Embryonic stem cell-specific signatures in cancer: insights into genomic regulatory networks and implications for medicine

Embryonic stem (ES) cells are of great interest as a model system for studying early developmental processes and because of their potential therapeutic applications in regenerative medicine. Obtaining a systematic understanding of the mechanisms that control the 'stemness' - self-renewal and pluripotency - of ES cells relies on high-throughput tools to define gene expression and regulatory networks at the genome level. Such recently developed systems biology approaches have revealed highly interconnected networks in which multiple regulatory factors act in combination. Interestingly, stem cells and cancer cells share some properties, notably self-renewal and a block in differentiation. Recently, several groups reported that expression signatures that are specific to ES cells are also found in many human cancers and in mouse cancer models, suggesting that these shared features might inform new approaches for cancer therapy. Here, we briefly summarize the key transcriptional regulators that contribute to the pluripotency of ES cells, the factors that account for the common gene expression patterns of ES and cancer cells, and the implications of these observations for future clinical applications.

[1]  T. Ichisaka,et al.  Induction of Pluripotent Stem Cells From Adult Human Fibroblasts by Defined Factors , 2008 .

[2]  Toshiro K. Ohsumi,et al.  Genome-wide identification of polycomb-associated RNAs by RIP-seq. , 2010, Molecular cell.

[3]  Richard A Young,et al.  Tcf3 is an integral component of the core regulatory circuitry of embryonic stem cells. , 2008, Genes & development.

[4]  Philip M. Long,et al.  Comment on " 'Stemness': Transcriptional Profiling of Embryonic and Adult Stem Cells" and "A Stem Cell Molecular Signature" (I) , 2003, Science.

[5]  Qikai Xu,et al.  A genome-wide RNAi screen identifies a new transcriptional module required for self-renewal. , 2009, Genes & development.

[6]  A. Regev,et al.  SOX2 Is an Amplified Lineage Survival Oncogene in Lung and Esophageal Squamous Cell Carcinomas , 2009, Nature Genetics.

[7]  B. Panning,et al.  An RNAi Screen of Chromatin Proteins Identifies Tip60-p400 as a Regulator of Embryonic Stem Cell Identity , 2008, Cell.

[8]  George Q. Daley,et al.  Disease-Specific Induced Pluripotent Stem Cells , 2008, Cell.

[9]  Megan F. Cole,et al.  Core Transcriptional Regulatory Circuitry in Human Embryonic Stem Cells , 2005, Cell.

[10]  R. Lovell-Badge,et al.  Multipotent cell lineages in early mouse development depend on SOX2 function. , 2003, Genes & development.

[11]  Stuart H. Orkin,et al.  A Myc Network Accounts for Similarities between Embryonic Stem and Cancer Cell Transcription Programs , 2010, Cell.

[12]  Takashi Aoi,et al.  Generation of induced pluripotent stem cells without Myc from mouse and human fibroblasts , 2008, Nature Biotechnology.

[13]  G. Daley,et al.  Common themes of dedifferentiation in somatic cell reprogramming and cancer. , 2008, Cold Spring Harbor symposia on quantitative biology.

[14]  Igor Shats,et al.  Using a stem cell-based signature to guide therapeutic selection in cancer. , 2011, Cancer research.

[15]  Hynek Wichterle,et al.  Induced Pluripotent Stem Cells Generated from Patients with ALS Can Be Differentiated into Motor Neurons , 2008, Science.

[16]  Debashis Ghosh,et al.  EZH2 is a marker of aggressive breast cancer and promotes neoplastic transformation of breast epithelial cells , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[17]  S. Yamanaka,et al.  Induction of Pluripotent Stem Cells from Mouse Embryonic and Adult Fibroblast Cultures by Defined Factors , 2006, Cell.

[18]  S. Ivy,et al.  Targeting cancer stem cells by inhibiting Wnt, Notch, and Hedgehog pathways , 2011, Nature Reviews Clinical Oncology.

[19]  Jin Han,et al.  Oct4 pseudogenes are transcribed in cancers. , 2005, Biochemical and biophysical research communications.

[20]  Howard Y. Chang,et al.  Hierarchical maintenance of MLL myeloid leukemia stem cells employs a transcriptional program shared with embryonic rather than adult stem cells. , 2009, Cell stem cell.

[21]  Julian Downward,et al.  Cancer biology: Signatures guide drug choice , 2006, Nature.

[22]  A. Clark The Stem Cell Identity of Testicular Cancer , 2007, Stem Cell Reviews.

[23]  M. Murakami,et al.  The Homeoprotein Nanog Is Required for Maintenance of Pluripotency in Mouse Epiblast and ES Cells , 2003, Cell.

[24]  George Q. Daley,et al.  Reprogramming of human somatic cells to pluripotency with defined factors , 2008, Nature.

[25]  Avi Ma’ayan,et al.  Systems biology of stem cell fate and cellular reprogramming , 2009, Nature Reviews Molecular Cell Biology.

[26]  X. Chen,et al.  The Oct4 and Nanog transcription network regulates pluripotency in mouse embryonic stem cells , 2006, Nature Genetics.

[27]  Marius Wernig,et al.  c-Myc is dispensable for direct reprogramming of mouse fibroblasts. , 2008, Cell stem cell.

[28]  B. Klein,et al.  Embryonic stem cell markers expression in cancers. , 2009, Biochemical and biophysical research communications.

[29]  T. Ichisaka,et al.  Induction of Pluripotent Stem Cells from Adult Human Fibroblasts by Defined Factors , 2007, Cell.

[30]  David Landeira,et al.  ESCs require PRC2 to direct the successful reprogramming of differentiated cells toward pluripotency. , 2010, Cell stem cell.

[31]  Jeffrey T. Chang,et al.  Oncogenic pathway signatures in human cancers as a guide to targeted therapies , 2006, Nature.

[32]  Eran Segal,et al.  Module map of stem cell genes guides creation of epithelial cancer stem cells. , 2008, Cell stem cell.

[33]  R. B. Redmon,et al.  Identity , 2021, Notre Dame J. Formal Log..

[34]  G. Hon,et al.  Next-generation genomics: an integrative approach , 2010, Nature Reviews Genetics.

[35]  T. Enver,et al.  Forcing cells to change lineages , 2009, Nature.

[36]  Paul Tempst,et al.  PRC2 Complexes with JARID2, MTF2, and esPRC2p48 in ES Cells to Modulate ES Cell Pluripotency and Somatic Cell Reprograming , 2011, Stem cells.

[37]  Ingo Roeder,et al.  Stem cell biology meets systems biology , 2009, Development.

[38]  L. Penn,et al.  Reflecting on 25 years with MYC , 2008, Nature Reviews Cancer.

[39]  John T. Dimos,et al.  A Stem Cell Molecular Signature , 2002, Science.

[40]  Anne-Claude Gavin,et al.  Recent advances in charting protein-protein interaction: mass spectrometry-based approaches. , 2011, Current opinion in biotechnology.

[41]  M. Babu,et al.  An Expanded Oct4 Interaction Network: Implications for Stem Cell Biology, Development, and Disease , 2010, Cell stem cell.

[42]  D. Reinberg,et al.  The Polycomb complex PRC2 and its mark in life , 2011, Nature.

[43]  P. Robson,et al.  Sall4 regulates distinct transcription circuitries in different blastocyst-derived stem cell lineages. , 2008, Cell stem cell.

[44]  D. Melton,et al.  "Stemness": Transcriptional Profiling of Embryonic and Adult Stem Cells , 2002, Science.

[45]  Philip R. Gafken,et al.  Myc influences global chromatin structure , 2006, The EMBO journal.

[46]  P. Knoepfler Why myc? An unexpected ingredient in the stem cell cocktail. , 2008, Cell stem cell.

[47]  Stuart H. Orkin,et al.  A protein interaction network for pluripotency of embryonic stem cells , 2006, Nature.

[48]  A. Evsikov,et al.  Comment on " 'Stemness': Transcriptional Profiling of Embryonic and Adult Stem Cells" and "A Stem Cell Molecular Signature" (II) , 2003, Science.

[49]  S. Orkin,et al.  Differential Roles of Sall4 Isoforms in Embryonic Stem Cell Pluripotency , 2010, Molecular and Cellular Biology.

[50]  Scott W. Lowe,et al.  Stem cells: The promises and perils of p53 , 2009, Nature.

[51]  Justin Lamb,et al.  The Connectivity Map: a new tool for biomedical research , 2007, Nature Reviews Cancer.

[52]  John L Cleveland,et al.  Myc pathways provoking cell suicide and cancer , 2003, Oncogene.

[53]  J. Lieberman,et al.  THE SILENT REVOLUTION : RNA Interference as Basic Biology , Research Tool , and Therapeutic , 2010 .

[54]  Paul A Clemons,et al.  The Connectivity Map: Using Gene-Expression Signatures to Connect Small Molecules, Genes, and Disease , 2006, Science.

[55]  G. Galbraith,et al.  In vitro reprogramming of fibroblasts into a pluripotent ES-cell-like state , 2008 .

[56]  S. Orkin,et al.  An Extended Transcriptional Network for Pluripotency of Embryonic Stem Cells (DOI:10.1016/j.cell.2008.02.039) , 2008 .

[57]  Megan F. Cole,et al.  Connecting microRNA Genes to the Core Transcriptional Regulatory Circuitry of Embryonic Stem Cells , 2008, Cell.

[58]  J. Zeitlinger,et al.  Polycomb complexes repress developmental regulators in murine embryonic stem cells , 2006, Nature.

[59]  Debbie L C van den Berg,et al.  An Oct4-Centered Protein Interaction Network in Embryonic Stem Cells , 2010, Cell stem cell.

[60]  M. Blasco,et al.  The Ink4/Arf locus is a barrier for iPS cell reprogramming , 2009, Nature.

[61]  T. Golub,et al.  Gene expression signature-based chemical genomic prediction identifies a novel class of HSP90 pathway modulators. , 2006, Cancer cell.

[62]  S. Orkin,et al.  Jumonji Modulates Polycomb Activity and Self-Renewal versus Differentiation of Stem Cells , 2009, Cell.

[63]  D. Koller,et al.  A module map showing conditional activity of expression modules in cancer , 2004, Nature Genetics.

[64]  J. Utikal,et al.  Immortalization eliminates a roadblock during cellular reprogramming into iPS cells , 2009, Nature.

[65]  Jeroen S. van Zon,et al.  Direct cell reprogramming is a stochastic process amenable to acceleration , 2009, Nature.

[66]  M. Kaufman,et al.  Establishment in culture of pluripotential cells from mouse embryos , 1981, Nature.

[67]  S. Orkin,et al.  An Extended Transcriptional Network for Pluripotency of Embryonic Stem Cells , 2008, Cell.

[68]  Y. Bergman,et al.  Oct-3/4 is a dose-dependent oncogenic fate determinant. , 2003, Cancer cell.

[69]  A. Hao,et al.  Expression of OCT4 pseudogenes in human tumours: lessons from glioma and breast carcinoma , 2011, The Journal of pathology.

[70]  R. Stewart,et al.  Induced Pluripotent Stem Cell Lines Derived from Human Somatic Cells , 2007, Science.

[71]  Li Chai,et al.  Genome-wide analysis reveals Sall4 to be a major regulator of pluripotency in murine-embryonic stem cells , 2008, Proceedings of the National Academy of Sciences.

[72]  R. Gregory,et al.  MicroRNA gene regulatory pathways in the establishment and maintenance of ESC identity. , 2010, Cell stem cell.

[73]  A. Regev,et al.  An embryonic stem cell–like gene expression signature in poorly differentiated aggressive human tumors , 2008, Nature Genetics.

[74]  G. Wahl,et al.  Inactivation of p53 in breast cancers correlates with stem cell transcriptional signatures , 2010, Proceedings of the National Academy of Sciences.

[75]  M. Ramalho-Santos,et al.  Open chromatin in pluripotency and reprogramming , 2010, Nature Reviews Molecular Cell Biology.

[76]  J. Nichols,et al.  Functional Expression Cloning of Nanog, a Pluripotency Sustaining Factor in Embryonic Stem Cells , 2003, Cell.

[77]  Megan F. Cole,et al.  Control of Developmental Regulators by Polycomb in Human Embryonic Stem Cells , 2006, Cell.

[78]  Todd R. Golub,et al.  BRAF mutation predicts sensitivity to MEK inhibition , 2006, Nature.

[79]  G. Martin,et al.  Isolation of a pluripotent cell line from early mouse embryos cultured in medium conditioned by teratocarcinoma stem cells. , 1981, Proceedings of the National Academy of Sciences of the United States of America.

[80]  N. D. Clarke,et al.  Integration of External Signaling Pathways with the Core Transcriptional Network in Embryonic Stem Cells , 2008, Cell.

[81]  H. Schöler,et al.  Formation of Pluripotent Stem Cells in the Mammalian Embryo Depends on the POU Transcription Factor Oct4 , 1998, Cell.

[82]  Zang Ai-hua,et al.  Stem Cells,Cancer and Cancer Stem Cells , 2005 .

[83]  T. Werbowetski-Ogilvie,et al.  Pluripotent human stem cell lines: what we can learn about cancer initiation. , 2008, Trends in molecular medicine.

[84]  S. Dhanasekaran,et al.  The polycomb group protein EZH2 is involved in progression of prostate cancer , 2002, Nature.

[85]  J. Taipale,et al.  The Hedgehog and Wnt signalling pathways in cancer , 2001, Nature.

[86]  Arend Sidow,et al.  Jarid2/Jumonji Coordinates Control of PRC2 Enzymatic Activity and Target Gene Occupancy in Pluripotent Cells , 2009, Cell.