Pancreatic cancer stem cells.

Cellular heterogeneity in cancer was observed decades ago by studies in mice which showed that distinct subpopulations of cells within a tumor mass are capable of driving tumorigenesis. Conceptualized from this finding was the stem-cell hypothesis for cancer, which suggests that only a specific subset of cancer cells within each tumor is responsible for tumor initiation and propagation, termed tumor initiating cells or cancer stem cells (CSCs). Recent data has been provided to support the existence of CSCs in human blood cell-derived cancers and solid organ tumors of the breast, brain, prostate, colon, and skin. Study of human pancreatic cancers has also revealed a specific subpopulation of cancer cells that possess the characteristics of CSCs. These pancreatic cancer stem cells express the cell surface markers CD44, CD24, and epithelial-specific antigen, and represent 0.5% to 1.0% of all pancreatic cancer cells. Along with the properties of self-renewal and multilineage differentiation, pancreatic CSCs display upregulation of important developmental genes that maintain self-renewal in normal stem cells, including Sonic hedgehog (SHH) and BMI-1. Signaling cascades that are integral in tumor metastasis are also upregulated in the pancreatic CSC. Understanding the biologic behavior and the molecular pathways that regulate growth, survival, and metastasis of pancreatic CSCs will help to identify novel therapeutic approaches to treat this dismal disease.

[1]  Julia Schüler,et al.  The EMT-activator ZEB1 promotes tumorigenicity by repressing stemness-inhibiting microRNAs , 2009, Nature Cell Biology.

[2]  L. Ellis,et al.  Consensus report of the national cancer institute clinical trials planning meeting on pancreas cancer treatment. , 2009, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[3]  A. Maitra,et al.  The hedgehog pathway and pancreatic cancer. , 2009, The New England journal of medicine.

[4]  J. D'haese,et al.  Combined targeted treatment to eliminate tumorigenic cancer stem cells in human pancreatic cancer. , 2009, Gastroenterology.

[5]  Min Zhang,et al.  MicroRNA miR-34 Inhibits Human Pancreatic Cancer Tumor-Initiating Cells , 2009, PloS one.

[6]  J. Dou,et al.  Identifying tumor stem‐like cells in mouse melanoma cell lines by analyzing the characteristics of side population cells , 2009, Cell biology international.

[7]  E. Wagner,et al.  Signal integration by JNK and p38 MAPK pathways in cancer development , 2009, Nature Reviews Cancer.

[8]  David Allard,et al.  Inhibition of Hedgehog Signaling Enhances Delivery of Chemotherapy in a Mouse Model of Pancreatic Cancer , 2009, Science.

[9]  P. Majumder,et al.  Inhibition of gamma-secretase activity inhibits tumor progression in a mouse model of pancreatic ductal adenocarcinoma. , 2009, Gastroenterology.

[10]  G. Feldmann,et al.  A direct pancreatic cancer xenograft model as a platform for cancer stem cell therapeutic development , 2009, Molecular Cancer Therapeutics.

[11]  M. Israel,et al.  Cancer stem cells are enriched in the side population cells in a mouse model of glioma. , 2008, Cancer research.

[12]  J. Visvader,et al.  Cancer stem cells in solid tumours: accumulating evidence and unresolved questions , 2008, Nature Reviews Cancer.

[13]  T. Golde,et al.  Rational targeting of Notch signaling in cancer , 2008, Oncogene.

[14]  Peng Huang,et al.  Isolation and biological analysis of tumor stem cells from pancreatic adenocarcinoma. , 2008, World journal of gastroenterology.

[15]  M. Clarke,et al.  Colorectal Cancer Stem Cells Are Enriched in Xenogeneic Tumors Following Chemotherapy , 2008, PloS one.

[16]  Wenjun Guo,et al.  The Epithelial-Mesenchymal Transition Generates Cells with Properties of Stem Cells , 2008, Cell.

[17]  Hua Tian,et al.  A paracrine requirement for hedgehog signalling in cancer , 2008, Nature.

[18]  P. Altevogt,et al.  Targeting CD24 for treatment of colorectal and pancreatic cancer by monoclonal antibodies or small interfering RNA. , 2008, Cancer research.

[19]  R. Urrutia,et al.  Primers on Molecular Pathways – Notch , 2008, Pancreatology.

[20]  C. D. Salcido,et al.  Brca1 breast tumors contain distinct CD44+/CD24- and CD133+ cells with cancer stem cell characteristics , 2008, Breast Cancer Research.

[21]  D. Birnbaum,et al.  ALDH1 is a marker of normal and malignant human mammary stem cells and a predictor of poor clinical outcome. , 2007, Cell stem cell.

[22]  M. Hollingsworth,et al.  Cancer metastasis facilitated by developmental pathways: Sonic hedgehog, Notch, and bone morphogenic proteins , 2007, Journal of cellular biochemistry.

[23]  M. Todaro,et al.  Colon cancer stem cells dictate tumor growth and resist cell death by production of interleukin-4. , 2007, Cell Stem Cell.

[24]  G. Gallick,et al.  Development and Characterization of Gemcitabine-Resistant Pancreatic Tumor Cells , 2007, Annals of Surgical Oncology.

[25]  C. Heeschen,et al.  Distinct populations of cancer stem cells determine tumor growth and metastatic activity in human pancreatic cancer. , 2007, Cell stem cell.

[26]  K. Garber.  Notch emerges as new cancer drug target. , 2007, Journal of the National Cancer Institute.

[27]  F. Radtke,et al.  Notch and cancer: a double-edged sword , 2007, Cellular and Molecular Life Sciences.

[28]  Eithne Costello,et al.  Biology and management of pancreatic cancer , 2007, Postgraduate Medical Journal.

[29]  J. Neoptolemos,et al.  A new approach to managing intraductal papillary mucinous pancreatic neoplasms , 2007, Gut.

[30]  S. Lam,et al.  Side population in human lung cancer cell lines and tumors is enriched with stem-like cancer cells. , 2007, Cancer research.

[31]  I. Ng,et al.  Identification and characterization of tumorigenic liver cancer stem/progenitor cells. , 2007, Gastroenterology.

[32]  D. Simeone,et al.  Cancer stem cells: a new paradigm for understanding tumor progression and therapeutic resistance. , 2007, Surgery.

[33]  S. Artavanis-Tsakonas,et al.  Crossing paths with Notch in the hyper-network. , 2007, Current opinion in cell biology.

[34]  M. Barbacid,et al.  Chronic pancreatitis is essential for induction of pancreatic ductal adenocarcinoma by K-Ras oncogenes in adult mice. , 2007, Cancer cell.

[35]  C. Iacobuzio-Donahue,et al.  Blockade of hedgehog signaling inhibits pancreatic cancer invasion and metastases: a new paradigm for combination therapy in solid cancers. , 2007, Cancer research.

[36]  W. Woodward,et al.  Wnt/β-catenin mediates radiation resistance of Sca1+ progenitors in an immortalized mammary gland cell line , 2007, Journal of Cell Science.

[37]  P. Sánchez,et al.  HEDGEHOG-GLI1 Signaling Regulates Human Glioma Growth, Cancer Stem Cell Self-Renewal, and Tumorigenicity , 2007, Current Biology.

[38]  I. Weissman,et al.  Identification of a subpopulation of cells with cancer stem cell properties in head and neck squamous cell carcinoma , 2007, Proceedings of the National Academy of Sciences.

[39]  W. Woodward,et al.  WNT/β-catenin mediates radiation resistance of mouse mammary progenitor cells , 2007, Proceedings of the National Academy of Sciences.

[40]  J. Dick,et al.  A human colon cancer cell capable of initiating tumour growth in immunodeficient mice , 2007, Nature.

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

[42]  Frank Pajonk,et al.  The response of CD24(-/low)/CD44+ breast cancer-initiating cells to radiation. , 2006, Journal of the National Cancer Institute.

[43]  Goberdhan P Dimri,et al.  Elevated Bmi-1 expression is associated with dysplastic cell transformation during oral carcinogenesis and is required for cancer cell replication and survival , 2006, British Journal of Cancer.

[44]  Mark W. Dewhirst,et al.  Glioma stem cells promote radioresistance by preferential activation of the DNA damage response , 2006, Nature.

[45]  Lee L. Rubin,et al.  Targeting the Hedgehog pathway in cancer , 2006, Nature Reviews Drug Discovery.

[46]  J. Dick,et al.  Targeting of CD44 eradicates human acute myeloid leukemic stem cells , 2006, Nature Medicine.

[47]  T. Golub,et al.  Transformation from committed progenitor to leukaemia stem cell initiated by MLL–AF9 , 2006, Nature.

[48]  Peter T Masiakos,et al.  Ovarian cancer side population defines cells with stem cell-like characteristics and Mullerian Inhibiting Substance responsiveness. , 2006, Proceedings of the National Academy of Sciences of the United States of America.

[49]  Tetsuhiro Chiba,et al.  Side population purified from hepatocellular carcinoma cells harbors cancer stem cell–like properties , 2006, Hepatology.

[50]  G. Dontu,et al.  Hedgehog signaling and Bmi-1 regulate self-renewal of normal and malignant human mammary stem cells. , 2006, Cancer research.

[51]  C. Sternberg,et al.  Current therapies and advances in the treatment of pancreatic cancer. , 2006, Critical reviews in oncology/hematology.

[52]  S. Morrison,et al.  Pten dependence distinguishes haematopoietic stem cells from leukaemia-initiating cells , 2006, Nature.

[53]  F. Radtke,et al.  Multiple functions of Notch signaling in self‐renewing organs and cancer , 2006, FEBS letters.

[54]  Sathish Kumar Mungamuri,et al.  Survival signaling by Notch1: mammalian target of rapamycin (mTOR)-dependent inhibition of p53. , 2006, Cancer research.

[55]  H. Li,et al.  Highly purified CD44+ prostate cancer cells from xenograft human tumors are enriched in tumorigenic and metastatic progenitor cells , 2006, Oncogene.

[56]  C. Brisken,et al.  Increased Wnt signaling triggers oncogenic conversion of human breast epithelial cells by a Notch-dependent mechanism. , 2006, Proceedings of the National Academy of Sciences of the United States of America.

[57]  J. Nolta,et al.  Selection based on CD133 and high aldehyde dehydrogenase activity isolates long-term reconstituting human hematopoietic stem cells. , 2006, Blood.

[58]  Max S Wicha,et al.  Cancer stem cells: an old idea--a paradigm shift. , 2006, Cancer research.

[59]  S. Volinia,et al.  Skin homing of Sézary cells involves SDF-1-CXCR4 signaling and down-regulation of CD26/dipeptidylpeptidase IV. , 2006, Blood.

[60]  W. Weichert,et al.  Cytoplasmic CD24 Expression in Colorectal Cancer Independently Correlates with Shortened Patient Survival , 2005, Clinical Cancer Research.

[61]  A. Donnenberg,et al.  Multiple Drug Resistance in Cancer Revisited: The Cancer Stem Cell Hypothesis , 2005, Journal of clinical pharmacology.

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

[63]  W. Sadee,et al.  ABCB5-mediated doxorubicin transport and chemoresistance in human malignant melanoma. , 2005, Cancer research.

[64]  Dennis C. Sgroi,et al.  Stromal Fibroblasts Present in Invasive Human Breast Carcinomas Promote Tumor Growth and Angiogenesis through Elevated SDF-1/CXCL12 Secretion , 2005, Cell.

[65]  C. Jordan.  Cancer stem cell biology: from leukemia to solid tumors. , 2004, Current opinion in cell biology.

[66]  R. Henkelman,et al.  Identification of human brain tumour initiating cells , 2004, Nature.

[67]  K. Akashi,et al.  MOZ-TIF2, but not BCR-ABL, confers properties of leukemic stem cells to committed murine hematopoietic progenitors. , 2004, Cancer cell.

[68]  T. Shimazaki,et al.  Human neural stem/progenitor cells, expanded in long‐term neurosphere culture, promote functional recovery after focal ischemia in Mongolian gerbils , 2004, Journal of neuroscience research.

[69]  Joo Heon Kim,et al.  Overexpression of Bmi-1 oncoprotein correlates with axillary lymph node metastases in invasive ductal breast cancer. , 2004, Breast.

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

[71]  S. Dedhar,et al.  Regulation of Snail transcription during epithelial to mesenchymal transition of tumor cells , 2004, Oncogene.

[72]  G. Dontu,et al.  Role of Notch signaling in cell-fate determination of human mammary stem/progenitor cells , 2004, Breast Cancer Research.

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

[74]  H. Nakauchi,et al.  Prospective isolation of multipotent pancreatic progenitors using flow-cytometric cell sorting. , 2004, Diabetes.

[75]  S. Ramaswamy,et al.  Twist, a Master Regulator of Morphogenesis, Plays an Essential Role in Tumor Metastasis , 2004, Cell.

[76]  M. Seno,et al.  Reversal of streptozotocin-induced hyperglycemia by transplantation of pseudoislets consisting of beta cells derived from ductal cells. , 2004, Endocrine journal.

[77]  C. Huff,et al.  Characterization of clonogenic multiple myeloma cells. , 2004, Blood.

[78]  M. Ascano,et al.  Regulation of Hedgehog signaling: a complex story. , 2004, Biochemical pharmacology.

[79]  Marina Pasca di Magliano,et al.  Hedgehog signalling in cancer formation and maintenance , 2003, Nature Reviews Cancer.

[80]  Daniel H. Geschwind,et al.  Cancerous stem cells can arise from pediatric brain tumors , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[81]  Yutaka Shimada,et al.  Widespread requirement for Hedgehog ligand stimulation in growth of digestive tract tumours , 2003, Nature.

[82]  Gregory Y. Lauwers,et al.  Hedgehog is an early and late mediator of pancreatic cancer tumorigenesis , 2003, Nature.

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

[84]  O. Korsgren,et al.  Characterization of endocrine progenitor cells and critical factors for their differentiation in human adult pancreatic cell culture. , 2003, Diabetes.

[85]  G. Sauvageau,et al.  Bmi-1 determines the proliferative capacity of normal and leukaemic stem cells , 2003, Nature.

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

[87]  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.

[88]  G. Kristiansen,et al.  Tumour Biological Aspects of CD24, A Mucin-Like Adhesion Molecule , 2003, Journal of Molecular Histology.

[89]  D. Meyer,et al.  Guidance of Primordial Germ Cell Migration by the Chemokine SDF-1 , 2002, Cell.

[90]  J. Habener,et al.  Insulinotropic hormone glucagon-like peptide-1 differentiation of human pancreatic islet-derived progenitor cells into insulin-producing cells. , 2002, Endocrinology.

[91]  E. Fearon,et al.  The SLUG zinc-finger protein represses E-cadherin in breast cancer. , 2002, Cancer research.

[92]  S. Nedvetzki,et al.  CD44 in Cancer , 2002, Critical reviews in clinical laboratory sciences.

[93]  I. Nasir,et al.  Regeneration of Pancreatic β Cells from Intra-Islet Precursor Cells in an Experimental Model of Diabetes. , 2001, Endocrinology.

[94]  I. Weissman,et al.  Stem cells, cancer, and cancer stem cells , 2001, Nature.

[95]  R. Klein,et al.  SDF-1 alpha induces chemotaxis and enhances Sonic hedgehog-induced proliferation of cerebellar granule cells. , 2001, Development.

[96]  J. Habener,et al.  Multipotential nestin-positive stem cells isolated from adult pancreatic islets differentiate ex vivo into pancreatic endocrine, exocrine, and hepatic phenotypes. , 2001, Diabetes.

[97]  Naoki Watanabe,et al.  Survivin as a Radioresistance Factor in Pancreatic Cancer , 2000, Japanese journal of cancer research : Gann.

[98]  D. Olive,et al.  Human acute myeloid leukemia CD34+/CD38- progenitor cells have decreased sensitivity to chemotherapy and Fas-induced apoptosis, reduced immunogenicity, and impaired dendritic cell transformation capacities. , 2000, Cancer research.

[99]  S. Bonner-Weir,et al.  In vitro cultivation of human islets from expanded ductal tissue. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[100]  J. Mcdonald,et al.  Transplanted embryonic stem cells survive, differentiate and promote recovery in injured rat spinal cord , 1999, Nature Medicine.

[101]  O. Colvin,et al.  Isolation of primitive human hematopoietic progenitors on the basis of aldehyde dehydrogenase activity. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[102]  R. DePinho,et al.  The oncogene and Polycomb-group gene bmi-1 regulates cell proliferation and senescence through the ink4a locus , 1999, Nature.

[103]  S. Rafii,et al.  The chemokine receptor CXCR-4 is expressed on CD34+ hematopoietic progenitors and leukemic cells and mediates transendothelial migration induced by stromal cell-derived factor-1. , 1998, Blood.

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

[105]  E. Dimagno,et al.  Hereditary pancreatitis and the risk of pancreatic cancer. International Hereditary Pancreatitis Study Group. , 1997, Journal of the National Cancer Institute.

[106]  T. Springer,et al.  The Chemokine SDF-1 Is a Chemoattractant for Human CD34+ Hematopoietic Progenitor Cells and Provides a New Mechanism to Explain the Mobilization of CD34+ Progenitors to Peripheral Blood , 1997, The Journal of experimental medicine.

[107]  O. Madsen,et al.  Pancreatic development and maturation of the islet B cell. Studies of pluripotent islet cultures. , 1996, European journal of biochemistry.

[108]  D. Klimstra,et al.  Long-term survival after curative resection for pancreatic ductal adenocarcinoma. Clinicopathologic analysis of 5-year survivors. , 1996, Annals of surgery.

[109]  J. Niederhuber,et al.  The national cancer data base report on pancreatic cancer , 1995, Cancer.

[110]  P. Altevogt,et al.  Heat stable antigen (mouse CD24) supports myeloid cell binding to endothelial and platelet P-selectin. , 1995, International immunology.

[111]  H. A. Bakker,et al.  Ep-CAM: a human epithelial antigen is a homophilic cell-cell adhesion molecule , 1994, The Journal of cell biology.

[112]  Y. Haupt,et al.  bmi-1 transgene induces lymphomas and collaborates with myc in tumorigenesis. , 1993, Oncogene.

[113]  A. Andrén-sandberg,et al.  Pancreatitis and the risk of pancreatic cancer , 1993 .

[114]  Anton Berns,et al.  Identification of cooperating oncogenes in Eμ-myc transgenic mice by provirus tagging , 1991, Cell.

[115]  D. Shibata,et al.  Most human carcinomas of the exocrine pancreas contain mutant c-K-ras genes , 1988, Cell.

[116]  B. Luo,et al.  A side population of cells from a human pancreatic carcinoma cell line harbors cancer stem cell characteristics. , 2009, Neoplasma.

[117]  A. Jemal,et al.  Cancer Statistics, 2007 , 2007, CA: a cancer journal for clinicians.

[118]  R. Hruban,et al.  Pancreatic cancer in mice and man: the Penn Workshop 2004. , 2006, Cancer research.

[119]  Mina J Bissell,et al.  Context, tissue plasticity, and cancer: are tumor stem cells also regulated by the microenvironment? , 2005, Cancer cell.

[120]  Chang-Nam Kim,et al.  The Bmi-1 oncoprotein is overexpressed in human colorectal cancer and correlates with the reduced p16INK4a/p14ARF proteins. , 2004, Cancer letters.

[121]  P. Herrlich,et al.  CD44: From adhesion molecules to signalling regulators , 2003, Nature Reviews Molecular Cell Biology.

[122]  R. Voort,et al.  Hepatocyte growth factor, Met, and CD44. Amenage a trois in B cells , 2000 .

[123]  N. Sarvetnick,et al.  A transgenic model for studying islet development. , 1994, Recent progress in hormone research.

[124]  Tumorigenesis and Neoplastic Progression Bmi-1 Is Essential for the Tumorigenicity of Neuroblastoma Cells , 2022 .