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Impact of interactions between normal and transformed epithelial cells and the relevance to cancer

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Abstract

The majority of human cancers are initiated when a single cell in an epithelial sheet becomes transformed. Cell transformation arises from the activation of oncoproteins and/or inactivation of tumor suppressor proteins. Recent studies have independently revealed that interaction and communication between transformed cells and their normal neighbors have a significant impact on the fate of the transformed cell. Several reports have shown that various phenomena occur at the interface between normal and transformed epithelial cells following the initial transformation event. In epithelia of Drosophila melanogaster, transformed and normal cells compete for survival in a process termed cell competition. This review will summarize current research and discuss the impact of these studies on our understanding of how primary tumors emerge and develop within a normal epithelium.

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Abbreviations

GJIC:

Gap junctional intercellular communication

cAMP:

Cyclic adenosine monophosphate

IP3:

Inositol triphosphate

MDCK:

Madin-Darby canine kidney

pMLC:

Phosphorylated myosin light chain

ROCK:

Rho kinase

MAPK:

Mitogen-activated protein kinase

ts-Src:

Temperature-sensitive mutant of v-Src

v-Src:

Sarcoma virus Src

EVL:

Enveloping layer

FAK:

Focal adhesion kinase

Csk:

C-terminal Src kinase

Rp:

Ribosomal protein

JNK:

c-Jun N-terminal kinase

Lgl:

Lethal giant larvae

Dlg:

Discs large

DPP:

Decapentaplegic

TGFβ:

Transforming growth factor β

SWH:

Salvador/Warts/Hippo

Yki:

Yorkie

Drp:

Draper

WASp:

Wiskott–Aldrich syndrome protein

PSR:

Phosphatidylserine receptor

Fwe:

Flower

SPARC:

Secreted protein acidic and rich in cysteine

References

  1. Nowell PC (2002) Tumor progression: a brief historical perspective. Semin Cancer Biol 12:261–266

    Article  PubMed  CAS  Google Scholar 

  2. Vogelstein B, Kinzler KW (2004) Cancer genes and the pathways they control. Nat Med 10:789–799

    Article  PubMed  CAS  Google Scholar 

  3. Elenbaas B, Weinberg RA (2001) Heterotypic signaling between epithelial tumor cells and fibroblasts in carcinoma formation. Exp Cell Res 264:169–184

    Article  PubMed  CAS  Google Scholar 

  4. Xing F, Saidou J, Watabe K (2010) Cancer associated fibroblasts (CAFs) in tumor microenvironment. Front Biosci 15:166–179

    Article  PubMed  CAS  Google Scholar 

  5. Krtolica A, Parrinello S, Lockett S, Desprez PY, Campisi J (2001) Senescent fibroblasts promote epithelial cell growth and tumorigenesis: a link between cancer and aging. Proc Natl Acad Sci USA 98:12072–12077

    Article  PubMed  CAS  Google Scholar 

  6. Lawrenson K, Grun B, Benjamin E, Jacobs IJ, Dafou D et al (2010) Senescent fibroblasts promote neoplastic transformation of partially transformed ovarian epithelial cells in a three-dimensional model of early stage ovarian cancer. Neoplasia 12:317–325

    PubMed  CAS  Google Scholar 

  7. Levental KR, Yu H, Kass L, Lakins JN, Egeblad M et al (2009) Matrix crosslinking forces tumor progression by enhancing integrin signaling. Cell 139:891–906

    Article  PubMed  CAS  Google Scholar 

  8. Provenzano PP, Inman DR, Eliceiri KW, Keely PJ (2009) Matrix density-induced mechanoregulation of breast cell phenotype, signaling and gene expression through a FAK-ERK linkage. Oncogene 28:4326–4343

    Article  PubMed  CAS  Google Scholar 

  9. Paszek MJ, Zahir N, Johnson KR, Lakins JN, Rozenberg GI et al (2005) Tensional homeostasis and the malignant phenotype. Cancer Cell 8:241–254

    Article  PubMed  CAS  Google Scholar 

  10. Stoker MG, Shearer M, O’Neill C (1966) Growth inhibition of polyoma-transformed cells by contact with static normal fibroblasts. J Cell Sci 1:297–310

    PubMed  CAS  Google Scholar 

  11. Hogan C, Kajita M, Lawrenson K, Fujita Y (2011) Interactions between normal and transformed epithelial cells: their contributions to tumourigenesis. Int J Biochem Cell Biol 43:496–503

    Article  PubMed  CAS  Google Scholar 

  12. Mehta PP, Bertram JS, Loewenstein WR (1986) Growth inhibition of transformed cells correlates with their junctional communication with normal cells. Cell 44:187–196

    Article  PubMed  CAS  Google Scholar 

  13. Goldberg GS, Martyn KD, Lau AF (1994) A connexin 43 antisense vector reduces the ability of normal cells to inhibit the foci formation of transformed cells. Mol Carcinog 11:106–114

    Article  PubMed  CAS  Google Scholar 

  14. Naus CC, Laird DW (2010) Implications and challenges of connexin connections to cancer. Nat Rev Cancer 10:435–441

    Article  PubMed  CAS  Google Scholar 

  15. Alexander DB, Ichikawa H, Bechberger JF, Valiunas V, Ohki M et al (2004) Normal cells control the growth of neighboring transformed cells independent of gap junctional communication and SRC activity. Cancer Res 64:1347–1358

    Article  PubMed  CAS  Google Scholar 

  16. Martin W, Zempel G, Hulser D, Willecke K (1991) Growth inhibition of oncogene-transformed rat fibroblasts by cocultured normal cells: relevance of metabolic cooperation mediated by gap junctions. Cancer Res 51:5348–5351

    PubMed  CAS  Google Scholar 

  17. Hogan C, Dupre-Crochet S, Norman M, Kajita M, Zimmermann C et al (2009) Characterization of the interface between normal and transformed epithelial cells. Nat Cell Biol 11:460–467

    Article  PubMed  CAS  Google Scholar 

  18. Kajita M, Hogan C, Harris AR, Dupre-Crochet S, Itasaki N et al (2010) Interaction with surrounding normal epithelial cells influences signalling pathways and behaviour of Src-transformed cells. J Cell Sci 123:171–180

    Article  PubMed  CAS  Google Scholar 

  19. Behrens J, Vakaet L, Friis R, Winterhager E, Van Roy F et al (1993) Loss of epithelial differentiation and gain of invasiveness correlates with tyrosine phosphorylation of the E-cadherin/beta-catenin complex in cells transformed with a temperature-sensitive v-SRC gene. J Cell Biol 120:757–766

    Article  PubMed  CAS  Google Scholar 

  20. Vigil D, Cherfils J, Rossman KL, Der CJ (2010) Ras superfamily GEFs and GAPs: validated and tractable targets for cancer therapy? Nat Rev Cancer 10:842–857

    Article  PubMed  CAS  Google Scholar 

  21. Karnoub AE, Weinberg RA (2008) Ras oncogenes: split personalities. Nat Rev Mol Cell Biol 9:517–531

    Article  PubMed  CAS  Google Scholar 

  22. Aleshin A, Finn RS (2010) SRC: a century of science brought to the clinic. Neoplasia 12:599–607

    PubMed  CAS  Google Scholar 

  23. Rosenblatt J, Raff MC, Cramer LP (2001) An epithelial cell destined for apoptosis signals its neighbors to extrude it by an actin- and myosin-dependent mechanism. Curr Biol 11:1847–1857

    Article  PubMed  CAS  Google Scholar 

  24. Krieg M, Arboleda-Estudillo Y, Puech PH, Kafer J, Graner F et al (2008) Tensile forces govern germ-layer organization in zebrafish. Nat Cell Biol 10:429–436

    Article  PubMed  CAS  Google Scholar 

  25. Tepass U, Godt D, Winklbauer R (2002) Cell sorting in animal development: signalling and adhesive mechanisms in the formation of tissue boundaries. Curr Opin Genet Dev 12:572–582

    Article  PubMed  CAS  Google Scholar 

  26. Heidmann D, Lehner CF (2001) Reduction of Cre recombinase toxicity in proliferating Drosophila cells by estrogen-dependent activity regulation. Dev Genes Evol 211:458–465

    Article  PubMed  CAS  Google Scholar 

  27. Prober DA, Edgar BA (2000) Ras1 promotes cellular growth in the Drosophila wing. Cell 100:435–446

    Article  PubMed  CAS  Google Scholar 

  28. Prober DA, Edgar BA (2002) Interactions between Ras1, dMyc, and dPI3 K signaling in the developing Drosophila wing. Genes Dev 16:2286–2299

    Article  PubMed  CAS  Google Scholar 

  29. Vidal M, Larson DE, Cagan RL (2006) Csk-deficient boundary cells are eliminated from normal Drosophila epithelia by exclusion, migration, and apoptosis. Dev Cell 10:33–44

    Article  PubMed  CAS  Google Scholar 

  30. O’Keefe DD, Prober DA, Moyle PS, Rickoll WL, Edgar BA (2007) Egfr/Ras signaling regulates DE-cadherin/Shotgun localization to control vein morphogenesis in the Drosophila wing. Dev Biol 311:25–39

    Article  PubMed  Google Scholar 

  31. Morata G, Ripoll P (1975) Minutes: mutants of Drosophila autonomously affecting cell division rate. Dev Biol 42:211–221

    Article  PubMed  CAS  Google Scholar 

  32. Moreno E, Basler K, Morata G (2002) Cells compete for decapentaplegic survival factor to prevent apoptosis in Drosophila wing development. Nature 416:755–759

    Article  PubMed  CAS  Google Scholar 

  33. de la Cova C, Abril M, Bellosta P, Gallant P, Johnston LA (2004) Drosophila myc regulates organ size by inducing cell competition. Cell 117:107–116

    Article  Google Scholar 

  34. Johnston LA, Prober DA, Edgar BA, Eisenman RN, Gallant P (1999) Drosophila myc regulates cellular growth during development. Cell 98:779–790

    Article  PubMed  CAS  Google Scholar 

  35. Moreno E, Basler K (2004) dMyc transforms cells into super-competitors. Cell 117:117–129

    Article  PubMed  CAS  Google Scholar 

  36. Harvey K, Tapon N (2007) The Salvador-Warts-Hippo pathway—an emerging tumour-suppressor network. Nat Rev Cancer 7:182–191

    Article  PubMed  CAS  Google Scholar 

  37. Tyler DM, Li W, Zhuo N, Pellock B, Baker NE (2007) Genes affecting cell competition in Drosophila. Genetics 175:643–657

    Article  PubMed  CAS  Google Scholar 

  38. Martin FA, Herrera SC, Morata G (2009) Cell competition, growth and size control in the Drosophila wing imaginal disc. Development 136:3747–3756

    Article  PubMed  CAS  Google Scholar 

  39. Humbert PO, Grzeschik NA, Brumby AM, Galea R, Elsum I et al (2008) Control of tumourigenesis by the Scribble/Dlg/Lgl polarity module. Oncogene 27:6888–6907

    Article  PubMed  CAS  Google Scholar 

  40. Zhan L, Rosenberg A, Bergami KC, Yu M, Xuan Z et al (2008) Deregulation of scribble promotes mammary tumorigenesis and reveals a role for cell polarity in carcinoma. Cell 135:865–878

    Article  PubMed  CAS  Google Scholar 

  41. Klezovitch O, Fernandez TE, Tapscott SJ, Vasioukhin V (2004) Loss of cell polarity causes severe brain dysplasia in Lgl1 knockout mice. Genes Dev 18:559–571

    Article  PubMed  CAS  Google Scholar 

  42. Brumby AM, Richardson HE (2003) scribble mutants cooperate with oncogenic Ras or Notch to cause neoplastic overgrowth in Drosophila. EMBO J 22:5769–5779

    Article  PubMed  CAS  Google Scholar 

  43. Grzeschik NA, Parsons LM, Richardson HE (2010) Lgl, the SWH pathway and tumorigenesis: It’s a matter of context & competition!. Cell Cycle 9:3202–3212

    Article  PubMed  CAS  Google Scholar 

  44. Grzeschik NA, Parsons LM, Allott ML, Harvey KF, Richardson HE (2010) Lgl, aPKC, and Crumbs regulate the Salvador/Warts/Hippo pathway through two distinct mechanisms. Curr Biol 20:573–581

    Article  PubMed  CAS  Google Scholar 

  45. Froldi F, Ziosi M, Garoia F, Pession A, Grzeschik NA et al (2010) The lethal giant larvae tumour suppressor mutation requires dMyc oncoprotein to promote clonal malignancy. BMC Biol 8:33

    Article  PubMed  Google Scholar 

  46. Ziosi M, Baena-Lopez LA, Grifoni D, Froldi F, Pession A, et al. (2010) dMyc functions downstream of Yorkie to promote the supercompetitive behavior of hippo pathway mutant cells. PLoS Genet 6

  47. Wu M, Pastor-Pareja JC, Xu T (2010) Interaction between Ras(V12) and scribbled clones induces tumour growth and invasion. Nature 463:545–548

    Article  PubMed  CAS  Google Scholar 

  48. Pagliarini RA, Xu T (2003) A genetic screen in Drosophila for metastatic behavior. Science 302:1227–1231

    Article  PubMed  CAS  Google Scholar 

  49. Menendez J, Perez-Garijo A, Calleja M, Morata G (2010) A tumor-suppressing mechanism in Drosophila involving cell competition and the Hippo pathway. Proc Natl Acad Sci USA 107:14651–14656

    Article  PubMed  CAS  Google Scholar 

  50. Tamori Y, Bialucha CU, Tian AG, Kajita M, Huang YC et al (2010) Involvement of Lgl and Mahjong/VprBP in cell competition. PLoS Biol 8:e1000422

    Article  PubMed  Google Scholar 

  51. Lambertsson A (1998) The minute genes in Drosophila and their molecular functions. Adv Genet 38:69–134

    Article  PubMed  CAS  Google Scholar 

  52. Johnston LA (2009) Competitive interactions between cells: death, growth, and geography. Science 324:1679–1682

    Article  PubMed  CAS  Google Scholar 

  53. Burke R, Basler K (1996) Dpp receptors are autonomously required for cell proliferation in the entire developing Drosophila wing. Development 122:2261–2269

    PubMed  CAS  Google Scholar 

  54. Senoo-Matsuda N, Johnston LA (2007) Soluble factors mediate competitive and cooperative interactions between cells expressing different levels of Drosophila Myc. Proc Natl Acad Sci USA 104:18543–18548

    Article  PubMed  CAS  Google Scholar 

  55. Li W, Baker NE (2007) Engulfment is required for cell competition. Cell 129:1215–1225

    Article  PubMed  CAS  Google Scholar 

  56. Grusche FA, Degoutin JL, Richardson HE, Harvey KF (2011) The Salvador/Warts/Hippo pathway controls regenerative tissue growth in Drosophila melanogaster. Dev Biol 350:255–266

    Article  PubMed  CAS  Google Scholar 

  57. Shaw RL, Kohlmaier A, Polesello C, Veelken C, Edgar BA et al (2010) The Hippo pathway regulates intestinal stem cell proliferation during Drosophila adult midgut regeneration. Development 137:4147–4158

    Article  PubMed  CAS  Google Scholar 

  58. Sun G, Irvine KD (2011) Regulation of Hippo signaling by Jun kinase signaling during compensatory cell proliferation and regeneration, and in neoplastic tumors. Dev Biol 350:139–151

    Article  PubMed  CAS  Google Scholar 

  59. Karpowicz P, Perez J, Perrimon N (2010) The Hippo tumor suppressor pathway regulates intestinal stem cell regeneration. Development 137:4135–4145

    Article  PubMed  CAS  Google Scholar 

  60. Rhiner C, Lopez-Gay JM, Soldini D, Casas-Tinto S, Martin FA et al (2010) Flower forms an extracellular code that reveals the fitness of a cell to its neighbors in Drosophila. Dev Cell 18:985–998

    Article  PubMed  CAS  Google Scholar 

  61. Portela M, Casas-Tinto S, Rhiner C, Lopez-Gay JM, Dominguez O et al (2010) Drosophila SPARC is a self-protective signal expressed by loser cells during cell competition. Dev Cell 19:562–573

    Article  PubMed  CAS  Google Scholar 

  62. Bradshaw AD (2009) The role of SPARC in extracellular matrix assembly. J Cell Commun Signal 3:239–246

    Article  PubMed  Google Scholar 

  63. Chlenski A, Cohn SL (2010) Modulation of matrix remodeling by SPARC in neoplastic progression. Semin Cell Dev Biol 21:55–65

    Article  PubMed  CAS  Google Scholar 

  64. Baker NE (2011) Cell competition. Curr Biol 21:R11–R15

    Article  PubMed  CAS  Google Scholar 

  65. Rhiner C, Moreno E (2009) Super competition as a possible mechanism to pioneer precancerous fields. Carcinogenesis 30:723–728

    Article  PubMed  CAS  Google Scholar 

  66. Braakhuis BJ, Brakenhoff RH, Leemans CR (2005) Second field tumors: a new opportunity for cancer prevention? Oncologist 10:493–500

    Article  PubMed  CAS  Google Scholar 

  67. Braakhuis BJ, Tabor MP, Kummer JA, Leemans CR, Brakenhoff RH (2003) A genetic explanation of Slaughter’s concept of field cancerization: evidence and clinical implications. Cancer Res 63:1727–1730

    PubMed  CAS  Google Scholar 

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Acknowledgments

I am grateful to Y. Fujita and M. Norman for the critical reading of the manuscript. This work is supported by MRC funding to the Cell Biology Unit.

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  1. MRC Laboratory for Molecular Cell Biology and Cell Biology Unit, University College London, Gower Street, London, WC1E 6BT, UK

    Catherine Hogan

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  1. Catherine Hogan
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Correspondence to Catherine Hogan.

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Hogan, C. Impact of interactions between normal and transformed epithelial cells and the relevance to cancer. Cell. Mol. Life Sci. 69, 203–213 (2012). https://doi.org/10.1007/s00018-011-0806-3

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