Cancer stem cells with genetic instability: the best vehicle with the best engine for cancer

Our understanding of the role of stem cells in cancer development is evolving quickly. In the course of tumor expansion, a subpopulation of tumor cells with stem cell-like features has been noted. These cancer stem cells give rise to transit amplifying tumor cells, which comprise the majority of the tumor mass prior to terminal differentiation. Combining this finding with genetic instability, a well-known engine for cancer development and metastases, a new model emerges for cancer where normal stem cells and their cellular pathway acquire stochastic malignant abilities. In this model, when cancer stem cells self-renew, many genetic variants are produced. Just as microbes ‘learn’ to defeat antibiotics, genetically heterogeneous cancer stem cells may possibly acquire resistance to various chemotherapeutic approaches. Drug-resistant microorganisms selected by spontaneous mutation of bacterial DNA may not be so different than the drug-resistant and genetically instable cancer stem cells recurring after chemotherapeutic treatment. In this gloomy view of cancer, cancer stem cells with genetic instability can be considered as ‘the best vehicle with the best engine’, a formidable challenge for the future development of new anticancer therapies.

[1]  H. Kantarjian,et al.  Discontinuation of imatinib therapy after achieving a molecular response. , 2004, Blood.

[2]  W. Alexander,et al.  Novel zinc finger gene implicated as myc collaborator by retrovirally accelerated lymphomagenesis in Eμ-myc transgenic mice , 1991, Cell.

[3]  M N Pollak,et al.  Perspectives on clonogenic tumor cells, stem cells, and oncogenes. , 1984, Cancer research.

[4]  A. Feinberg,et al.  Use of restriction fragment length polymorphisms to determine the clonal origin of human tumors. , 1985, Science.

[5]  F. Gage,et al.  Epigenetic control of neural stem cell fate. , 2004, Current opinion in genetics & development.

[6]  I. Fidler,et al.  Metastasis results from preexisting variant cells within a malignant tumor. , 1977, Science.

[7]  Gretchen Vogel,et al.  'Stemness' Genes Still Elusive , 2003, Science.

[8]  Irving L Weissman,et al.  Biology of hematopoietic stem cells and progenitors: implications for clinical application. , 2003, Annual review of immunology.

[9]  A. Deisseroth,et al.  Biological characterization of stem cell present in mobilized peripheral blood of CML patients. , 1994, Bone marrow transplantation.

[10]  Dahua Chen,et al.  Gene Circuitry Controlling a Stem Cell Niche , 2005, Current Biology.

[11]  C. Sawyers,et al.  Targeted cancer therapy , 2004, Nature.

[12]  John Cairns,et al.  Mutation selection and the natural history of cancer , 1975, Nature.

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

[14]  Laurie E Ailles,et al.  Granulocyte-macrophage progenitors as candidate leukemic stem cells in blast-crisis CML. , 2004, The New England journal of medicine.

[15]  I. Weissman,et al.  Isolation of a candidate human hematopoietic stem-cell population. , 1992, Proceedings of the National Academy of Sciences of the United States of America.

[16]  Y. Numata,et al.  Epithelial and stromal genetic instability contributes to genesis of colorectal adenomas , 2005, Gut.

[17]  A. Hamburger,et al.  Primary bioassay of human tumor stem cells. , 1977, Science.

[18]  C. Jefford,et al.  Mechanisms of chromosome instability in cancers. , 2006, Critical reviews in oncology/hematology.

[19]  E. Nigg,et al.  Origins and consequences of centrosome aberrations in human cancers , 2006, International journal of cancer.

[20]  Sean J. Morrison,et al.  Asymmetric and symmetric stem-cell divisions in development and cancer , 2006, Nature.

[21]  E Georg Luebeck,et al.  Multistage carcinogenesis and the incidence of colorectal cancer , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[22]  Jürg Zimmermann,et al.  Effects of a selective inhibitor of the Abl tyrosine kinase on the growth of Bcr–Abl positive cells , 1996, Nature Medicine.

[23]  J. Dick,et al.  Human acute myeloid leukemia is organized as a hierarchy that originates from a primitive hematopoietic cell , 1997, Nature Medicine.

[24]  L. Ricci-Vitiani,et al.  Identification and expansion of human colon-cancer-initiating cells , 2007, Nature.

[25]  N. Wright,et al.  The clonal origin and clonal evolution of epithelial tumours , 2000, International journal of experimental pathology.

[26]  K. Münger,et al.  Centrosome abnormalities, genomic instability and carcinogenic progression. , 2001, Biochimica et biophysica acta.

[27]  P. Nowell.  Tumor progression: a brief historical perspective. , 2002, Seminars in cancer biology.

[28]  Martin A. Nowak,et al.  The significance of unstable chromosomes in colorectal cancer , 2003, Nature Reviews Cancer.

[29]  Gretchen Vogel,et al.  Stem cells. 'Stemness' genes still elusive. , 2003, Science.

[30]  Peter A. Jones,et al.  The Epigenomics of Cancer , 2007, Cell.

[31]  J. Dick,et al.  Breast cancer stem cells revealed , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[32]  I. Fidler,et al.  Biological diversity in metastatic neoplasms: origins and implications. , 1982, Science.

[33]  P. Peltomäki.  Role of DNA mismatch repair defects in the pathogenesis of human cancer. , 2003, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[34]  R. Ward,et al.  Colorectal cancer: a model for epigenetic tumorigenesis , 2006, Gut.

[35]  S. Yuspa,et al.  Two-stage tumor promotion in mouse skin: an alternative interpretation. , 1985, Journal of the National Cancer Institute.

[36]  Irving L. Weissman,et al.  Normal and leukemic hematopoiesis: Are leukemias a stem cell disorder or a reacquisition of stem cell characteristics? , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[37]  I. Weissman,et al.  Purification and characterization of mouse hematopoietic stem cells. , 1988, Science.

[38]  A. Álvarez-Buylla,et al.  Neural stem cells in mammalian development. , 2006, Current opinion in cell biology.

[39]  J. Furth,et al.  The Transmission of Leukemia of Mice with a Single Cell , 1937 .

[40]  Ugo Orfanelli,et al.  Isolation and Characterization of Tumorigenic, Stem-like Neural Precursors from Human Glioblastoma , 2004, Cancer Research.

[41]  Cynthia Hawkins,et al.  Identification of a cancer stem cell in human brain tumors. , 2003, Cancer research.

[42]  Junia V. Melo,et al.  Chronic myeloid leukaemia as a model of disease evolution in human cancer , 2007, Nature Reviews Cancer.

[43]  Martin A Nowak,et al.  Can chromosomal instability initiate tumorigenesis? , 2005, Seminars in cancer biology.

[44]  P. Fialkow,et al.  Clonal origin of human tumors. , 1979, Annual review of medicine.

[45]  S. Morrison,et al.  Prospective identification of tumorigenic breast cancer cells , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[46]  A. Spradling,et al.  Male and Female Drosophila Germline Stem Cells: Two Versions of Immortality , 2007, Science.

[47]  S. Barnett,et al.  Oligodendrocyte-type-2 astrocyte (O-2A) progenitor cells transformed with c-myc and H-ras form high-grade glioma after stereotactic injection into the rat brain. , 1998, Carcinogenesis.

[48]  G. Bratthauer,et al.  Concurrent and independent genetic alterations in the stromal and epithelial cells of mammary carcinoma: implications for tumorigenesis. , 2000, Cancer research.

[49]  D. Anderson,et al.  Stem Cells and Pattern Formation in the Nervous System The Possible versus the Actual , 2001, Neuron.

[50]  Irving L. Weissman,et al.  Bmi-1 is required for maintenance of adult self-renewing haematopoietic stem cells , 2003, Nature.

[51]  E. Caussinus,et al.  Induction of tumor growth by altered stem-cell asymmetric division in Drosophila melanogaster , 2005, Nature Genetics.

[52]  P. Vineis,et al.  The population dynamics of cancer: a Darwinian perspective. , 2006, International journal of epidemiology.

[53]  G. Tonini,et al.  Genetic and epigenetic alterations in neuroblastoma. , 2003, Cancer letters.

[54]  C. Sawyers,et al.  Efficacy and safety of a specific inhibitor of the BCR-ABL tyrosine kinase in chronic myeloid leukemia. , 2001, The New England journal of medicine.

[55]  Michael F. Clarke,et al.  Phenotypic characterization of human colorectal cancer stem cells , 2007, Proceedings of the National Academy of Sciences.

[56]  Irving L Weissman,et al.  Bmi‐1‐Green Fluorescent Protein‐Knock‐In Mice Reveal the Dynamic Regulation of Bmi‐1 Expression in Normal and Leukemic Hematopoietic Cells , 2007, Stem cells.

[57]  T. Holyoake,et al.  Primitive, quiescent, Philadelphia-positive stem cells from patients with chronic myeloid leukemia are insensitive to STI571 in vitro. , 2002, Blood.

[58]  C. Eng,et al.  Genomic instability within tumor stroma and clinicopathological characteristics of sporadic primary invasive breast carcinoma. , 2007, JAMA.

[59]  D. Alberts,et al.  Quantitation of differential sensitivity of human-tumor stem cells to anticancer drugs. , 1978, The New England journal of medicine.

[60]  H. Kantarjian,et al.  Dynamics of BCR-ABL kinase domain mutations in chronic myeloid leukemia after sequential treatment with multiple tyrosine kinase inhibitors. , 2007, Blood.

[61]  P. Nowell,et al.  A minute chromosome in human chronic granulocytic leukemia , 1960 .

[62]  O. Sieber,et al.  Genomic instability — the engine of tumorigenesis? , 2003, Nature Reviews Cancer.

[63]  J. Dick,et al.  Normal and leukemic SCID-repopulating cells (SRC) coexist in the bone marrow and peripheral blood from CML patients in chronic phase, whereas leukemic SRC are detected in blast crisis. , 1996, Blood.

[64]  A. Shiras,et al.  Spontaneous Transformation of Human Adult Nontumorigenic Stem Cells to Cancer Stem Cells Is Driven by Genomic Instability in a Human Model of Glioblastoma , 2007, Stem cells.

[65]  F. Spencer,et al.  Systematic genome instability screens in yeast and their potential relevance to cancer , 2007, Proceedings of the National Academy of Sciences.

[66]  J. Till,et al.  A direct measurement of the radiation sensitivity of normal mouse bone marrow cells. , 1961, Radiation research.

[67]  S. Morrison,et al.  Stem cell self-renewal and cancer cell proliferation are regulated by common networks that balance the activation of proto-oncogenes and tumor suppressors. , 2005, Cold Spring Harbor symposia on quantitative biology.

[68]  J. German.  Genes which increase chromosomal instability in somatic cells and predispose to cancer. , 1972, Progress in medical genetics.

[69]  Jorge Cortes,et al.  Clonal evolution in chronic myelogenous leukemia. , 2004, Hematology/oncology clinics of North America.

[70]  R. Morris.  A perspective on keratinocyte stem cells as targets for skin carcinogenesis. , 2004, Differentiation; research in biological diversity.

[71]  G. B. Pierce,et al.  Maturation arrest of stem cell differentiation is a common pathway for the cellular origin of teratocarcinomas and epithelial cancers. , 1994, Laboratory investigation; a journal of technical methods and pathology.

[72]  K. Kinzler,et al.  Cancer genes and the pathways they control , 2004, Nature Medicine.

[73]  I. Weissman,et al.  Direct isolation of human central nervous system stem cells. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[74]  M. Amagai,et al.  Lymphomatoid Papulosis Followed by Ki‐1 Positive Anaplastic Large Cell Lymphoma: Proliferation of a Common T‐Cell Clone , 1995, Journal of dermatology (Print).

[75]  J. Reiffers,et al.  5-Fluorouracil-resistant CD34+ cell population from peripheral blood of CML patients contains BCR-ABL-negative progenitor cells. , 1995, Experimental hematology.

[76]  K. Kinzler,et al.  Genetic instabilities in human cancers , 1998, Nature.