Presentation on theme: "Aging and Cancer: the Double-edged sword of cellular senescence And How to teach an old cell new tricks! Lawrence Berkeley National Laboratory and Buck."— Presentation transcript:
Aging and Cancer: the Double-edged sword of cellular senescence And How to teach an old cell new tricks! Lawrence Berkeley National Laboratory and Buck Institute for Age Research
Cancer Rises Exponentially with Age AGE INCIDENCE Age is largest single risk factor Incidence vs mortality
What Causes Cancer? Mutations, mutations, mutations … AND A permissive tissue
Organisms with renewable tissues had to evolve mechanisms to prevent cancer Tumor Suppressor Mechanisms
Tumor Suppressor Mechanisms/Genes (eliminates or arrests potential cancer cells) Apoptosis (programmed cell death) Cellular senescence CARETAKERS Prevent or repair genomic damage (prevent mutations) GATEKEEPERS Control cellular responses to damage
Caretaker tumor suppressor genes are longevity assurance genes Gatekeeper tumor suppressor genes are antagonistically pleiotropic
Antagonistic Pleiotropy What’s good for you when you are young, can be bad for you when you are old.
Aging before cell phones …….. 100% SURVIVORS AGE "Natural" Environment (hazards, predators, infection, etc.) 80 and > 3-4 "Protected" Environment (climate control, biomedical intervention etc.) 40 yrsHUMANS: 4 mosMICE:
Cellular Senescence: A Gatekeeper Tumor Suppressor Induced by potentially oncogenic stimuli Most tumor cells acquire mutations that abrogate the senescence response Controlled by p53 and pRB -- tumor suppressors inactivated in most tumors Mouse models/human cancer-prone syndromes
Short/dysfunctional telomeres (REPLICATIVE SENESCENCE) DNA Damage Oncogenes Chromatin Instability Stress/ Signals Cellular Senescence: Induced by Potentially Cancer-Causing Events Irreversible arrest of cell proliferation
The senescence response is not simply an arrest of cell growth
The Senescent Phenotype Irreversible Growth Arrest Resistance to Apoptosis Altered Differentiated Functions
Selected/Unselected (deleterious) Traits Irreversible Growth Arrest Resistance to Apoptosis Altered Differentiated Functions Cellular Senescence and Antagonistic Pleiotropy Unselected traits of little consequence, unless senescent cells accumulate to appreciable levels
Senescent Cells Accumulate In Vivo With Increasing Age Skin Retina Liver At Sites of Age-Related Pathology Venous ulcers Atherosclerotic plaques Benign prostatic hyperplasia Preneoplastic hepatic lesions
Senescent Cells May Contribute to Aging Phenotypes/Diseases ……. Including Cancer
Ana Krtolica Simona Parrinello Steve Lockett - LBNL Imaging Group Pierre Desprez - CPMC Proc. Natl Acad. Sci USA 98:12072-12077 (2001)
Epithelial Fluorescence HaCATSCp2S1 Senescent Fibroblasts Stimulate the Proliferation of Premalignant Epithelial Cells Premalignant Epithelial Cells Fibroblasts: Presenescent Senescent
Epithelial Fluorescence Adult NHEK Neonatal NHEK Adult HMEC Senescent Fibroblasts Do NOT Stimulate Normal Epithelial Cells Fibroblasts: Presenescent Senescent Genetically Normal Human Epithelial Cells
Senescent Fibroblasts Stimulate Tumorigenesis of Premalignant Epithelial Cells In Vivo Days 4080120 Tumor size (mm 3 x 10) 100 0 0 200 100 0 200 SCp2 cells alone + Presenescent Fibroblasts + Senescent Fibroblasts
Presenescent WI-38 fibroblasts (high p16): DNA synthesis + proliferation 0 40 80 100 % growth GFPp16 RNAi + Sn p16 RNAi + Sn + GSE Sn + GFP + LgT Sn + p16 RNA + LgT p16 RNAi + Sn + LgT 1) + lenti-p16-RNAi ----> Senescence 2) + lenti-GSE
p53 maintains the senescent state; p16 maintains a dominant barrier to reversal The senescent phenotype is reversible upon p53 inactivation …… Providing the p16/pRB pathway has not been engaged Why does p16 render the senescence growth arrest irreversible?
HYPOTHESIS: p16 enables pRB to establish an “irreversibly” repressive chromatin state that, once established, is independent of p16 or pRB Senescent cells form RB-dependent heterochromatic domains that repress positive acting cell cycle genes Lowe and colleagues, Cell, 2003 Once cells express high levels of p16, they no longer require p16 or active pRB to maintain the senescence growth arrest
Senescence is not necessarily irreversible in human cells Hint: ask about mouse cells! p53 inactivation is not a recommended therapy (but p53 modifiers, such as SIR2, may be!) What determines the extent to which cells express p16? How can we reverse the p16/pRB-initiated chromatin?
Aging and Tumor Suppression Tumor suppressors Aging Phenotypes Cancer Can tumor suppression and aging be uncoupled??