+ SenescentFibroblasts,Krtolica A et al., Proc Natl Acad Sci, 2001,Modeling effects of senescentcells in the mouse:Oxygen matters,Senescent phenotype of mouse fibroblasts,Mouse cells undergo rapid replicative senescence in cult
8、ure, despite long telomeres + telomerase,SCp2,HaCAT,S1,Human Fibroblasts,Mouse Fibroblasts (MEFs),Severe oxidative damage causes replicative senescence of murine cells in culture,Parrinello et al., Nature Cell Biol, 2003,How do senescent cells influence the behavior of neighboring cells?,The senesce
9、nce-associated secretory phenotype is conserved and complex,Jean-Philippe Coppe, Pierre Desprez, Ana Krtolica, Simona Parrinello, Christopher Patil,Conclusions from antibody arrays,Senescent stromal cells overexpress/secrete many cytokines, proteases, growth factors (senescence secretory phenotype),
10、There are similarities in the secretory phenotypes of senescent human and mouse stromal cells, BUT oxygen matters,There are many similarities among cells induced to senesce by different stimuli,Can the senescent phenotype be reversed without reversing the senescent growth arrest?,Parrinello et al., J Cell Sci, 2005,Senescent fibroblasts stimulate MEC ductal hyperplasia through MMP-3,THANKS!Jean-Philippe Coppe Ana Krtolica Christopher PatilSimona Parrinello (U College London) Christian Beausejour (McGill U)Pierre Desprez - CPMC Joe Gray, Rich Neve - LBNL Kalin Kauser - Berlex,
