Heterogeneity of Cell Death

Cell death constitutes a number of heterogeneous processes. Despite the dynamic nature of cell death, studies of cell death have primarily focused on apoptosis, and cell death has often been viewed as static events occurring in linear pathways. In this article we review cell death heterogeneity with specific focus on 4 aspects of cell death: the type of cell death; how it is induced; its mechanism(s); the results of cell death, and the implications of cell death heterogeneity for both basic and clinical research. This specifically reveals that cell death occurs in multiple overlapping forms that simultaneously occur within a population. Network and pathway heterogeneity in cell death is also discussed. Failure to integrate cell death heterogeneity within analyses can lead to inaccurate predictions of the amount of cell death that takes place in a tumor. Similarly, many molecular methods employed in cell death studies homogenize a population removing heterogeneity between individual cells and can be deceiving. Finally, and most importantly, cell death heterogeneity is linked to the formation of new genome systems through induction of aneuploidy and genome chaos (rapid genome reorganization).

[1]  H. Heng,et al.  Genetic and Epigenetic Heterogeneity in Cancer , 2011 .

[2]  H. Heng,et al.  Genetic and epigenetic heterogeneity in cancer: the ultimate challenge for drug therapy. , 2010, Current drug targets.

[3]  G. Salvesen,et al.  The protein structures that shape caspase activity, specificity, activation and inhibition. , 2004, The Biochemical journal.

[4]  R A Knight,et al.  Molecular definitions of cell death subroutines: recommendations of the Nomenclature Committee on Cell Death 2012 , 2011, Cell Death and Differentiation.

[5]  I. Roninson,et al.  If not apoptosis, then what? Treatment-induced senescence and mitotic catastrophe in tumor cells. , 2001, Drug resistance updates : reviews and commentaries in antimicrobial and anticancer chemotherapy.

[6]  Y. Yurov,et al.  Chromosomal mosaicism goes global , 2008, Molecular Cytogenetics.

[7]  H. Heng,et al.  Stochastic cancer progression driven by non‐clonal chromosome aberrations , 2006, Journal of cellular physiology.

[8]  L. Salmena,et al.  Requirement for caspase-8 in NF-kappaB activation by antigen receptor. , 2005, Science.

[9]  Ling Wei,et al.  Ionic Mechanism of Ouabain-Induced Concurrent Apoptosis and Necrosis in Individual Cultured Cortical Neurons , 2002, The Journal of Neuroscience.

[10]  Guo Liu,et al.  Decoding the genome beyond sequencing: the new phase of genomic research. , 2011, Genomics.

[11]  G. Kroemer,et al.  Mitotic catastrophe constitutes a special case of apoptosis whose suppression entails aneuploidy , 2004, Oncogene.

[12]  A. Kimchi,et al.  The dependence receptor UNC5H2/B triggers apoptosis via PP2A-mediated dephosphorylation of DAP kinase. , 2010, Molecular cell.

[13]  A. Wyllie,et al.  Apoptosis: A Basic Biological Phenomenon with Wide-ranging Implications in Tissue Kinetics , 1972, British Journal of Cancer.

[14]  M. Darding,et al.  IAPs: Guardians of RIPK1 , 2011, Cell Death and Differentiation.

[15]  L. Galluzzi,et al.  Shigella targets the mitochondrial checkpoint of programmed necrosis. , 2009, Cell host & microbe.

[16]  K. Choi,et al.  Cdc2 and Cdk2 play critical roles in low dose doxorubicin-induced cell death through mitotic catastrophe but not in high dose doxorubicin-induced apoptosis. , 2005, Biochemical and biophysical research communications.

[17]  Sarah M. Regan,et al.  Comparison of mitotic cell death by chromosome fragmentation to premature chromosome condensation , 2010, Molecular Cytogenetics.

[18]  G. Heppner,et al.  Mutagenic activity of tumor-associated macrophages in Salmonella typhimurium strains TA98 and TA 100. , 1984, Cancer research.

[19]  A. Levine,et al.  The tumor suppressor p53: Cancer and aging , 2008, Cell cycle.

[20]  A. Kimchi,et al.  The paradox of autophagy and its implication in cancer etiology and therapy , 2009, Apoptosis.

[21]  G. Heppner Tumor heterogeneity. , 1984, Cancer research.

[22]  Batoul Y. Abdallah,et al.  Evolutionary mechanisms and diversity in cancer. , 2011, Advances in cancer research.

[23]  R. Lockshin,et al.  Apoptosis in Developmental Processes , 2010 .

[24]  Yigong Shi,et al.  Molecular mechanisms of caspase regulation during apoptosis , 2004, Nature Reviews Molecular Cell Biology.

[25]  H. Steller,et al.  Pathways regulating apoptosis during patterning and development. , 2007, Current opinion in genetics & development.

[26]  H. Saya,et al.  Spindle checkpoint function is required for mitotic catastrophe induced by DNA-damaging agents , 2004, Oncogene.

[27]  H. Heng,et al.  SEX REDUCES GENETIC VARIATION: A MULTIDISCIPLINARY REVIEW , 2011, Evolution; international journal of organic evolution.

[28]  H. Heng,et al.  Imaging genome abnormalities in cancer research , 2004, Cell & chromosome.

[29]  S. Nagata,et al.  Autoimmunity and the Clearance of Dead Cells , 2010, Cell.

[30]  Michael O. Hengartner,et al.  Developmental cell biology: Developmental apoptosis in C. elegans: a complex CEDnario , 2006, Nature Reviews Molecular Cell Biology.

[31]  H. Heng Missing heritability and stochastic genome alterations , 2010, Nature Reviews Genetics.

[32]  Batoul Y. Abdallah,et al.  Why imatinib remains an exception of cancer research , 2013, Journal of cellular physiology.

[33]  R. Milo,et al.  Variability and memory of protein levels in human cells , 2006, Nature.

[34]  N. Carter,et al.  Massive Genomic Rearrangement Acquired in a Single Catastrophic Event during Cancer Development , 2011, Cell.

[35]  William W. Chen,et al.  Classic and contemporary approaches to modeling biochemical reactions. , 2010, Genes & development.

[36]  G. Wu,et al.  Overexpression of BCL2 blocks TNF-related apoptosis-inducing ligand (TRAIL)-induced apoptosis in human lung cancer cells. , 2001, Biochemical and biophysical research communications.

[37]  Peter K. Sorger,et al.  Measuring and Modeling Apoptosis in Single Cells , 2011, Cell.

[38]  Denis Thieffry,et al.  Mathematical Modelling of Cell-Fate Decision in Response to Death Receptor Engagement , 2010, PLoS Comput. Biol..

[39]  M. Cragg,et al.  Mitotic death: a mechanism of survival? A review , 2001, Cancer Cell International.

[40]  Batoul Y. Abdallah,et al.  Diverse system stresses: common mechanisms of chromosome fragmentation , 2011, Cell Death and Disease.

[41]  M. Blagosklonny Apoptosis, proliferation, differentiation: in search of the order. , 2003, Seminars in cancer biology.

[42]  J. Medema,et al.  Apoptosis and non-apoptotic deaths in cancer development and treatment response. , 2008, Cancer treatment reviews.

[43]  W. W. Nichols,et al.  Measles associated chromosome breakage , 2005, Archiv für die gesamte Virusforschung.

[44]  H. Heng,et al.  Genetic and epigenetic heterogeneity in cancer: A genome‐centric perspective , 2009, Journal of cellular physiology.

[45]  Mi Ae Kim,et al.  Bcl-xL blocks high dose doxorubicin-induced apoptosis but not low dose doxorubicin-induced cell death through mitotic catastrophe. , 2007, Biochemical and biophysical research communications.

[46]  L. Salmena,et al.  Requirement for Caspase-8 in NF-κB Activation by Antigen Receptor , 2005, Science.

[47]  P. Thong,et al.  Sequestration of mitotic (M‐phase) chromosomes in autophagosomes: Mitotic programmed cell death in human Chang liver cells induced by an OH* burst from vanadyl(4) , 1996, The Anatomical record.

[48]  H. Heng,et al.  Mitotic cell death by chromosome fragmentation. , 2007, Cancer research.

[49]  Guido Kroemer,et al.  Cell death by mitotic catastrophe: a molecular definition , 2004, Oncogene.

[50]  Joshua Stevens,et al.  Cancer progression by non‐clonal chromosome aberrations , 2006, Journal of cellular biochemistry.

[51]  H. Simon,et al.  Inflammation-Associated Autophagy-Related Programmed Necrotic Death of Human Neutrophils Characterized by Organelle Fusion Events , 2011, The Journal of Immunology.

[52]  P. Tompa,et al.  Intrinsic disorder in cell signaling and gene transcription , 2012, Molecular and Cellular Endocrinology.

[53]  M. Olivier,et al.  Recent advances in p53 research: an interdisciplinary perspective , 2009, Cancer Gene Therapy.

[54]  J. Hendry,et al.  Apoptosis and mitotic cell death: their relative contributions to normal-tissue and tumour radiation response. , 1997, International journal of radiation biology.

[55]  J. Tavaré,et al.  Rapid caspase‐3 activation during apoptosis revealed using fluorescence‐resonance energy transfer , 2000, EMBO reports.

[56]  H. Heng The genome‐centric concept: resynthesis of evolutionary theory , 2009, BioEssays : news and reviews in molecular, cellular and developmental biology.

[57]  Rui Wang,et al.  Modeling of the role of a Bax-activation switch in the mitochondrial apoptosis decision. , 2007, Biophysical journal.

[58]  Henry H.Q. Heng,et al.  Bio-Complexity: Challenging Reductionism , 2013 .

[59]  J. Bielas,et al.  Quantification of random genomic mutations , 2005, Nature Methods.

[60]  D. Green,et al.  A Single Cell Analysis of Apoptosis: Ordering the Apoptotic Phenotype , 2000, Annals of the New York Academy of Sciences.

[61]  Frank Davidoff,et al.  Heterogeneity is not always noise: lessons from improvement. , 2009, JAMA.

[62]  E. Morselli,et al.  Life, death and burial: multifaceted impact of autophagy. , 2008, Biochemical Society transactions.

[63]  P. Vandenabeele,et al.  Molecular mechanisms of necroptosis: an ordered cellular explosion , 2010, Nature Reviews Molecular Cell Biology.

[64]  M. Abend Reasons to reconsider the significance of apoptosis for cancer therapy , 2003, International journal of radiation biology.

[65]  S. Kondo,et al.  Apoptosis by antitumor agents and other factors in relation to cell cycle checkpoints. , 1995, Journal of radiation research.

[66]  Deyan Luan,et al.  Computationally Derived Points of Fragility of a Human Cascade Are Consistent with Current Therapeutic Strategies , 2007, PLoS Comput. Biol..

[67]  Gerard I. Evan,et al.  The coordinate release of cytochrome c during apoptosis is rapid, complete and kinetically invariant , 2000, Nature Cell Biology.

[68]  G. Kroemer,et al.  The apoptosis/autophagy paradox: autophagic vacuolization before apoptotic death , 2005, Journal of Cell Science.

[69]  H. Heng Cancer genome sequencing: the challenges ahead. , 2007, BioEssays : news and reviews in molecular, cellular and developmental biology.

[70]  J. Tschopp,et al.  Caspase Activation Is Required for T Cell Proliferation , 1999, The Journal of experimental medicine.

[71]  H. Heng,et al.  The dynamics of cancer chromosomes and genomes , 2007, Cytogenetic and Genome Research.

[72]  L. Galluzzi,et al.  RIP kinases initiate programmed necrosis. , 2009, Journal of molecular cell biology.

[73]  John Calvin Reed,et al.  The Patched dependence receptor triggers apoptosis through a DRAL–caspase-9 complex , 2009, Nature Cell Biology.

[74]  Nektarios Tavernarakis,et al.  No death without life: vital functions of apoptotic effectors , 2008, Cell Death and Differentiation.

[75]  Batoul Y. Abdallah,et al.  Genome constraint through sexual reproduction: application of 4D-Genomics in reproductive biology , 2013, Systems biology in reproductive medicine.

[76]  Govind Bhagat,et al.  Promotion of tumorigenesis by heterozygous disruption of the beclin 1 autophagy gene. , 2003, The Journal of clinical investigation.

[77]  B. F. Taylor,et al.  p53 Suppression of Arsenite-Induced Mitotic Catastrophe Is Mediated by p21CIP1/WAF1 , 2006, Journal of Pharmacology and Experimental Therapeutics.

[78]  H. Heng,et al.  The evolutionary mechanism of cancer , 2010, Journal of cellular biochemistry.

[79]  Lars Holmgren,et al.  Horizontal transfer of oncogenes by uptake of apoptotic bodies , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[80]  R. Milo,et al.  Dynamic Proteomics of Individual Cancer Cells in Response to a Drug , 2008, Science.

[81]  S. H. Baek When signaling kinases meet histones and histone modifiers in the nucleus. , 2011, Molecular cell.

[82]  Guido Kroemer,et al.  Mitochondrio‐nuclear translocation of AIF in apoptosis and necrosis , 2000, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[83]  V. Sgaramella Variability of our somatic (epi)genomes. , 2010, Science.