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Is cell competition relevant to cancer?

Abstract

Cell competition is a type of short-range cell–cell interaction described in Drosophila melanogaster, in which cells expressing different levels of a particular protein are able to discriminate between their relative levels of that protein in such a way that one of the cells disappears from the tissue (the loser), whereas the other (the winner) not only survives but also proliferates to fill the space left by the disappearing cells. Some tumour-promoting mutations are able to induce cell competition in D. melanogaster, but could cell competition become a target for therapeutic intervention, or early detection, in human cancer?

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Figure 1: The numbers of cancer.
Figure 2: A simple but stringent definition for cell competition-mediated apoptosis.
Figure 3: The ligand capture hypothesis.
Figure 4: Cell competition and cancer therapies.
Figure 5: Oncogene cooperation and cell competition as a hallmark of cancer.

References

  1. 1

    Fialkow, P. J. Clonal origin of human tumors. Ann. Rev. Med. 30, 135–143 (1979).

    CAS  Article  Google Scholar 

  2. 2

    Weinberg, R. A. The Biology of Cancer 39–43 (Garland Science, New York, 2007).

    Google Scholar 

  3. 3

    Miller, S. J., Lavker, R. M. & Sun, T. T. Interpreting epithelial cancer biology in the context of stem cells: tumor properties and therapeutic implications. Biochim. Biophys. Acta 1756, 25–52. (2005).

    CAS  PubMed  Google Scholar 

  4. 4

    Kumar, V., Fausto, N. & Abbas, A. Robbins & Cotran Pathologic Basis of Disease 7th edn (Saunders, Philadelphia, 2004).

    Google Scholar 

  5. 5

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

    CAS  Article  Google Scholar 

  6. 6

    Simpson, P. Parameters of cell competition in the compartments of the wing disc of Drosophila. Dev. Biol. 69, 182–193 (1979).

    CAS  Article  Google Scholar 

  7. 7

    Simpson, P. & Morata, G. Differential mitotic rates and patterns of growth in compartments in the Drosophila wing. Dev. Biol. 85, 299–308 (1981).

    CAS  Article  Google Scholar 

  8. 8

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

    CAS  Article  Google Scholar 

  9. 9

    de la Cova, C., Abril, M., Bellosta, P., Gallart, P. & Johnston, L. A. Drosophila myc regulates organ size by inducing cell competition. Cell 117, 107–116 (2004).

    CAS  Article  Google Scholar 

  10. 10

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

    CAS  Article  Google Scholar 

  11. 11

    Li, W. & Baker, N. E. Engulfment is required for cell competition. Cell 15, 1215–1225 (2007).

    Article  Google Scholar 

  12. 12

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

    CAS  Article  Google Scholar 

  13. 13

    Marygold, S. J. et al. The ribosomal protein genes and Minute loci of Drosophila melanogaster. Genome Biol. 8, R216 (2007).

    Article  Google Scholar 

  14. 14

    Oliver, E. R., Saunders, T. L., Tarle, S. A. & Glaser, T. Ribosomal protein L24 defect in belly spot and tail (Bst), a mouse Minute. Development 131, 3907–3920 (2004).

    CAS  Article  Google Scholar 

  15. 15

    Johnston, L. A., Prober, D. A., Edgar, B. A., Eisenman, R. N. & Gallant, P. Drosophila Myc regulates cellular growth during development. Cell 98, 779–790 (1999).

    CAS  Article  Google Scholar 

  16. 16

    Hariharan, I. K. & Bilder, D. Regulation of imaginal disc growth by tumor-suppressor genes in Drosophila. Annu. Rev. Genet. 40, 335–361 (2006).

    CAS  Article  Google Scholar 

  17. 17

    Brumby, A. M. & Richardson, H. E. scribble mutants cooperate with oncogenic Ras or Notch to cause neoplastic overgrowth in Drosophila. EMBO J. 22, 5769–5779 (2003).

    CAS  Article  Google Scholar 

  18. 18

    Agrawal, N., Kango, M., Mishra, A. & Sinha, P. Neoplastic transformation and aberrant cell-cell interactions in genetic mosaics of lethal(2)giant larvae (lgl), a tumor suppressor gene of Drosophila. Dev. Biol. 172, 218–229 (1995).

    CAS  Article  Google Scholar 

  19. 19

    Woods, D. F. & Bryant, P. J. The discs-large tumor suppressor gene of Drosophila encodes a guanylate kinase homolog localized at septate junctions. Cell 66, 451–464 (1991).

    CAS  Article  Google Scholar 

  20. 20

    Humbert, P., Russell, S., Richardson, H. Dlg, Scribble and Lgl in cell polarity, cell proliferation and cancer. Bioessays 25, 542–553 (2003).

    CAS  Article  Google Scholar 

  21. 21

    Bilder, D., Li, M. & Perrimon, N. Cooperative regulation of cell polarity and growth by Drosophila tumor suppressors. Science, 289, 113–116 (2000).

    CAS  Article  Google Scholar 

  22. 22

    Grzeschik, N. A., Amin, N., Secombe, J., Brumby, A. M. & Richardson, H. E. Abnormalities in cell proliferation and apico-basal cell polarity are separable in Drosophila lgl mutant clones in the developing eye. Dev. Biol. 311, 106–123 (2007).

    CAS  Article  Google Scholar 

  23. 23

    Brumby, A. M. & Richardson, H. E. Using Drosophila melanogaster to map human cancer pathways. Nature Rev. Cancer 5, 626–639 (2005).

    CAS  Article  Google Scholar 

  24. 24

    Kanda, H. & Miura, M. Regulatory roles of JNK in programmed cell death. J. Biochem. 136, 1–6 (2004).

    CAS  Article  Google Scholar 

  25. 25

    Neufeld, T. P., de la Cruz, A. F., Johnston, L. A. & Edgar, B. A. Coordination of growth and cell division in the Drosophila wing. Cell 93, 1183–1193 (1998).

    CAS  Article  Google Scholar 

  26. 26

    Prober, D. A. & Edgar, B. A. Ras1 promotes cellular growth in the Drosophila wing. Cell 100, 435–446 (2000).

    CAS  Article  Google Scholar 

  27. 27

    Vidal, M. & Larson, D. E. & Cagan, R. L. Csk-deficient boundary cells are eliminated from normal Drosophila epithelia by exclusion, migration, and apoptosis. Dev. Cell 10, 33–44 (2006).

    CAS  Article  Google Scholar 

  28. 28

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

    CAS  PubMed  Google Scholar 

  29. 29

    Ja´zwi´nska, A., Kirov, N., Wieschaus, E., Roth, S. & Rushlow, C. The Drosophila gene brinker reveals a novel mechanism of Dpp target gene regulation. Cell 96, 563–573 (1999).

    Article  Google Scholar 

  30. 30

    Campbell, G., Tomlinson, A. Transducing the Dpp morphogen gradient in the wing of Drosophila: regulation of Dpp targets by brinker. Cell 96, 553–562 (1999).

    CAS  Article  Google Scholar 

  31. 31

    Martin, F. A., Perez-Garijo, A., Moreno, E. & Morata, G. The brinker gradient controls wing growth in Drosophila. Development 131, 4921–4930 (2004).

    CAS  Article  Google Scholar 

  32. 32

    Herranz, H., Morata, G. & Milan, M. calderon encodes an organic cation transporter of the major facilitator superfamily required for cell growth and proliferation of Drosophila tissues. Development 133, 2617–2625 (2006).

    CAS  Article  Google Scholar 

  33. 33

    Bohni, R. et al. Autonomous control of cell and organ size by CHICO, a Drosophila homolog of vertebrate IRS1–4. Cell 97, 865–875 (1999).

    CAS  Article  Google Scholar 

  34. 34

    Maynard Smith, J. & Szathmáry, E. The Major Transitions in Evolution (Freeman, Oxford, 1995).

    Google Scholar 

  35. 35

    Oertel, M., Menthena, A., Dabeva, M. D. & Shafritz, D. A. Cell competition leads to a high level of normal liver reconstitution by transplanted fetal liver stem/progenitor cells. Gastroenterology 130, 507–520 (2006).

    Article  Google Scholar 

  36. 36

    Orian, A. et al. Genomic binding by the Drosophila Myc, Max, Mad/Mnt transcription factor network. Genes Dev. 17, 1101–1114 (2003).

    CAS  Article  Google Scholar 

  37. 37

    Grewal, S. S., Li, L., Orian, A., Eisenman, R. N. & Edgar BA. Myc-dependent regulation of ribosomal RNA synthesis during Drosophila development. Nature Cell Biol. 7, 295–302 (2005).

    CAS  Article  Google Scholar 

  38. 38

    Diaz, B. & Moreno, E. The competitive nature of cells. Exp. Cell Res. 306, 317–322 (2005).

    CAS  Article  Google Scholar 

  39. 39

    Adachi-Yamada, T., Fujimura-Kamada, K., Nishida, Y. & Matsumoto, K. Distortion of proximodistal information causes JNK-dependent apoptosis in Drosophila wing. Nature 400, 166–169 (1999).

    CAS  Article  Google Scholar 

  40. 40

    Adachi-Yamada, T. & O'Connor, M. B. Morphogenetic apoptosis: a mechanism for correcting discontinuities in morphogen gradients. Dev. Biol. 251, 74–90 (2002).

    CAS  Article  Google Scholar 

  41. 41

    Moreno, E., Yan, M. & Basler, K. Evolution of TNF signaling mechanisms: JNK-dependent apoptosis triggered by Eiger, the Drosophila homolog of the TNF superfamily. Curr. Biol. 12, 1263–1268 (2002).

    CAS  Article  Google Scholar 

  42. 42

    Bangs, P. & White, K. Regulation and execution of apoptosis during Drosophila development. Dev. Dyn. 218, 68–79 (2000).

    CAS  Article  Google Scholar 

  43. 43

    Tyler, D. M, Li, W., Zhuo, N., Pellock, B. & Baker, N. E. Genes affecting cell competition in Drosophila. Genetics 175, 643–657 (2007).

    CAS  Article  Google Scholar 

  44. 44

    Shen, J. & Dahmann, C. Extrusion of cells with inappropriate Dpp signaling from Drosophila wing disc epithelia. Science 307, 1789–1790 (2005).

    CAS  Article  Google Scholar 

  45. 45

    Gibson, M. C. & Perrimon, N. Extrusion and death of DPP/BMP-compromised epithelial cells in the developing Drosophila wing. Science 307, 1785–1789 (2005).

    CAS  Article  Google Scholar 

  46. 46

    Manjon, C., Sanchez-Herrero, E. & Suzanne, M. Sharp boundaries of Dpp signalling trigger local cell death required for Drosophila leg morphogenesis. Nature Cell Biol. 9, 57–63 (2007).

    CAS  Article  Google Scholar 

  47. 47

    Hoeppner, D. J., Hengartner, M. O. & Schnabel, R. Engulfment genes cooperate with ced-3 to promote cell death in Caenorhabditis elegans. Nature 412, 202–206 (2001).

    CAS  Article  Google Scholar 

  48. 48

    Reddien, P. W., Cameron, S. & Horvitz, H. R. Phagocytosis promotes programmed cell death in C. elegans. Nature 412, 198–202 (2001).

    CAS  Article  Google Scholar 

  49. 49

    Zhou, Z., Hartweig, E. & Horvitz, H. R. CED-1 is a transmembrane receptor that mediates cell corpse engulfment in C. elegans. Cell 104, 43–56 (2001).

    CAS  Article  Google Scholar 

  50. 50

    Freeman, M. R., Delrow, J., Kim, J., Johnson, E. & Doe, C. Q. Unwrapping glial biology: Gcm target genes regulating glial development, diversification, and function. Neuron 38, 567–580 (2003).

    CAS  Article  Google Scholar 

  51. 51

    Manaka, J. et al. Draper-mediated and phosphatidylserine-independent phagocytosis of apoptotic cells by Drosophila hemocytes/macrophages. J. Biol. Chem. 279, 48466–48476 (2004).

    CAS  Article  Google Scholar 

  52. 52

    Pearson, A. M. et al. Identification of cytoskeletal regulatory proteins required for efficient phagocytosis in Drosophila. Microbes Infect. 5, 815–824 (2003).

    CAS  Article  Google Scholar 

  53. 53

    Zhang, J. et al., Antigen receptor-induced activation and cytoskeletal rearrangement are impaired in Wiskott–Aldrich syndrome protein-deficient lymphocytes. J. Exp. Med. 190 1329–1342 (1999).

    CAS  Article  Google Scholar 

  54. 54

    Lorenzi, R., Brickell, R., Katz, D. R., Kinnon, C. & Thrasher, A. J. Wiskott–Aldrich syndrome protein is necessary for efficient IgG-mediated phagocytosis. Blood 95, 2943–2946 (2000).

    CAS  PubMed  Google Scholar 

  55. 55

    Fadok, V. A. et al. A receptor for phosphatidylserine-specific clearance of apoptotic cells. Nature 405, 85–90 (2000).

    CAS  Article  Google Scholar 

  56. 56

    Mitchell, J. E. et al. The presumptive phosphatidylserine receptor is dispensable for innate anti-inflammatory recognition and clearance of apoptotic cells. J. Biol. Chem. 281, 5718–5725 (2006).

    CAS  Article  Google Scholar 

  57. 57

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

    CAS  Article  Google Scholar 

  58. 58

    Saucedo, L. J. & Edgar, B. A. Filling out the Hippo pathway. Nature Rev. Mol. Cell Biol. 8, 613–621 (2007).

    CAS  Article  Google Scholar 

  59. 59

    Edgar, B. A. From cell structure to transcription: Hippo forges a new path. Cell 124, 267–273 (2006).

    CAS  Article  Google Scholar 

  60. 60

    Vita, M. & Henriksson, M. The Myc oncoprotein as a therapeutic target for human cancer. Semin. Cancer Biol. 16, 318–330 (2006).

    CAS  Article  Google Scholar 

  61. 61

    Dakubo, G. D., Jakupciak, J. P., Birch-Machin, M. A. & Parr, R. L. Clinical implications and utility of field cancerization. Cancer Cell Int. 7, 2 (2007).

    Article  Google Scholar 

  62. 62

    Hoglund, M. Bladder cancer, a two phased disease? Semin. Cancer Biol. 17, 225–232 (2007).

    Article  Google Scholar 

  63. 63

    Gurova, K. V. & Gudkov, A. V. Paradoxical role of apoptosis in tumor progression. J. Cell Biochem. 88, 128–137 (2003).

    CAS  Article  Google Scholar 

  64. 64

    Joensuu, H., Pylkkänen, L. & Toikkanen, S. Bcl-2 protein expression and long-term survival in breast cancer. Am. J. Pathol. 145, 1191–1198 (1994).

    CAS  PubMed  PubMed Central  Google Scholar 

  65. 65

    Adams, J. M. & Cory, S. The Bcl-2 apoptotic switch in cancer development and therapy. Oncogene 26, 1324–1337 (2007).

    CAS  Article  Google Scholar 

  66. 66

    Muller, H. J. Artificial transmutation of the gene. Science 46, 84–88 (1927).

    Article  Google Scholar 

  67. 67

    Hartwell, L. H. & Kastan, M. B. Cell cycle control and cancer. Science 266, 1821–1832 (1994).

    CAS  Article  Google Scholar 

  68. 68

    Nurse, P. Genetic control of cell size at cell division in yeast. Nature 256, 547–551 (1975).

    CAS  Article  Google Scholar 

  69. 69

    Evans, T., Rosenthal, J., Youngblom, D., Distel, D. & Hunt, T. Cyclin: a protein specified by maternal mRNA in sea urchin eggs that is destroyed at each cleavage division. Cell 33, 389–396 (1983).

    CAS  Article  Google Scholar 

  70. 70

    Ellis, H. M. & Horvitz, H. R. Genetic control of programmed cell death in the nematode C. elegans. Cell 44, 817–829 (1986).

    CAS  Article  Google Scholar 

  71. 71

    Land, H., Parada, L. F. & Weinberg, R. A. Tumorigenic conversion of primary embryo fibroblasts requires at least two cooperating oncogenes. Nature 304, 596–601 (1983).

    CAS  Article  Google Scholar 

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Acknowledgements

To my father in law, Alfred Rhiner, who died from adrenal adenocarcinoma in 2007. We all miss you, Fred. I thank C. Rhiner, M. Serrano, J. M. López-Gay and I. Flores for critically reading the manuscript and for suggestions.

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Moreno, E. Is cell competition relevant to cancer?. Nat Rev Cancer 8, 141–147 (2008). https://doi.org/10.1038/nrc2252

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