The senescence-associated secretory phenotype: the dark side of tumor suppression.

Cellular senescence is a tumor-suppressive mechanism that permanently arrests cells at risk for malignant transformation. However, accumulating evidence shows that senescent cells can have deleterious effects on the tissue microenvironment. The most significant of these effects is the acquisition of a senescence-associated secretory phenotype (SASP) that turns senescent fibroblasts into proinflammatory cells that have the ability to promote tumor progression.

[1]  S. Lowe,et al.  Senescence and tumour clearance is triggered by p53 restoration in murine liver carcinomas , 2011, Nature.

[2]  J. Campisi,et al.  Persistent DNA damage signaling triggers senescence-associated inflammatory cytokine secretion , 2009, Nature Cell Biology.

[3]  M. Narita,et al.  SASP reflects senescence , 2009, EMBO reports.

[4]  D. Peeper,et al.  Senescence-messaging secretome: SMS-ing cellular stress , 2009, Nature Reviews Cancer.

[5]  Judith Campisi,et al.  Senescence-Associated Secretory Phenotypes Reveal Cell-Nonautonomous Functions of Oncogenic RAS and the p53 Tumor Suppressor , 2008, PLoS biology.

[6]  D. Terrian,et al.  Senescence-associated exosome release from human prostate cancer cells. , 2008, Cancer research.

[7]  Michael R Green,et al.  Senescence: Not Just for Tumor Suppression , 2008, Cell.

[8]  J. Campisi,et al.  A Role for Fibroblasts in Mediating the Effects of Tobacco-Induced Epithelial Cell Growth and Invasion , 2008, Molecular Cancer Research.

[9]  D. Peeper,et al.  Oncogene-Induced Senescence Relayed by an Interleukin-Dependent Inflammatory Network , 2008, Cell.

[10]  Jonathan Melamed,et al.  Chemokine Signaling via the CXCR2 Receptor Reinforces Senescence , 2008, Cell.

[11]  Michael R. Green,et al.  Oncogenic BRAF Induces Senescence and Apoptosis through Pathways Mediated by the Secreted Protein IGFBP7 , 2008, Cell.

[12]  J. Campisi,et al.  Cellular senescence: when bad things happen to good cells , 2007, Nature Reviews Molecular Cell Biology.

[13]  Manuel Serrano,et al.  The common biology of cancer and ageing , 2007, Nature.

[14]  P. Adams Remodeling chromatin for senescence , 2007, Aging cell.

[15]  F. Ishikawa,et al.  Cellular senescence and chromatin structure , 2007, Chromosoma.

[16]  K. Wiman,et al.  Reactivation of mutant p53: molecular mechanisms and therapeutic potential , 2007, Oncogene.

[17]  J. Bridger,et al.  Alterations to Nuclear Architecture and Genome Behavior in Senescent Cells , 2007, Annals of the New York Academy of Sciences.

[18]  P. Hornsby,et al.  Senescent human fibroblasts increase the early growth of xenograft tumors via matrix metalloproteinase secretion. , 2007, Cancer research.

[19]  M. Narita Cellular senescence and chromatin organisation , 2007, British Journal of Cancer.

[20]  T. Jacks,et al.  Restoration of p53 function leads to tumour regression in vivo , 2007, Nature.

[21]  Carlos Cordon-Cardo,et al.  Senescence and tumour clearance is triggered by p53 restoration in murine liver carcinomas , 2007, Nature.

[22]  J. Yates,et al.  PRAK Is Essential for ras-Induced Senescence and Tumor Suppression , 2007, Cell.

[23]  C. Johannessen,et al.  A negative feedback signaling network underlies oncogene-induced senescence. , 2006, Cancer cell.

[24]  J. Campisi,et al.  Secretion of Vascular Endothelial Growth Factor by Primary Human Fibroblasts at Senescence* , 2006, Journal of Biological Chemistry.

[25]  A. Frey Myeloid suppressor cells regulate the adaptive immune response to cancer. , 2006, The Journal of clinical investigation.

[26]  K. Ligon,et al.  p16INK4a induces an age-dependent decline in islet regenerative potential , 2006, Nature.

[27]  R. DePinho,et al.  Stem-cell ageing modified by the cyclin-dependent kinase inhibitor p16INK4a , 2006, Nature.

[28]  S. Morrison,et al.  Increasing p16INK4a expression decreases forebrain progenitors and neurogenesis during ageing , 2006, Nature.

[29]  I. Komuro,et al.  Angiotensin II Induces Premature Senescence of Vascular Smooth Muscle Cells and Accelerates the Development of Atherosclerosis via a p21-Dependent Pathway , 2006, Circulation.

[30]  R. Bernards,et al.  Plasminogen activator inhibitor-1 is a critical downstream target of p53 in the induction of replicative senescence , 2006, Nature Cell Biology.

[31]  Shu-Chun Lin,et al.  Ripe areca nut extract induces G1 phase arrests and senescence-associated phenotypes in normal human oral keratinocyte. , 2006, Carcinogenesis.

[32]  M. Serrano,et al.  The power and the promise of oncogene-induced senescence markers , 2006, Nature Reviews Cancer.

[33]  Alberto Mantovani,et al.  Tumour-associated macrophages are a distinct M2 polarised population promoting tumour progression: potential targets of anti-cancer therapy. , 2006, European journal of cancer.

[34]  A. Verkleij,et al.  Protein expression dynamics during replicative senescence of endothelial cells studied by 2‐D difference in‐gel electrophoresis , 2006, Electrophoresis.

[35]  M. Burdick,et al.  Cancer CXC chemokine networks and tumour angiogenesis. , 2006, European journal of cancer.

[36]  C. Schmitt,et al.  Oncogene-induced senescence: putting the brakes on tumor development. , 2006, Cancer research.

[37]  A. Ben-Baruch Inflammation-associated immune suppression in cancer: the roles played by cytokines, chemokines and additional mediators. , 2006, Seminars in cancer biology.

[38]  P. Nelson,et al.  The gene expression program of prostate fibroblast senescence modulates neoplastic epithelial cell proliferation through paracrine mechanisms. , 2006, Cancer research.

[39]  L. Coussens,et al.  Paradoxical roles of the immune system during cancer development , 2006, Nature Reviews Cancer.

[40]  Robert D. Cardiff,et al.  Selective Evolution of Stromal Mesenchyme with p53 Loss in Response to Epithelial Tumorigenesis , 2005, Cell.

[41]  R. Shah,et al.  CXCL12 overexpression and secretion by aging fibroblasts enhance human prostate epithelial proliferation in vitro , 2005, Aging cell.

[42]  Feng Yang,et al.  Stromal expression of connective tissue growth factor promotes angiogenesis and prostate cancer tumorigenesis. , 2005, Cancer research.

[43]  Edward G Lakatta,et al.  Arterial aging: is it an immutable cardiovascular risk factor? , 2005, Hypertension.

[44]  S. Schwarze,et al.  The identification of senescence-specific genes during the induction of senescence in prostate cancer cells. , 2005, Neoplasia.

[45]  S. Lowe,et al.  Senescence comes of age , 2005, Nature Medicine.

[46]  M. Barbacid,et al.  Tumour biology: Senescence in premalignant tumours , 2005, Nature.

[47]  J. Shay,et al.  BRAFE600-associated senescence-like cell cycle arrest of human naevi , 2005, Nature.

[48]  H. Stein,et al.  Oncogene-induced senescence as an initial barrier in lymphoma development , 2005, Nature.

[49]  Jason A. Koutcher,et al.  Crucial role of p53-dependent cellular senescence in suppression of Pten-deficient tumorigenesis , 2005, Nature.

[50]  J. Little,et al.  Cellular mechanisms for low-dose ionizing radiation-induced perturbation of the breast tissue microenvironment. , 2005, Cancer research.

[51]  K. Becker,et al.  Gene expression responses to DNA damage are altered in human aging and in Werner Syndrome , 2005, Oncogene.

[52]  J. Joyce,et al.  Therapeutic Targeting of the Tumor Microenvironment. , 2021, Cancer discovery.

[53]  S. Bode-Böger,et al.  Asymmetric dimethylarginine (ADMA) accelerates cell senescence , 2005, Vascular medicine.

[54]  R. Weinberg,et al.  The signals and pathways activating cellular senescence. , 2005, The international journal of biochemistry & cell biology.

[55]  H. Kiaris,et al.  Evidence for nonautonomous effect of p53 tumor suppressor in carcinogenesis. , 2005, Cancer research.

[56]  Robert S. Balaban,et al.  Mitochondria, Oxidants, and Aging , 2005, Cell.

[57]  G. Martin Genetic Modulation of Senescent Phenotypes in Homo sapiens , 2005, Cell.

[58]  J. Campisi Senescent Cells, Tumor Suppression, and Organismal Aging: Good Citizens, Bad Neighbors , 2005, Cell.

[59]  K. Chien,et al.  Longevity and Lineages: Toward the Integrative Biology of Degenerative Diseases in Heart, Muscle, and Bone , 2005, Cell.

[60]  Frederick W. Alt,et al.  DNA Repair, Genome Stability, and Aging , 2005, Cell.

[61]  J. Campisi,et al.  Stromal-epithelial interactions in aging and cancer: senescent fibroblasts alter epithelial cell differentiation , 2004, Journal of Cell Science.

[62]  研宙 大内田,et al.  Radiation to stromal fibroblasts increases invasiveness of pancreatic cancer cells through tumor-stromal interactions , 2005 .

[63]  P. Fisher,et al.  Modulating T cell signals using CD3/CD28 Xcyte™ Dynabeads® allows for selective expansion or deletion of antigen-specific T cells , 2004 .

[64]  P. Fisher,et al.  Human Polynucleotide Phosphorylase (hPNPaseold-35) , 2004, Cancer Research.

[65]  In-Hwan Song,et al.  Exploration of replicative senescence-associated genes in human dermal fibroblasts by cDNA microarray technology , 2004, Experimental Gerontology.

[66]  Stanley N Cohen,et al.  Disparate effects of telomere attrition on gene expression during replicative senescence of human mammary epithelial cells cultured under different conditions , 2004, Oncogene.

[67]  Atul J Butte,et al.  Genome‐scale expression profiling of Hutchinson–Gilford progeria syndrome reveals widespread transcriptional misregulation leading to mesodermal/mesenchymal defects and accelerated atherosclerosis , 2004, Aging cell.

[68]  Michael T. Lotze,et al.  Inflammation and necrosis promote tumour growth , 2004, Nature Reviews Immunology.

[69]  F. Balkwill Cancer and the chemokine network , 2004, Nature Reviews Cancer.

[70]  Jeen-Woo Park,et al.  Expression of connective tissue growth factor, a biomarker in senescence of human diploid fibroblasts, is up-regulated by a transforming growth factor-beta-mediated signaling pathway. , 2004, Biochemical and biophysical research communications.

[71]  A. Mantovani,et al.  Chemokines in neoplastic progression. , 2004, Seminars in cancer biology.

[72]  John M Sedivy,et al.  Telomere shortening triggers senescence of human cells through a pathway involving ATM, p53, and p21(CIP1), but not p16(INK4a). , 2004, Molecular cell.

[73]  I. Roninson,et al.  Tumor suppressor maspin is up-regulated during keratinocyte senescence, exerting a paracrine antiangiogenic activity. , 2004, Cancer research.

[74]  D. Galloway,et al.  Normal Human Fibroblasts Are Resistant to RAS-Induced Senescence , 2004, Molecular and Cellular Biology.

[75]  D. Bar-Sagi,et al.  Ras-induced interleukin-8 expression plays a critical role in tumor growth and angiogenesis. , 2004, Cancer cell.

[76]  K. Mohammad,et al.  Modulation of mammalian life span by the short isoform of p53. , 2004, Genes & development.

[77]  R. Weinberg,et al.  When cells get stressed: an integrative view of cellular senescence. , 2004, The Journal of clinical investigation.

[78]  R. Nishigaki,et al.  Searching for genes involved in arteriosclerosis: proteomic analysis of cultured human umbilical vein endothelial cells undergoing replicative senescence. , 2003, Cell structure and function.

[79]  W. Birchmeier,et al.  Met, metastasis, motility and more , 2003, Nature Reviews Molecular Cell Biology.

[80]  Qin M. Chen,et al.  Novel mechanisms of sublethal oxidant toxicity: induction of premature senescence in human fibroblasts confers tumor promoter activity. , 2003, Experimental cell research.

[81]  P. Claudio,et al.  Molecular basis of angiogenesis and cancer , 2003, Oncogene.

[82]  S. Husson,et al.  Gelatinase B/MMP-9 and neutrophil collagenase/MMP-8 process the chemokines human GCP-2/CXCL6, ENA-78/CXCL5 and mouse GCP-2/LIX and modulate their physiological activities. , 2003, European journal of biochemistry.

[83]  Masashi Narita,et al.  Reversal of human cellular senescence: roles of the p53 and p16 pathways , 2003, The EMBO journal.

[84]  E. Block,et al.  Senescence-enhanced oxidative stress is associated with deficiency of mitochondrial cytochrome c oxidase in vascular endothelial cells , 2003, Mechanisms of Ageing and Development.

[85]  W. Hornebeck,et al.  Proteolyzed matrix as a template for the regulation of tumor progression. , 2003, Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie.

[86]  S. Drăghici,et al.  Epigenetic silencing of multiple interferon pathway genes after cellular immortalization , 2003, Oncogene.

[87]  S. Lowe,et al.  Rb-Mediated Heterochromatin Formation and Silencing of E2F Target Genes during Cellular Senescence , 2003, Cell.

[88]  Z. Ungvari,et al.  Aging‐induced proinflammatory shift in cytokine expression profile in rat coronary arteries , 2003, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[89]  Patricia D. Castro,et al.  Cellular senescence in the pathogenesis of benign prostatic hyperplasia , 2003, The Prostate.

[90]  C. Schmitt Senescence, apoptosis and therapy — cutting the lifelines of cancer , 2003, Nature Reviews Cancer.

[91]  Stanley N Cohen,et al.  Senescence-specific gene expression fingerprints reveal cell-type-dependent physical clustering of up-regulated chromosomal loci , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[92]  D. Brenner,et al.  Replicative senescence of activated human hepatic stellate cells is accompanied by a pronounced inflammatory but less fibrogenic phenotype , 2003, Hepatology.

[93]  K. Becker,et al.  The transcriptional response after oxidative stress is defective in Cockayne syndrome group B cells , 2003, Oncogene.

[94]  J. Foekens,et al.  Aging of stromal-derived human breast fibroblasts might contribute to breast cancer progression , 2003, Thrombosis and Haemostasis.

[95]  P. Chène Inhibiting the p53–MDM2 interaction: an important target for cancer therapy , 2003, Nature Reviews Cancer.

[96]  C. Berking,et al.  Differential response of primary and metastatic melanomas to neutrophils attracted by IL‐8 , 2003, International journal of cancer.

[97]  Goberdhan P Dimri,et al.  Control of the Replicative Life Span of Human Fibroblasts by p16 and the Polycomb Protein Bmi-1 , 2003, Molecular and Cellular Biology.

[98]  P. Carmeliet,et al.  uPAR: a versatile signalling orchestrator , 2002, Nature Reviews Molecular Cell Biology.

[99]  A. Menssen,et al.  Characterization of epithelial senescence by serial analysis of gene expression: identification of genes potentially involved in prostate cancer. , 2002, Cancer research.

[100]  J. Wallace,et al.  Matrix metalloproteinase processing of monocyte chemoattractant proteins generates CC chemokine receptor antagonists with anti-inflammatory properties in vivo. , 2002, Blood.

[101]  P. Dhawan,et al.  Role of CXCL1 in tumorigenesis of melanoma , 2002, Journal of leukocyte biology.

[102]  M. Goligorsky,et al.  Glycated Collagen I Induces Premature Senescence-Like Phenotypic Changes in Endothelial Cells , 2002, Circulation research.

[103]  J. Thiery Epithelial–mesenchymal transitions in tumour progression , 2002, Nature Reviews Cancer.

[104]  Li Fang,et al.  Inhibition of p21‐mediated ROS accumulation can rescue p21‐induced senescence , 2002, The EMBO journal.

[105]  J. Brooks,et al.  Novel Pathways Associated with Bypassing Cellular Senescence in Human Prostate Epithelial Cells* 210 , 2002, The Journal of Biological Chemistry.

[106]  B. Vandenbunder,et al.  Hepatocyte growth factor/scatter factor activates the ETS1 transcription factor by a RAS-RAF-MEK-ERK signaling pathway , 2002, Oncogene.

[107]  Motowo Nakajima,et al.  Radiation-induced increase in invasive potential of human pancreatic cancer cells and its blockade by a matrix metalloproteinase inhibitor, CGS27023. , 2002, Clinical cancer research : an official journal of the American Association for Cancer Research.

[108]  A. Zlotnik,et al.  Chemokines: agents for the immunotherapy of cancer? , 2002, Nature Reviews Immunology.

[109]  Stephen N. Jones,et al.  p53 mutant mice that display early ageing-associated phenotypes , 2002, Nature.

[110]  B. Vandenbunder,et al.  Hepatocyte growth factor/scatter factor activates the ETS1 transcription factor by a RAS-RAF-MEK-ERK signaling pathway , 2002, Oncogene.

[111]  I. Roninson,et al.  Molecular determinants of terminal growth arrest induced in tumor cells by a chemotherapeutic agent , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[112]  J. Campisi,et al.  Senescent fibroblasts promote epithelial cell growth and tumorigenesis: A link between cancer and aging , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[113]  J. Ward,et al.  Eotaxin (CCL11) Induces In Vivo Angiogenic Responses by Human CCR3+ Endothelial Cells1 , 2001, The Journal of Immunology.

[114]  M Locati,et al.  Decoy receptors: a strategy to regulate inflammatory cytokines and chemokines. , 2001, Trends in immunology.

[115]  M. Herlyn,et al.  Low-Level Monocyte Chemoattractant Protein-1 Stimulation of Monocytes Leads to Tumor Formation in Nontumorigenic Melanoma Cells1 , 2001, The Journal of Immunology.

[116]  W. Park,et al.  Gene profile of replicative senescence is different from progeria or elderly donor. , 2001, Biochemical and biophysical research communications.

[117]  F. Orr,et al.  Tumor cell interactions with the microvasculature: a rate-limiting step in metastasis. , 2001, Surgical oncology clinics of North America.

[118]  K. Camphausen,et al.  Radiation therapy to a primary tumor accelerates metastatic growth in mice. , 2001, Cancer research.

[119]  T. Lüscher,et al.  Enhanced Peroxynitrite Formation Is Associated with Vascular Aging , 2000, The Journal of experimental medicine.

[120]  D. Ribatti,et al.  I-309 binds to and activates endothelial cell functions and acts as an angiogenic molecule in vivo. , 2000, Blood.

[121]  N. Holbrook,et al.  Oxidants, oxidative stress and the biology of ageing , 2000, Nature.

[122]  M. Benson,et al.  Expression of senescence-associated beta-galactosidase in enlarged prostates from men with benign prostatic hyperplasia. , 2000, Urology.

[123]  D. Lockhart,et al.  Mitotic misregulation and human aging. , 2000, Science.

[124]  H. Katinger,et al.  Subtractive Hybridization of mRNA from early passage and senescent endothelial cells , 2000, Experimental Gerontology.

[125]  M. Barcellos-Hoff,et al.  Irradiated mammary gland stroma promotes the expression of tumorigenic potential by unirradiated epithelial cells. , 2000, Cancer research.

[126]  S. Plymate,et al.  Characterization of insulin-like growth factor-binding protein-related proteins (IGFBP-rPs) 1, 2, and 3 in human prostate epithelial cells: potential roles for IGFBP-rP1 and 2 in senescence of the prostatic epithelium. , 2000, Endocrinology.

[127]  B. Foster,et al.  Pharmacological rescue of mutant p53 conformation and function. , 1999, Science.

[128]  D. Shelton,et al.  Microarray analysis of replicative senescence , 1999, Current Biology.

[129]  K. Hirokawa,et al.  Induction of the p16INK4a senescence gene as a new therapeutic strategy for the treatment of rheumatoid arthritis , 1999, Nature Medicine.

[130]  V. Ferrans,et al.  Ras Proteins Induce Senescence by Altering the Intracellular Levels of Reactive Oxygen Species* , 1999, The Journal of Biological Chemistry.

[131]  D. Palmieri,et al.  Age-related expression of PEDF/EPC-1 in human endometrial stromal fibroblasts: implications for interactive senescence. , 1999, Experimental cell research.

[132]  A. Ridley,et al.  Activation of both MAP kinase and phosphatidylinositide 3-kinase by Ras is required for hepatocyte growth factor/scatter factor-induced adherens junction disassembly. , 1998, Molecular biology of the cell.

[133]  P. Higgins,et al.  Increased transcription and modified growth state‐dependent expression of the plasminogen activator inhibitor type‐1 gene characterize the senescent phenotype in human diploid fibroblasts , 1998, Journal of cellular physiology.

[134]  B. Groner,et al.  Restoration of the growth suppression function of mutant p53 by a synthetic peptide derived from the p53 C-terminal domain , 1997, Nature Medicine.

[135]  R. Thweatt,et al.  Characterization Of IGFBP-3, PAI-1 and SPARC mRNA expression in senescent fibroblasts , 1996, Mechanisms of Ageing and Development.

[136]  J. Shay,et al.  Altered expression of plasminogen activator and plasminogen activator inhibitor during cellular senescence , 1996, Experimental Gerontology.

[137]  G. Zeng,et al.  Differential regulation of collagenase and stromelysin mRNA in late passage cultures of human fibroblasts. , 1996, Experimental cell research.

[138]  P. Higgins,et al.  Differential growth state‐dependent regulation of plasminogen activator inhibitor type‐1 expression in senescent IMR‐90 human diploid fibroblasts , 1995, Journal of cellular physiology.

[139]  C Roskelley,et al.  A biomarker that identifies senescent human cells in culture and in aging skin in vivo. , 1995, Proceedings of the National Academy of Sciences of the United States of America.

[140]  J. Maier,et al.  Senescence-dependent regulation of type 1 plasminogen activator inhibitor in human vascular endothelial cells. , 1995, Experimental cell research.

[141]  J. McLachlan,et al.  Immunological functions of aged human monocytes. , 1995, Pathobiology : journal of immunopathology, molecular and cellular biology.

[142]  R. Thweatt,et al.  Altered regulation of fibronectin gene expression in Werner syndrome fibroblasts. , 1994, Experimental cell research.

[143]  S. Brown,et al.  Post-transcriptional regulation of interleukin 1 alpha in various strains of young and senescent human umbilical vein endothelial cells. , 1994, Proceedings of the National Academy of Sciences of the United States of America.

[144]  M. Ikeda,et al.  Reduction of nitric oxide producing activity associated with in vitro aging in cultured human umbilical vein endothelial cell. , 1993, Biochemical and biophysical research communications.

[145]  D. Schadendorf,et al.  IL-8 produced by human malignant melanoma cells in vitro is an essential autocrine growth factor. , 1993, Journal of immunology.

[146]  L. Heppel,et al.  Stimulation of aged human lung fibroblasts by extracellular ATP via suppression of arachidonate metabolism. , 1993, The Journal of biological chemistry.

[147]  M. Kobayashi,et al.  Enhanced expression of fibronectin during in vivo cellular aging of human vascular endothelial cells and skin fibroblasts. , 1993, Experimental cell research.

[148]  A. J. Millis,et al.  Differential expression of metalloproteinase and tissue inhibitor of metalloproteinase genes in aged human fibroblasts. , 1992, Experimental cell research.

[149]  C. Baglioni,et al.  Expression of interleukin 1-inducible genes and production of interleukin 1 by aging human fibroblasts. , 1992, Proceedings of the National Academy of Sciences of the United States of America.

[150]  R. Derynck,et al.  Effects of MGSA/GRO alpha on melanocyte transformation. , 1991, Oncogene.

[151]  D. Roeder,et al.  Extension of the life-span of human endothelial cells by an interleukin-1 alpha antisense oligomer. , 1990, Science.

[152]  J. R. Smith,et al.  Replicative senescence of human skin fibroblasts correlates with a loss of regulation and overexpression of collagenase activity. , 1989, Experimental cell research.

[153]  I. M. Neiman,et al.  [Inflammation and cancer]. , 1974, Patologicheskaia fiziologiia i eksperimental'naia terapiia.