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Learning About Retinoblastoma from Mouse Models That Missed

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Animal Models of Brain Tumors

Part of the book series: Neuromethods ((NM,volume 77))

Abstract

Retinoblastoma has been an attractive cancer for mouse modeling, as it is thought to develop in response to the inactivation of a single gene (RB) and thus provides an extraordinary opportunity to dissect mechanisms of tumor initiation. However, difficulties have repeatedly arisen in efforts to model this malignancy. For example, mice with inactivating Rb mutations fail to develop retinoblastoma, and instead develop pituitary and thyroid cancers. Moreover, mice with combined mutations in Rb and Rb-related genes develop retinal tumors that differ from human retinoblastomas in important aspects, including the mutations necessary to form the tumors, the retinal cell phenotypes of the tumors, and potentially the tumor cell of origin. Despite these discrepancies, mouse models may provide insight into human retinoblastoma by revealing features that contribute to retinal tumors in both species. Nevertheless, the mouse’s inexact representation of retinoblastoma challenges us to develop more accurate models and to decipher how human-specific circuitry sensitizes to the loss of Rb and enables retinoblastoma initiation.

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References

  1. Chow RL, Lang RA (2001) Early eye development in vertebrates. Annu Rev Cell Dev Biol 17:255–296

    Article  PubMed  CAS  Google Scholar 

  2. Albert DM (1987) Historic review of retinoblastoma. Ophthalmology 94:654–662

    PubMed  CAS  Google Scholar 

  3. Weller CV (1941) The inheritance of retinoblastoma and its relationship to practical eugenics. Cancer Res 1:517–535

    Google Scholar 

  4. Knudson AG Jr (1971) Mutation and cancer: statistical study of retinoblastoma. Proc Natl Acad Sci USA 68:820–823

    Article  PubMed  Google Scholar 

  5. Cavenee WK, Dryja TP, Phillips RA, Benedict WF, Godbout R, Gallie BL, Murphree AL, Strong LC, White RL (1983) Expression of recessive alleles by chromosomal mechanisms in retinoblastoma. Nature 305:779–784

    Article  PubMed  CAS  Google Scholar 

  6. Dunn JM, Phillips RA, Becker AJ, Gallie BL (1988) Identification of germline and somatic mutations affecting the retinoblastoma gene. Science 241:1797–1800

    Article  PubMed  CAS  Google Scholar 

  7. Friend SH, Bernards R, Rogelj S, Weinberg RA, Rapaport JM, Albert DM, Dryja TP (1986) A human DNA segment with properties of the gene that predisposes to retinoblastoma and osteosarcoma. Nature 323:643–646

    Article  PubMed  CAS  Google Scholar 

  8. Corson TW, Gallie BL (2007) One hit, two hits, three hits, more? Genomic changes in the development of retinoblastoma. Genes Chromosomes Cancer 46:617–634

    Article  PubMed  CAS  Google Scholar 

  9. Dimaras H, Khetan V, Halliday W, Orlic M, Prigoda NL, Piovesan B, Marrano P, Corson TW, Eagle RC Jr, Squire JA, Gallie BL (2008) Loss of RB1 induces non-proliferative retinoma; increasing genomic instability correlates with progression to retinoblastoma. Hum Mol Genet 17(10): 1363–1372

    Article  PubMed  CAS  Google Scholar 

  10. Abramson DH, Gombos DS (1996) The topography of bilateral retinoblastoma lesions. Retina 16:232–239

    Article  PubMed  CAS  Google Scholar 

  11. Balmer A, Munier F, Gailloud C (1991) Retinoma. Case studies. Ophthalmic Paediatr Genet 12:131–137

    Article  PubMed  CAS  Google Scholar 

  12. Singh AD, Santos CM, Shields CL, Shields JA, Eagle RC Jr (2000) Observations on 17 patients with retinocytoma. Arch Ophthalmol 118:199–205

    Article  PubMed  CAS  Google Scholar 

  13. Flexner S (1891) A peculiar glioma (neuroepithelioma?) of the retina. Bull Johns Hopkins Hosp Balt 2:115–119

    Google Scholar 

  14. Ts’o MO, Zimmerman LE, Fine BS (1970) The nature of retinoblastoma. I. Photoreceptor differentiation: a clinical and histopathologic study. Am J Ophthalmol 69:339–349

    PubMed  Google Scholar 

  15. Gonzalez-Fernandez F, Lopes MB, Garcia-Fernandez JM, Foster RG, De Grip WJ, Rosemberg S, Newman SA, VandenBerg SR (1992) Expression of developmentally defined retinal phenotypes in the histogenesis of retinoblastoma. Am J Pathol 141:363–375

    PubMed  CAS  Google Scholar 

  16. Nork TM, Schwartz TL, Doshi HM, Millecchia LL (1995) Retinoblastoma. Cell of origin. Arch Ophthalmol 113:791–802

    Article  PubMed  CAS  Google Scholar 

  17. Rodrigues MM, Rajagopalan S, Lee L, Nair CN, Advani SH, Donoso L, Chader GJ, Wiggert B (1992) Retinoblastoma: messenger RNA for interphotoreceptor retinoid binding protein. Curr Eye Res 11:425–433

    Article  PubMed  CAS  Google Scholar 

  18. Bogenmann E, Lochrie MA, Simon MI (1988) Cone cell-specific genes expressed in retinoblastoma. Science 240:76–78

    Article  PubMed  CAS  Google Scholar 

  19. Kyritsis AP, Tsokos M, Triche TJ, Chader GJ (1984) Retinoblastoma—origin from a primitive neuroectodermal cell? Nature 307:471–473

    Article  PubMed  CAS  Google Scholar 

  20. Virtanen I, Kivela T, Bugnoli M, Mencarelli C, Pallini V, Albert DM, Tarkkanen A (1988) Expression of intermediate filaments and synaptophysin show neuronal properties and lack of glial characteristics in Y79 retinoblastoma cells. Lab Invest 59:649–656

    PubMed  CAS  Google Scholar 

  21. Jacks T, Fazeli A, Schmitt EM, Bronson RT, Goodell MA, Weinberg RA (1992) Effects of an Rb mutation in the mouse. Nature 359:295–300

    Article  PubMed  CAS  Google Scholar 

  22. Lee EY, Chang CY, Hu N, Wang YC, Lai CC, Herrup K, Lee WH, Bradley A (1992) Mice deficient for Rb are nonviable and show defects in neurogenesis and haematopoiesis. Nature 359:288–294

    Article  PubMed  CAS  Google Scholar 

  23. Clarke AR, Maandag ER, van Roon M, van der Lugt NM, van der Valk M, Hooper ML, Berns A, te Riele H (1992) Requirement for a functional Rb-1 gene in murine development. Nature 359:328–330

    Article  PubMed  CAS  Google Scholar 

  24. Hu N, Gutsmann A, Herbert DC, Bradley A, Lee WH, Lee EY (1994) Heterozygous Rb-1 delta 20/+mice are predisposed to tumors of the pituitary gland with a nearly complete penetrance. Oncogene 9:1021–1027

    PubMed  CAS  Google Scholar 

  25. Williams BO, Remington L, Albert DM, Mukai S, Bronson RT, Jacks T (1994) Cooperative tumorigenic effects of germline mutations in Rb and p53. Nat Genet 7:480–484

    Article  PubMed  CAS  Google Scholar 

  26. Maandag EC, van der Valk M, Vlaar M, Feltkamp C, O’Brien J, van Roon M, van der Lugt N, Berns A, te Riele H (1994) Developmental rescue of an embryonic-lethal mutation in the retinoblastoma gene in chimeric mice. EMBO J 13:4260–4268

    PubMed  CAS  Google Scholar 

  27. Williams BO, Schmitt EM, Remington L, Bronson RT, Albert DM, Weinberg RA, Jacks T (1994) Extensive contribution of Rb-deficient cells to adult chimeric mice with limited histopathological consequences. EMBO J 13:4251–4259

    PubMed  CAS  Google Scholar 

  28. Classon M, Dyson N (2001) p107 and p130: versatile proteins with interesting pockets. Exp Cell Res 264:135–147

    Article  PubMed  CAS  Google Scholar 

  29. Lee MH, Williams BO, Mulligan G, Mukai S, Bronson RT, Dyson N, Harlow E, Jacks T (1996) Targeted disruption of p107: functional overlap between p107 and Rb. Genes Dev 10:1621–1632

    Article  PubMed  CAS  Google Scholar 

  30. Dannenberg JH, Schuijff L, Dekker M, van der Valk M, te Riele H (2004) Tissue-specific tumor suppressor activity of retinoblastoma gene homologs p107 and p130. Genes Dev 18:2952–2962

    Article  PubMed  CAS  Google Scholar 

  31. Robanus-Maandag E, Dekker M, van der Valk M, Carrozza ML, Jeanny JC, Dannenberg JH, Berns A, te Riele H (1998) p107 is a suppressor of retinoblastoma development in pRb-deficient mice. Genes Dev 12:1599–1609

    Article  PubMed  CAS  Google Scholar 

  32. Chen D, Livne-bar I, Vanderluit JL, Slack RS, Agochiya M, Bremner R (2004) Cell-specific effects of RB or RB/p107 loss on retinal development implicate an intrinsically death-resistant cell-of-origin in retinoblastoma. Cancer Cell 5:539–551

    Article  PubMed  CAS  Google Scholar 

  33. MacPherson D, Sage J, Kim T, Ho D, McLaughlin ME, Jacks T (2004) Cell type-specific effects of Rb deletion in the murine retina. Genes Dev 18:1681–1694

    Article  PubMed  CAS  Google Scholar 

  34. Zhang J, Schweers B, Dyer MA (2004) The first knockout mouse model of retinoblastoma. Cell Cycle 3:952–959

    PubMed  CAS  Google Scholar 

  35. Zhang J, Gray J, Wu L, Leone G, Rowan S, Cepko CL, Zhu X, Craft CM, Dyer MA (2004) Rb regulates proliferation and rod photoreceptor development in the mouse retina. Nat Genet 36:351–360

    Article  PubMed  Google Scholar 

  36. Chen D, Opavsky R, Pacal M, Tanimoto N, Wenzel P, Seeliger MW, Leone G, Bremner R (2007) Rb-mediated neuronal differentiation through cell-cycle-independent regulation of E2f3a. PLoS Biol 5:e179

    Article  PubMed  Google Scholar 

  37. MacPherson D, Conkrite K, Tam M, Mukai S, Mu D, Jacks T (2007) Murine bilateral retinoblastoma exhibiting rapid-onset, metastatic progression and N-myc gene amplification. EMBO J 26:784–794

    Article  PubMed  CAS  Google Scholar 

  38. Ajioka I, Martins RA, Bayazitov IT, Donovan S, Johnson DA, Frase S, Cicero SA, Boyd K, Zakharenko SS, Dyer MA (2007) Differentiated horizontal interneurons clonally expand to form metastatic retinoblastoma in mice. Cell 131:378–390

    Article  PubMed  CAS  Google Scholar 

  39. Xu XL, Fang Y, Lee TC, Forrest D, Gregory-Evans C, Almeida D, Liu A, Jhanwar SC, Abramson DH, Cobrinik D (2009) Retinoblastoma has properties of a cone precursor tumor and depends upon cone-specific MDM2 signaling. Cell 137:1018–1031

    Article  PubMed  CAS  Google Scholar 

  40. Xu XL, Lee TC, Offor N, Cheng C, Liu A, Fang Y, Jhanwar SC, Abramson DH, Cobrinik D (2010) Tumor-associated retinal astrocytes promote retinoblastoma cell proliferation through production of IGFBP-5. Am J Pathol 177:424–435

    Article  PubMed  CAS  Google Scholar 

  41. Kowalik TF, DeGregori J, Leone G, Jakoi L, Nevins JR (1998) E2F1-specific induction of apoptosis and p53 accumulation, which is blocked by Mdm2. Cell Growth Differ 9:113–118

    PubMed  CAS  Google Scholar 

  42. Lomazzi M, Moroni MC, Jensen MR, Frittoli E, Helin K (2002) Suppression of the p53- or pRB-mediated G1 checkpoint is required for E2F-induced S-phase entry. Nat Genet 31:190–194

    Article  PubMed  CAS  Google Scholar 

  43. Weiss WA, Aldape K, Mohapatra G, Feuerstein BG, Bishop JM (1997) Targeted expression of MYCN causes neuroblastoma in transgenic mice. EMBO J 16:2985–2995

    Article  PubMed  CAS  Google Scholar 

  44. Rangarajan A, Weinberg RA (2003) Opinion: comparative biology of mouse versus human cells: modelling human cancer in mice. Nat Rev Cancer 3:952–959

    Article  PubMed  CAS  Google Scholar 

  45. Demetrius L (2005) Of mice and men. When it comes to studying ageing and the means to slow it down, mice are not just small humans. EMBO Rep 6(S1):S39–S44

    Article  PubMed  CAS  Google Scholar 

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Acknowledgments

The author acknowledges support from the Fund for Ophthalmic Knowledge, the Elsa U. Pardee Foundation, and the NIH (1R01CA137124) during the preparation of this review, and thanks Rod Bremner for critical reading of the manuscript.

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Authors and Affiliations

  1. Department of Pediatrics, Memorial Sloan-Kettering Cancer Center, New York, NY, USA

    David Cobrinik

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  1. David Cobrinik
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Correspondence to David Cobrinik .

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Editors and Affiliations

  1. Instituto Cajal, Molecular, Cellular & Developmental Neur, CSIC, Avda. Doctor Arce 37, Madrid, 28002, Spain

    Ricardo Martínez Murillo

  2. de la Rioja (CIBIR), Oncology Area, Centro de Investigación Biomédica, C/ Piqueras 98, Logroño, 26006, Spain

    Alfredo Martínez

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Cobrinik, D. (2012). Learning About Retinoblastoma from Mouse Models That Missed. In: Martínez Murillo, R., Martínez, A. (eds) Animal Models of Brain Tumors. Neuromethods, vol 77. Humana Press, Totowa, NJ. https://doi.org/10.1007/7657_2011_25

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  • DOI: https://doi.org/10.1007/7657_2011_25

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  • Publisher Name: Humana Press, Totowa, NJ

  • Print ISBN: 978-1-62703-208-7

  • Online ISBN: 978-1-62703-209-4

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