Cell polarity and cancer – cell and tissue polarity as a non-canonical tumor suppressor

Correct establishment and maintenance of cell polarity is required for the development and homeostasis of all metazoans. Cell-polarity mechanisms are responsible not only for the diversification of cell shapes but also for regulation of the asymmetric cell divisions of stem cells that are crucial for their correct self-renewal and differentiation. Disruption of cell polarity is a hallmark of cancer. Furthermore, recent evidence indicates that loss of cell polarity is intimately involved in cancer: several crucial cell-polarity proteins are known proto-oncogenes or tumor suppressors, basic mechanisms of cell polarity are often targeted by oncogenic signaling pathways, and deregulation of asymmetric cell divisions of stem or progenitor cells may be responsible for abnormal self-renewal and differentiation of cancer stem cells. Data from in vivo and three-dimensional (3D) cell-culture models demonstrate that tissue organization attenuates the phenotypic outcome of oncogenic signaling. We suggest that polarized 3D tissue organization uses cell-cell and cell-substratum adhesion structures to reinforce and maintain the cell polarity of pre-cancerous cells. In this model, polarized 3D tissue organization functions as a non-canonical tumor suppressor that prevents the manifestation of neoplastic features in mutant cells and, ultimately, suppresses tumor development and progression.

[1]  F. Gamboni-Robertson,et al.  Protein kinase C zeta isoform is critical for proliferation in human glioblastoma cell lines. , 2000, Journal of neuro-oncology.

[2]  H. Lane,et al.  ERBB Receptors and Cancer: The Complexity of Targeted Inhibitors , 2005, Nature Reviews Cancer.

[3]  C. Larabell,et al.  Reversion of the Malignant Phenotype of Human Breast Cells in Three-Dimensional Culture and In Vivo by Integrin Blocking Antibodies , 1997, The Journal of cell biology.

[4]  J. Shay,et al.  Putative telomere-independent mechanisms of replicative aging reflect inadequate growth conditions. , 2001, Genes & development.

[5]  M. Caplan,et al.  AMP-activated protein kinase regulates the assembly of epithelial tight junctions , 2006, Proceedings of the National Academy of Sciences.

[6]  C. Doe,et al.  Drosophila Aurora-A kinase inhibits neuroblast self-renewal by regulating aPKC/Numb cortical polarity and spindle orientation. , 2006, Genes & development.

[7]  H. Green,et al.  Epidermal growth factor and the multiplication of cultured human epidermal keratinocytes , 1977, Nature.

[8]  W. Fitzgerald,et al.  Isolation and Clonal Analysis of Human Epidermal Keratinocyte Stem Cells in Long‐Term Culture , 2003, Stem cells.

[9]  C. Streuli.  Faculty Opinions recommendation of Beta 4 integrin amplifies ErbB2 signaling to promote mammary tumorigenesis. , 2006 .

[10]  J. Huibregtse,et al.  Human Scribble (Vartul) Is Targeted for Ubiquitin-Mediated Degradation by the High-Risk Papillomavirus E6 Proteins and the E6AP Ubiquitin-Protein Ligase , 2000, Molecular and Cellular Biology.

[11]  K. Mechtler,et al.  Asymmetric Segregation of the Tumor Suppressor Brat Regulates Self-Renewal in Drosophila Neural Stem Cells , 2006, Cell.

[12]  T. Noda,et al.  Inactivation of aPKCλ results in the loss of adherens junctions in neuroepithelial cells without affecting neurogenesis in mouse neocortex , 2006, Development.

[13]  C. Doe,et al.  Drosophila aPKC regulates cell polarity and cell proliferation in neuroblasts and epithelia , 2003, The Journal of cell biology.

[14]  D. Radisky,et al.  Polarity and proliferation are controlled by distinct signaling pathways downstream of PI3-kinase in breast epithelial tumor cells , 2004, The Journal of cell biology.

[15]  C. Doe,et al.  Dlg, Scrib and Lgl regulate neuroblast cell size and mitotic spindle asymmetry , 2003, Nature Cell Biology.

[16]  Gordon B Mills,et al.  Atypical PKCiota contributes to poor prognosis through loss of apical-basal polarity and cyclin E overexpression in ovarian cancer. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[17]  Y. Taketani,et al.  Analysis of the expression and localisation of a LAP protein, human scribble, in the normal and neoplastic epithelium of uterine cervix , 2004, British Journal of Cancer.

[18]  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.

[19]  Elaine Fuchs,et al.  Directed Actin Polymerization Is the Driving Force for Epithelial Cell–Cell Adhesion , 2000, Cell.

[20]  D. Birnbaum,et al.  Junctional recruitment of mammalian Scribble relies on E-cadherin engagement , 2005, Oncogene.

[21]  T. Akiyama,et al.  PDZ domain-binding motif of human T-cell leukemia virus type 1 Tax oncoprotein augments the transforming activity in a rat fibroblast cell line. , 2004, Virology.

[22]  P. Bryant,et al.  Localization of proteins to the apico-lateral junctions of Drosophila epithelia. , 1997, Developmental genetics.

[23]  A J Krush,et al.  Increased risk of cancer in the Peutz-Jeghers syndrome. , 1987, The New England journal of medicine.

[24]  D. Gary Gilliland,et al.  Cancer biology: Summing up cancer stem cells , 2005, Nature.

[25]  M. Fujita,et al.  E6AP-Dependent Degradation of DLG4/PSD95 by High-Risk Human Papillomavirus Type 18 E6 Protein , 2006, Journal of Virology.

[26]  Yi Zhang,et al.  Structures of a Human Papillomavirus (HPV) E6 Polypeptide Bound to MAGUK Proteins: Mechanisms of Targeting Tumor Suppressors by a High-Risk HPV Oncoprotein , 2007, Journal of Virology.

[27]  L. Banks,et al.  Differential expression of the human homologue of drosophila discs large oncosuppressor in histologic samples from human papillomavirus–associated lesions as a marker for progression to malignancy , 2004, International journal of cancer.

[28]  I. Gipson,et al.  Actin 'purse string' filaments are anchored by E-cadherin-mediated adherens junctions at the leading edge of the epithelial wound, providing coordinated cell movement. , 1998, Journal of cell science.

[29]  W. Chia,et al.  Polo inhibits progenitor self-renewal and regulates Numb asymmetry by phosphorylating Pon , 2007, Nature.

[30]  Marissa E. Nolan,et al.  Par6–aPKC uncouples ErbB2 induced disruption of polarized epithelial organization from proliferation control , 2006, Nature Cell Biology.

[31]  Yue Zhang,et al.  Regulation of the Polarity Protein Par6 by TGFß Receptors Controls Epithelial Cell Plasticity , 2005, Science.

[32]  K. Illmensee,et al.  Totipotency and normal differentiation of single teratocarcinoma cells cloned by injection into blastocysts. , 1976, Proceedings of the National Academy of Sciences of the United States of America.

[33]  S. Bowman,et al.  The Drosophila NuMA Homolog Mud regulates spindle orientation in asymmetric cell division. , 2006, Developmental cell.

[34]  M. Barbacid,et al.  Cell cycle kinases in cancer. , 2007, Current opinion in genetics & development.

[35]  N. Perrimon,et al.  Localization of apical epithelial determinants by the basolateral PDZ protein Scribble , 2000, Nature.

[36]  W. Nelson,et al.  Adherens and tight junctions: structure, function and connections to the actin cytoskeleton. , 2008, Biochimica et biophysica acta.

[37]  Miranda Thomas,et al.  HPV E6 specifically targets different cellular pools of its PDZ domain-containing tumour suppressor substrates for proteasome-mediated degradation , 2004, Oncogene.

[38]  A. Copp,et al.  Disruption of scribble (Scrb1) causes severe neural tube defects in the circletail mouse. , 2003, Human molecular genetics.

[39]  N. Yang,et al.  Integrative genomic analysis of protein kinase C (PKC) family identifies PKCiota as a biomarker and potential oncogene in ovarian carcinoma. , 2006, Cancer research.

[40]  H. Zentgraf,et al.  The von Hippel-Lindau tumor suppressor protein controls ciliogenesis by orienting microtubule growth , 2006, The Journal of cell biology.

[41]  W. Kaelin,et al.  The von Hippel-Lindau tumor suppressor protein: roles in cancer and oxygen sensing. , 2005, Cold Spring Harbor symposia on quantitative biology.

[42]  C. Kai,et al.  The PDZ Protein Tax-interacting Protein-1 Inhibits β-Catenin Transcriptional Activity and Growth of Colorectal Cancer Cells* , 2003, Journal of Biological Chemistry.

[43]  K. Mechtler,et al.  The Par complex directs asymmetric cell division by phosphorylating the cytoskeletal protein Lgl , 2003, Nature.

[44]  A. Fields,et al.  Protein kinase Cι is required for Ras transformation and colon carcinogenesis in vivo , 2004, The Journal of cell biology.

[45]  A. Banerjee,et al.  Protein Kinase C ζ Isoform is Critical for Proliferation in Human Glioblastoma Cell Lines , 2000, Journal of Neuro-Oncology.

[46]  N. Minato,et al.  The von Hippel-Lindau Tumor Suppressor Protein Mediates Ubiquitination of Activated Atypical Protein Kinase C* , 2001, The Journal of Biological Chemistry.

[47]  R. Morris,et al.  Enhanced long-term potentiation and impaired learning in mice with mutant postsynaptic density-95 protein , 1998, Nature.

[48]  C. Lohse,et al.  Atypical protein kinase Cι is an oncogene in human non-small cell lung cancer , 2005 .

[49]  A. Bosserhoff,et al.  Reduced expression of Hugl-1, the human homologue of Drosophila tumour suppressor gene lgl, contributes to progression of colorectal cancer , 2005, Oncogene.

[50]  L. Banks,et al.  HPV E6 degradation of p53 and PDZ containing substrates in an E6AP null background , 2008, Oncogene.

[51]  Watt,et al.  Journal of Cell Science , 1996, Nature.

[52]  L. Banks,et al.  Human discs large and scrib are localized at the same regions in colon mucosa and changes in their expression patterns are correlated with loss of tissue architecture during malignant progression , 2006, International journal of cancer.

[53]  C. Lohse,et al.  Atypical protein kinase C iota is an oncogene in human non-small cell lung cancer. , 2005, Cancer research.

[54]  Jérôme Boudeau,et al.  LKB1 is a master kinase that activates 13 kinases of the AMPK subfamily, including MARK/PAR‐1 , 2004, The EMBO journal.

[55]  D. Bilder.  Epithelial polarity and proliferation control: links from the Drosophila neoplastic tumor suppressors. , 2004, Genes & development.

[56]  R. Benton,et al.  Drosophila PAR-1 and 14-3-3 Inhibit Bazooka/PAR-3 to Establish Complementary Cortical Domains in Polarized Cells , 2003, Cell.

[57]  Miranda Thomas,et al.  HPV E6 and MAGUK protein interactions: determination of the molecular basis for specific protein recognition and degradation , 2001, Oncogene.

[58]  T. Pawson,et al.  A polarity complex of mPar-6 and atypical PKC binds, phosphorylates and regulates mammalian Lgl , 2003, Nature Cell Biology.

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

[60]  T. Mäkelä,et al.  Suppression of oncogenic properties of c-Myc by LKB1-controlled epithelial organization , 2007, Proceedings of the National Academy of Sciences.

[61]  C. Rongo,et al.  DLG-1 is a MAGUK similar to SAP97 and is required for adherens junction formation. , 2001, Molecular biology of the cell.

[62]  P. Gao,et al.  Protein kinase C zeta is required for epidermal growth factor-induced chemotaxis of human breast cancer cells. , 2005, Cancer research.

[63]  Anirban Datta,et al.  PTEN-Mediated Apical Segregation of Phosphoinositides Controls Epithelial Morphogenesis through Cdc42 , 2007, Cell.

[64]  A. Wodarz.  Molecular control of cell polarity and asymmetric cell division in Drosophila neuroblasts. , 2005, Current opinion in cell biology.

[65]  J. Wrana,et al.  Regulation of the Polarity Protein Par6 by TGFb Receptors Controls , 2005 .

[66]  Irving L. Weissman,et al.  Pten, Tumorigenesis, and Stem Cell Self-Renewal , 2006, Cell.

[67]  R. Xavier,et al.  Discs-large homolog 1 regulates smooth muscle orientation in the mouse ureter , 2006, Proceedings of the National Academy of Sciences.

[68]  G. Inghirami,et al.  β4 Integrin Amplifies ErbB2 Signaling to Promote Mammary Tumorigenesis , 2006, Cell.

[69]  J. Massagué,et al.  The logic of TGFβ signaling , 2006 .

[70]  Leslie E. Martin,et al.  Protein kinase Cζ mediates epidermal growth factor-induced growth of head and neck tumor cells by regulating mitogen-activated protein kinase , 2006 .

[71]  M. Moasser.  The oncogene HER2: its signaling and transforming functions and its role in human cancer pathogenesis , 2007, Oncogene.

[72]  T. Vallenius,et al.  The LKB1 tumor suppressor kinase in human disease. , 2007, Biochimica et biophysica acta.

[73]  Mina J Bissell,et al.  Tumor reversion: Correction of malignant behavior by microenvironmental cues , 2003, International journal of cancer.

[74]  V. Thannickal,et al.  Faculty Opinions recommendation of Regulation of the polarity protein Par6 by TGFbeta receptors controls epithelial cell plasticity. , 2005 .

[75]  A. Bosserhoff,et al.  Expression of Hugl-1 is strongly reduced in malignant melanoma , 2006, Oncogene.

[76]  M. Bissell,et al.  Of extracellular matrix, scaffolds, and signaling: tissue architecture regulates development, homeostasis, and cancer. , 2006, Annual review of cell and developmental biology.

[77]  A. Fields,et al.  A novel small-molecule inhibitor of protein kinase Ciota blocks transformed growth of non-small-cell lung cancer cells. , 2006, Cancer research.

[78]  M. Caligiuri,et al.  A cell initiating human acute myeloid leukaemia after transplantation into SCID mice , 1994, Nature.

[79]  A. Fields,et al.  A novel small-molecule inhibitor of protein kinase Ciota blocks transformed growth of non-small-cell lung cancer cells. , 2006, Cancer research.

[80]  J. Massagué,et al.  The logic of TGFbeta signaling. , 2006, FEBS letters.

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

[82]  Jean Paul Thiery,et al.  Epithelial-mesenchymal transitions in development and pathologies. , 2003, Current opinion in cell biology.

[83]  C. Larabell,et al.  Reciprocal interactions between beta1-integrin and epidermal growth factor receptor in three-dimensional basement membrane breast cultures: a different perspective in epithelial biology. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[84]  Joerg Betschinger,et al.  Sequential roles of Cdc42, Par-6, aPKC, and Lgl in the establishment of epithelial polarity during Drosophila embryogenesis. , 2004, Developmental cell.

[85]  Inke Näthke,et al.  Cell polarity in development and cancer , 2007, Nature Cell Biology.

[86]  T. Takayama,et al.  Essential role of protein kinase C ζ in transducing a motility signal induced by superoxide and a chemotactic peptide, fMLP , 2007, The Journal of cell biology.

[87]  Kristin J. Robinson,et al.  Lgl, Pins and aPKC regulate neuroblast self-renewal versus differentiation , 2006, Nature.

[88]  I. Macara,et al.  Par-3 controls tight junction assembly through the Rac exchange factor Tiam1 , 2005, Nature Cell Biology.

[89]  Hans C Clevers,et al.  Complete Polarization of Single Intestinal Epithelial Cells upon Activation of LKB1 by STRAD , 2004, Cell.

[90]  C. Doe,et al.  Brat is a Miranda cargo protein that promotes neuronal differentiation and inhibits neuroblast self-renewal. , 2006, Developmental cell.

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

[92]  I. Mian,et al.  Tissue architecture: the ultimate regulator of breast epithelial function. , 2003, Current opinion in cell biology.

[93]  R. Plasterk,et al.  The diverse functions of microRNAs in animal development and disease. , 2006, Developmental cell.

[94]  J. Ainge,et al.  Synapse-Associated Protein 102/dlgh3 Couples the NMDA Receptor to Specific Plasticity Pathways and Learning Strategies , 2007, The Journal of Neuroscience.

[95]  W. Kaelin.  The von Hippel-Lindau Tumor Suppressor Protein and Clear Cell Renal Carcinoma , 2007, Clinical Cancer Research.

[96]  Sophie Lelièvre,et al.  beta4 integrin-dependent formation of polarized three-dimensional architecture confers resistance to apoptosis in normal and malignant mammary epithelium. , 2002, Cancer cell.

[97]  P. Damonte,et al.  Fate of embryonal carcinoma cells injected into postimplantation mouse embryos. , 2005, Differentiation; research in biological diversity.

[98]  U. Heberlein,et al.  Aurora-A acts as a tumor suppressor and regulates self-renewal of Drosophila neuroblasts. , 2006, Genes & development.

[99]  L. Banks,et al.  Oncogenic human papillomavirus E6 proteins target the discs large tumour suppressor for proteasome-mediated degradation , 1999, Oncogene.

[100]  Nastaran Zahir,et al.  Death in the third dimension: apoptosis regulation and tissue architecture. , 2004, Current opinion in genetics & development.

[101]  Paul Martin,et al.  Healing of incisional wounds in the embryonic chick wing bud: characterization of the actin purse-string and demonstration of a requirement for Rho activation , 1996, The Journal of cell biology.

[102]  S. S. Lee,et al.  Binding of human virus oncoproteins to hDlg/SAP97, a mammalian homolog of the Drosophila discs large tumor suppressor protein. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[103]  G. Carpenter,et al.  ErbB receptors: new insights on mechanisms and biology. , 2006, Trends in cell biology.

[104]  A. Suzuki,et al.  The PAR-aPKC system: lessons in polarity , 2006, Journal of Cell Science.

[105]  Miranda Thomas,et al.  HPV E6 targeted degradation of the discs large protein: evidence for the involvement of a novel ubiquitin ligase , 2000, Oncogene.

[106]  H. Beug,et al.  Molecular requirements for epithelial-mesenchymal transition during tumor progression. , 2005, Current opinion in cell biology.

[107]  Y. Barrandon,et al.  LONG-TERM REGENERATION OF HUMAN EPIDERMIS ON THIRD DEGREE BURNS TRANSPLANTED WITH AUTOLOGOUS CULTURED EPITHELIUM GROWN ON A FIBRIN MATRIX1,2 , 2000, Transplantation.

[108]  Jun Hee Lee,et al.  Energy-dependent regulation of cell structure by AMP-activated protein kinase , 2007, Nature.

[109]  M. Fujita,et al.  E 6 AP-Dependent Degradation of DLG 4 / PSD 95 by High-Risk Human Papillomavirus Type 18 E 6 Protein , 2007 .

[110]  S. Tapscott,et al.  Loss of cell polarity causes severe brain dysplasia in Lgl1 knockout mice. , 2004, Genes & development.

[111]  M. Bissell,et al.  Inability of Rous sarcoma virus to cause sarcomas in the avian embryo , 1984, Nature.

[112]  C. Doe,et al.  The NuMA-related Mud protein binds Pins and regulates spindle orientation in Drosophila neuroblasts , 2006, Nature Cell Biology.

[113]  A. Balmain,et al.  Integration of positive and negative growth signals during ras pathway activation in vivo. , 2000, Current opinion in genetics & development.

[114]  平田 明.  PDZ domain-binding motif of human T-cell leukemia virus type 1 Tax oncoprotein augments the transforming activity in a rat fibroblast cell line , 2004 .

[115]  E. Fuchs,et al.  Catenins: keeping cells from getting their signals crossed. , 2006, Developmental cell.

[116]  B. Margolis,et al.  Apicobasal polarity complexes , 2005, Journal of Cell Science.

[117]  R. Brinster.  THE EFFECT OF CELLS TRANSFERRED INTO THE MOUSE BLASTOCYST ON SUBSEQUENT DEVELOPMENT , 1974, The Journal of experimental medicine.

[118]  D. St Johnston,et al.  LKB1 and AMPK maintain epithelial cell polarity under energetic stress , 2007, The Journal of cell biology.

[119]  K. Illmensee,et al.  Normal genetically mosaic mice produced from malignant teratocarcinoma cells. , 1975, Proceedings of the National Academy of Sciences of the United States of America.

[120]  D. Bredt,et al.  PSD-93 Knock-Out Mice Reveal That Neuronal MAGUKs Are Not Required for Development or Function of Parallel Fiber Synapses in Cerebellum , 2001, The Journal of Neuroscience.

[121]  John D. Potter,et al.  Morphogens, morphostats, microarchitecture and malignancy , 2007, Nature Reviews Cancer.

[122]  M. Peifer,et al.  aPKC controls microtubule organization to balance adherens junction symmetry and planar polarity during development. , 2007, Developmental cell.

[123]  O. Klezovitch,et al.  Cadherin-catenin proteins in vertebrate development. , 2006, Current opinion in cell biology.

[124]  T. Raabe,et al.  Drosophila Pins-binding protein Mud regulates spindle-polarity coupling and centrosome organization , 2006, Nature Cell Biology.