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Lawrence Berkeley National Laboratory September 10, 2005 SENS2, Cambridge Cellular senescence, cancer and aging Buck Institute for Age Research Suppressing cancer costs -- aging Tumor Suppressor mechanisms Aging Phenotypes Late life phenotypes, including cancer Caretakers Gatekeepers (prevent/ (eliminate/arrest repair DNA damaged, damage, mutant cells) mutations) (antagonistic pleiotropy) Apoptosis Deplete proliferating/ stem cell pools ---> Tissue atrophy/degeneration Senescence Longevity assurance Deplete proliferating/stem pools Cell dysfunction ---> loss 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 suppressor pathways (p53 and pRB) • Mouse model, human tumor data ----> importance of cell senescence for limiting cancer progression Cellular Senescence Induced by Many (Cancer-Causing) Stimuli Chromatin Instability DNA Damage Irreversible arrest of cell proliferation Supraphysiological Mitogenic/ Stress Signals Oncogenes Short/dysfunctional telomeres (REPLICATIVE SENESCENCE) CELLULAR SENECENCE: Complex Senescent Phenotype Irreversible Growth Arrest Resistance to Apoptosis Altered Function/Gene Expression The senescent phenotype: Altered pattern of gene expression Cell cycle regulation Cell structure Metabolism Biologically active secreted molecules Proteinases Cytokines Growth factors YOUNG TISSUE YOUNG TISSUE EPITHELIUM "Initiated" Cell Epithelial EPITHELIUM Basement Membrane Cells Basement Membrane STROMA Fibroblasts STROMA AGING ? AGING ? Senescent Epithelial Cell Senescent Epithelial Cell OLD TISSUE OLD TISSUE EPITHELIUM EPITHELIUM Basement Membrane Basement Membrane STROMA STROMA Senescent Fibroblast Degradative & inflammatory molecules, growth factors, etc INCIDENCE Degradative enzymes, Inflammatory cytokines, etc. Neoplastic Growth Senescent Fibroblast Mutations Senescent cells CANCER AGE 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 mammary epithelial cells BM + PreS Fb BM + Sen Fb Pre-S Fb Sen Fb b-casein E-cadherin b-casein DAPI Parrinello et al., J Cell Sci, 2005 Senescent fibroblasts disrupt ductal morphogenesis of normal mammary epithelial cells Presenescent fibroblasts Senescent fibroblasts Primary duct Secondary duct Number Core Area Core PRIMARY SECONDARY TERTIARY 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 Tumor size (mm3 x 10) 100 SCp2 cells alone 0 200 100 + Presenescent Fibroblasts 0 200 + Senescent Fibroblasts 100 0 40 Krtolica A et al., Proc Natl Acad Sci, 2001 80 120 Days Modeling effects of senescent cells in the mouse: Oxygen matters Senescent phenotype of mouse fibroblasts Mouse cells undergo rapid replicative senescence in culture, despite long telomeres + telomerase Epithelial Cell Growth Presenescent Senescent Human Fibroblasts HaCAT SCp2 S1 Mouse Fibroblasts (MEFs) SCp2 HaCAT S1 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 senescence-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) There are many similarities among cells induced to senesce by different stimuli There are similarities in the secretory phenotypes of senescent human and mouse stromal cells, BUT oxygen matters Can the senescent phenotype be reversed without reversing the senescent growth arrest? Senescent fibroblasts stimulate MEC ductal hyperplasia through MMP-3 QuickTime™ and a TIFF (LZW) decompressor are needed to see this picture. QuickTime™ and a TIFF (LZW) decompressor are needed to see this picture. QuickTime™ and a TIFF (LZW) decompressor are needed to see this picture. Parrinello et al., J Cell Sci, 2005 THANKS! Jean-Philippe Coppe Ana Krtolica Christopher Patil Simona Parrinello (U College London) Christian Beausejour (McGill U) Pierre Desprez -- CPMC Joe Gray, Rich Neve -- LBNL Kalin Kauser -- Berlex