Timing is everything: stochastic origins of cell-to-cell variability in cancer cell death.

The diversity of cell populations is regulated by extracellular and intracellular variability. The latter includes genetic, epigenetic and stochastic variability, all contributing to the experimentally observed heterogeneity in response to external death-inducing stimuli. Studies of sources and regulation of variability in commitment to apoptotic cancer cell death are likely to identify the fundamental features of apoptotic protein networks that are responsible for determining the ultimate cell fate. Systems biology approaches, involving computer simulations of the biochemical reactions accompanied, if possible, by experimental verification of selected components of the model, are proving useful in determining the origins of cell-to-cell variability in response to external stress stimuli. Here we summarize our current understanding of the origins of stochastic variability in cells' commitment to apoptosis, and its implications in the field on cancer therapy.

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

[2]  P. Swain,et al.  Gene Regulation at the Single-Cell Level , 2005, Science.

[3]  N. Fox,et al.  Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) receptor-1 and receptor-2 agonists for cancer therapy , 2010, Expert opinion on biological therapy.

[4]  A. Letai,et al.  Mimicking the BH3 domain to kill cancer cells , 2008, Oncogene.

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

[6]  Joanna Skommer,et al.  Bcl-2 inhibits apoptosis by increasing the time-to-death and intrinsic cell-to-cell variations in the mitochondrial pathway of cell death , 2010, Apoptosis.

[7]  T. Nguyen,et al.  Monte Carlo simulation of cell death signaling predicts large cell-to-cell stochastic fluctuations through the type 2 pathway of apoptosis. , 2008, Biophysical journal.

[8]  Donald Wlodkowic,et al.  Microfluidic single-cell array cytometry for the analysis of tumor apoptosis. , 2009, Analytical chemistry.

[9]  E. D. de Vries,et al.  Modulation of death receptor pathways in oncology. , 2003, Drugs of today.

[10]  Anne E Carpenter,et al.  Cell microarrays and RNA interference chip away at gene function , 2005, Nature Genetics.

[11]  M. Serrano,et al.  Senescence in tumours: evidence from mice and humans , 2010, Nature Reviews Cancer.

[12]  D. Green,et al.  The Pathophysiology of Mitochondrial Cell Death , 2004, Science.

[13]  Donald Wlodkowic,et al.  Cell death goes LIVE: Technological advances in real-time tracking of cell death , 2010, Cell cycle.

[14]  Martin L Yarmush,et al.  Living-cell microarrays. , 2009, Annual review of biomedical engineering.

[15]  D. Gillespie.  Exact Stochastic Simulation of Coupled Chemical Reactions , 1977 .

[16]  Philippe Bastiaens,et al.  Systems biology: When it is time to die , 2009, Nature.

[17]  M. Rehm,et al.  Dynamics of outer mitochondrial membrane permeabilization during apoptosis , 2009, Cell Death and Differentiation.

[18]  A. Folch,et al.  Large-scale single-cell trapping and imaging using microwell arrays. , 2005, Analytical chemistry.

[19]  A. Letai.  BH3 domains as BCL-2 inhibitors: prototype cancer therapeutics , 2003, Expert opinion on biological therapy.

[20]  M. Rehm,et al.  Real Time Analysis of Tumor Necrosis Factor-related Apoptosis-inducing Ligand/Cycloheximide-induced Caspase Activities during Apoptosis Initiation* , 2008, Journal of Biological Chemistry.

[21]  Donald Wlodkowic,et al.  ER-Golgi network--a future target for anti-cancer therapy. , 2009, Leukemia research.

[22]  Donald Wlodkowic,et al.  Microfluidic single cell arrays to interrogate signalling dynamics of individual, patient-derived hematopoietic stem cells. , 2009, Lab on a chip.

[23]  S. Raychaudhuri,et al.  Neuroglobin protects nerve cells from apoptosis by inhibiting the intrinsic pathway of cell death , 2009, Apoptosis.

[24]  Alexander van Oudenaarden,et al.  Stochastic gene expression out-of-steady-state in the cyanobacterial circadian clock , 2007, Nature.

[25]  Martin A. Nowak,et al.  Dynamics of chronic myeloid leukaemia , 2005, Nature.

[26]  D. Lauffenburger,et al.  Modeling a Snap-Action, Variable-Delay Switch Controlling Extrinsic Cell Death , 2008, PLoS biology.

[27]  P. Sorger,et al.  Non-genetic origins of cell-to-cell variability in TRAIL-induced apoptosis , 2009, Nature.

[28]  Mark Shackleton,et al.  Efficient tumour formation by single human melanoma cells , 2008 .

[29]  B. Frieden,et al.  Adaptive therapy. , 2009, Cancer research.