Cellular and Molecular Neurobiology

, Volume 25, Issue 5, pp 795–806 | Cite as

Giant Cells: Contradiction to Two-Hit Model of Tuber Formation?

  • Jaroslaw Jozwiak
  • Sergiusz Jozwiak


  1. 1.

    Tuberous sclerosis (TSC) is an autosomal dominant disease characterized by the formation of hamartomatous lesions in many organs, including brain, heart or kidneys. It has been found that TSC is caused by the mutation in one of two tumor suppressor genes: TSC1 or TSC2, encoding hamartin and tuberin, respectively.

  2. 2.

    According to Knudson’s two-hit model of tumorigenesis, second-hit mutation and resulting loss of heterozygosity (LOH) of a tumor suppressor gene is necessary for tumor formation. In fact, LOH is commonly found in several types of hamartomas formed in the process of tuberous sclerosis, but, interestingly, not in brain lesions, containing characteristic giant cells.

  3. 3.

    In the present paper we review literature covering origination of giant cells and present several hypotheses explaining why in spite of the presence of hamartin and tuberin, brain lesions form in TSC patients.



giant cells loss of heterozygosity SEGA 


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  1. Anderson, A. E., Yang, X., and Young, R. H. (2002). Epithelioid angiomyolipoma of the ovary: A case report and literature review. Int. J. Gynecol. Pathol. 21:69–73.CrossRefPubMedGoogle Scholar
  2. Bender, B. L., and Yunis, E. J. (1980). Central nervous system pathology of tuberous sclerosis in children. Ultrastruct. Pathol. 1:287–299.PubMedGoogle Scholar
  3. Brown, J. P., Couillard-Despres, S., Cooper-Kuhn, C. M., Winkler, J., Aigner, L., and Kuhn, H. G. (2003). Transient expression of doublecortin during adult neurogenesis. J. Comp. Neurol. 467:1–10.CrossRefPubMedGoogle Scholar
  4. Chan, J. A., Zhang, H., Roberts, P. S., Jozwiak, S., Wieslawa, G., Lewin-Kowalik, J., Kotulska, K., and Kwiatkowski, D. J. (2004). Pathogenesis of tuberous sclerosis subependymal giant cell astrocytomas: Biallelic inactivation of TSC1 or TSC2 leads to mTOR activation. J. Neuropathol. Exp. Neurol. 63:1236–1242.PubMedGoogle Scholar
  5. Cheadle, J. P., Reeve, M. P., Sampson, J. R., and Kwiatkowski, D. J. (2000). Molecular genetic advances in tuberous sclerosis. Hum. Genet. 107:97–114.CrossRefPubMedGoogle Scholar
  6. Chou, T. M., and Chou, S. M. (1989). Tuberous sclerosis in the premature infant: A report of a case with immunohistochemistry on the CNS. Clin. Neuropathol. 8:45–52.PubMedGoogle Scholar
  7. Cil, A. P., Haberal, A., Hucumenoglu, S., Kovalak, E. E., and Gunes, M. (2004). Angiomyolipoma of the uterus associated with tuberous sclerosis: Case report and review of the literature. Gynecol. Oncol. 94:593–596.CrossRefPubMedGoogle Scholar
  8. Dabora, S. L., Jozwiak, S., Franz, D. N., Roberts, P. S., Nieto, A., Chung, J., Choy, Y. S., Reeve, M. P., Thiele, E., Egelhoff, J. C., Kasprzyk-Obara, J., Domanska-Pakiela, D., and Kwiatkowski, D. J. (2001). Mutational analysis in a cohort of 224 tuberous sclerosis patients indicates increased severity of TSC2, compared with TSC1, disease in multiple organs. Am. J. Hum. Genet. 68:64–80.CrossRefPubMedGoogle Scholar
  9. European Tuberous Sclerosis Consortium. (1993). Identification and characterization of the tuberous sclerosis gene on chromosome 16. The European Chromosome 16 Tuberous Sclerosis Consortium. Cell75:1305–1315.Google Scholar
  10. Guha, A. (1998). Ras activation in astrocytomas and neurofibromas. Can. J. Neurol. Sci. 25:267–281.PubMedGoogle Scholar
  11. Gyure, K. A., and Prayson, R. A. (1997). Subependymal giant cell astrocytoma: A clinicopathologic study with HMB45 and MIB-1 immunohistochemical analysis. Mod. Pathol. 10:313–317.PubMedGoogle Scholar
  12. Hall, J. G. (1988). Review and hypotheses: Somatic mosaicism: observations related to clinical genetics. Am. J. Hum. Genet. 43:355–363.PubMedGoogle Scholar
  13. Henske, E. P., Scheithauer, B. W., Short, M. P., Wollmann, R., Nahmias, J., Hornigold, N., van Slegtenhorst, M., Welsh, C. T., and Kwiatkowski, D. J. (1996). Allelic loss is frequent in tuberous sclerosis kidney lesions but rare in brain lesions. Am. J. Hum. Genet. 59:400–406.PubMedGoogle Scholar
  14. Henske, E. P., Wessner, L. L., Golden, J., Scheithauer, B. W., Vortmeyer, A. O., Zhuang, Z., Klein-Szanto, A. J., Kwiatkowski, D. J., and Yeung, R. S. (1997). Loss of tuberin in both subependymal giant cell astrocytomas and angiomyolipomas supports a two-hit model for the pathogenesis of tuberous sclerosis tumors. Am. J. Pathol. 151:1639–1647.PubMedGoogle Scholar
  15. Hino, A., Hirokawa, M., Takamura, K., and Sano, T. (2002). Imprint cytology of epithelioid angiomyolipoma in a patient with tuberous sclerosis. A case report. Acta Cytol. 46:545–549.PubMedGoogle Scholar
  16. Hirose, T., Scheithauer, B. W., Lopes, M. B., Gerber, H. A., Altermatt, H. J., Hukee, M. J., VandenBerg, S. R., and Charlesworth, J. C. (1995). Tuber and subependymal giant cell astrocytoma associated with tuberous sclerosis: An immunohistochemical, ultrastructural, and immunoelectron and microscopic study. Acta Neuropathol. (Berl):. 90:387–399.Google Scholar
  17. Inoki, K., Li, Y., Xu, T., and Guan, K. L. (2003). Rheb GTPase is a direct target of TSC2 GAP activity and regulates mTOR signaling. Genes Dev. 17:1829–1834.CrossRefPubMedGoogle Scholar
  18. Jansen, F. E., Notenboom, R. G., Nellist, M., Goedbloed, M. A., Halley, D. J., de Graan, P. N., and van Nieuwenhuizen, O. (2004). Differential localization of hamartin and tuberin and increased S6 phosphorylation in a tuber. Neurology 63:1293–1295.PubMedGoogle Scholar
  19. Jay, V., Edwards, V., and Rutka, J. T. (1993). Crystalline inclusions in a subependymal giant cell tumor in a patient with tuberous sclerosis. Ultrastruct. Pathol. 17:503–513.PubMedGoogle Scholar
  20. Ji, Y., Zhu, X., Xu, J., Zhou, J., Tan, Y., Wang, J., Fan, J., and Zhou, Y. (2001). Hepatic angiomyolipoma: A clinicopathologic study of 10 cases. Chin. Med. J. (Engl).: 114:280–285.Google Scholar
  21. Johnson, M. W., Kerfoot, C., Bushnell, T., Li, M., and Vinters, H. V. (2001). Hamartin and tuberin expression in human tissues. Mod. Pathol. 14:202–210.CrossRefPubMedGoogle Scholar
  22. Jones, A. C., Shyamsundar, M. M., Thomas, M. W., Maynard, J., Idziaszczyk, S., Tomkins, S., Sampson, J. R., and Cheadle, J. P. (1999). Comprehensive mutation analysis of TSC1 and TSC2-and phenotypic correlations in 150 families with tuberous sclerosis. Am. J. Hum. Genet. 64:1305–1315.CrossRefPubMedGoogle Scholar
  23. Jozwiak, S., Dabora, S., Kasprzyk-Obara, J., Domanska-Pakiela, D., and Grajkowska, W. (2001). Tests for loss of heterozygosity in tuberous sclerosis. Przegl. Lek. 58 (Suppl. 1):12–15.PubMedGoogle Scholar
  24. Jozwiak, S., Goodman, M., and Lamm, S. H. (1998). Poor mental development in patients with tuberous sclerosis complex: Clinical risk factors. Arch. Neurol. 55:379–384.CrossRefPubMedGoogle Scholar
  25. Jozwiak, S., Kwiatkowski, D., Kotulska, K., Larysz-Brysz, M., Lewin-Kowalik, J., Grajkowska, W., and Roszkowski, M. (2004). Tuberin and hamartin expression is reduced in the majority of subependymal giant cell astrocytomas in tuberous sclerosis complex consistent with a two-hit model of pathogenesis. J. Child. Neurol. 19:102–106.PubMedGoogle Scholar
  26. Knowles, M. A., Habuchi, T., Kennedy, W., and Cuthbert-Heavens, D. (2003). Mutation spectrum of the 9q34 tuberous sclerosis gene TSC1 in transitional cell carcinoma of the bladder. Cancer Res. 63:7652–7656.PubMedGoogle Scholar
  27. Knudson, A. G. (1971). Mutation and cancer: Statistical study of retinoblastoma. Proc. Natl. Acad. Sci. U.S.A. 68:820–823.PubMedGoogle Scholar
  28. Kwiatkowska, J., Wigowska-Sowinska, J., Napierala, D., Slomski, R., and Kwiatkowski, D. J. (1999). Mosaicism in tuberous sclerosis as a potential cause of the failure of molecular diagnosis. N. Engl. J. Med. 340:703–707.CrossRefPubMedGoogle Scholar
  29. Kwiatkowski, D. J. (2003). Tuberous sclerosis: From tubers to mTOR. Ann. Hum. Genet. 67:87–96.CrossRefPubMedGoogle Scholar
  30. Laeng, R. H., Scheithauer, B. W., and Altermatt, H. J. (1998). Anti-neuronal nuclear autoantibodies, types 1 and 2: Their utility in the study of tumors of the nervous system. Acta Neuropathol. (Berl).: 96:329–339.CrossRefGoogle Scholar
  31. Lamb, R. F., Roy, C., Diefenbach, T. J., Vinters, H. V., Johnson, M. W., Jay, D. G., and Hall, A. (2000). The TSC1 tumour suppressor hamartin regulates cell adhesion through ERM proteins and the GTPase Rho. Nat. Cell Biol. 2:281–287.CrossRefPubMedGoogle Scholar
  32. Lantuejoul, S., Ferretti, G., Negoescu, A., Parent, B., and Brambilla, E. (1997). Multifocal alveolar hyperplasia associated with lymphangioleiomyomatosis in tuberous sclerosis. Histopathology. 30:570–575.CrossRefPubMedGoogle Scholar
  33. Lee, A., Maldonado, M., Baybis, M., Walsh, C. A., Scheithauer, B., Yeung, R., Parent, J., Weiner, H. L., and Crino, P. B. (2003). Markers of cellular proliferation are expressed in cortical tubers. Ann Neurol. 53:668–673.CrossRefPubMedGoogle Scholar
  34. Lee, L., Sudentas, P., Donohue, B., Asrican, K., Worku, A., Walker, V., Sun, Y., Schmidt, K., Albert, M. S., El-Hashemite, N., Lader, A. S., Onda, H., Zhang, H., Kwiatkowski, D. J., and Dabora, S. L. (2005). Efficacy of a rapamycin analog (CCI-779) and IFN-gamma in tuberous sclerosis mouse models. Genes Chromosomes Cancer 42:213–227.CrossRefPubMedGoogle Scholar
  35. Menchine, M., Emelin, J. K., Mischel, P. S., Haag, T. A., Norman, M. G., Pepkowitz, S. H., Welsh, C. T., Townsend, J. J., and Vinters, H. V. (1996). Tissue and cell-type specific expression of the tuberous sclerosis gene, TSC2, in human tissues. Mod. Pathol. 9:1071–1080.PubMedGoogle Scholar
  36. Meikle, L., McMullen, J. R., Sherwood, M. C., Lader, A. S., Walker, V., Chan, J. A., and Kwiatkowski, D. J. (2005). A mouse model of cardiac rhabdomyoma generated by loss of TSC1 in ventricular myocytes. Hum. Mol. Genet. 14:429–435.CrossRefPubMedGoogle Scholar
  37. Mizuguchi, M., Mori, M., Nozaki, Y., Momoi, M. Y., Itoh, M., Takashima, S., and Hino, O. (2004). Absence of allelic loss in cytomegalic neurons of cortical tuber in the Eker rat model of tuberous sclerosis. Acta Neuropathol. (Berl).:107:47–52.CrossRefGoogle Scholar
  38. Mizuguchi, M., and Takashima, S. (2001). Neuropathology of tuberous sclerosis. Brain Dev. 23:508–515.CrossRefPubMedGoogle Scholar
  39. Mizuguchi, M., Yamanouchi, H., Becker, L. E., Itoh, M., and Takashima, S. (2002). Doublecortin immunoreactivity in giant cells of tuberous sclerosis and focal cortical dysplasia. Acta Neuropathol. (Berl).:104:418–424.Google Scholar
  40. Niida, Y., Stemmer-Rachamimov, A. O., Logrip, M., Tapon, D., Perez, R., Kwiatkowski, D. J., Sims, K., MacCollin, M., Louis, D. N., and Ramesh, V. (2001). Survey of somatic mutations in tuberous sclerosis complex (TSC) hamartomas suggests different genetic mechanisms for pathogenesis of TSC lesions. Am. J. Hum. Genet. 69:493–503.CrossRefPubMedGoogle Scholar
  41. Onda, H., Crino, P. B., Zhang, H., Murphey, R. D., Rastelli, L., Gould Rothberg, B. E., and Kwiatkowski, D. J. (2002). TSC2 null murine neuroepithelial cells are a model for human tuber giant cells, and show activation of an mTOR pathway. Mol. Cell Neurosci. 21:561–574.CrossRefPubMedGoogle Scholar
  42. Park, S. H., Pepkowitz, S. H., Kerfoot, C., De Rosa, M. J., Poukens, V., Wienecke, R., DeClue, J. E., and Vinters, H. V. (1997). Tuberous sclerosis in a 20-week gestation fetus: Immunohistochemical study. Acta Neuropathol. (Berl).: 94:180–186.CrossRefGoogle Scholar
  43. Plank, T. L., Logginidou, H., Klein-Szanto, A., and Henske, E. P. (1999). The expression of hamartin, the product of the TSC1 gene, in normal human tissues and in TSC1 and TSC2-linked angiomyolipomas. Mod. Pathol. 12:539–545.PubMedGoogle Scholar
  44. Povey, S., Burley, M. W., Attwood, J., Benham, F., Hunt, D., Jeremiah, S. J., Franklin, D., Gillett, G., Malas, S., Robson, E. B., Tippett, P., Edwards, J. H., Kwiatkowski, D. J., Super, M., Mueller, R., Fryer, A., Clarke, A., Webb, D., and Osborne, J. (1994). Two loci for tuberous sclerosis: One on 9q34 and one on 16p13. Ann. Hum. Genet. 58:107–127.PubMedGoogle Scholar
  45. Ramesh, V. (2003). Aspects of tuberous sclerosis complex (TSC) protein function in the brain. Biochem. Soc. Trans. 31:579–583.CrossRefPubMedGoogle Scholar
  46. Ribalta, T., Lloreta, J., Munne, A., Serrano, S., and Cardesa, A. (2000). Malignant pigmented clear cell epithelioid tumor of the kidney: Clear cell (“sugar”) tumor versus malignant melanoma. Hum. Pathol. 31:516–519.CrossRefPubMedGoogle Scholar
  47. Roberts, P. S., Ramesh, V., Dabora, S., Kwiatkowski, D. J. (2003). A 34 bp deletion within TSC2 is a rare polymorphism, not a pathogenic mutation. Ann. Hum. Genet. 67:495–503.CrossRefPubMedGoogle Scholar
  48. Roske, B., Stoltenburg, G., Baier, P. M., Konig, R., and Schlote, W. (2003). Tuberous sclerosis complex with disseminated telencephalic distribution of atypical cells and their relation to corticogenesis. Clin. Neuropathol. 22:119–128.PubMedGoogle Scholar
  49. Roszkowski, M., Drabik, K., Barszcz, S., and Jozwiak, S. (1995). Surgical treatment of intraventricular tumors associated with tuberous sclerosis. Childs Nerv. Syst. 11:335–339.CrossRefPubMedGoogle Scholar
  50. Roux, P. P., Ballif, B. A., Anjum, R., Gygi, S. P., and Blenis, J. (2004). Tumor-promoting phorbol esters and activated Ras inactivate the tuberous sclerosis tumor suppressor complex via p90 ribosomal S6 kinase. Proc. Natl. Acad. Sci. U.S.A. 101:13489–13494.CrossRefPubMedGoogle Scholar
  51. Sampson, J. R., Maheshwar, M. M., Aspinwall, R., Thompson, P., Cheadle, J. P., Ravine, D., Roy, S., Haan, E., Bernstein, J., and Harris, P. C. (1997). Renal cystic disease in tuberous sclerosis: Role of the polycystic kidney disease 1 gene. Am. J. Hum. Genet. 61:843–851.PubMedGoogle Scholar
  52. Sharma, M. C., Ralte, A. M., Gaekwad, S., Santosh, V., Shankar, S. K., and Sarkar, C. (2004). Subependymal giant cell astrocytoma-a clinicopathological study of 23 cases with special emphasis on histogenesis. Pathol. Oncol. Res. 10:219–224.PubMedGoogle Scholar
  53. van Slegtenhorst, M., de Hoogt, R., Hermans, C., Nellist, M., Janssen, B., Verhoef, S., Lindhout, D., van den Ouweland, A., Halley, D., Young, J., Burley, M., Jeremiah, S., Woodward, K., Nahmias, J., Fox, M., Ekong, R., Osborne, J., Wolfe, J., Povey, S., Snell, R. G., Cheadle, J. P., Jones, A. C., Tachataki, M., Ravine, D., Sampson, J. R., Reeve, M. P., Richardson, P., Wilmer, F., Munro, C., Hawkins, T. L., Sepp, T., Ali, J. B. M., Ward, S., Green, A. J., Yates, J. R. W., Kwiatkowska, J., Henske, E. P., Short, M. P., Haines, J. H., Jozwiak, S., and Kwiatkowski, D. J. (1997). Identification of the tuberous sclerosis gene TSC1 on chromosome 9q34. Science. 277:805–808.CrossRefPubMedGoogle Scholar
  54. Soucek, T., Pusch, O., Wienecke, R., DeClue, J. E., and Hengstschlager, M. (1997). Role of the tuberous sclerosis gene-2 product in cell cycle control. Loss of the tuberous sclerosis gene-2 induces quiescent cells to enter S phase. J. Biol. Chem. 272:29301–29308.CrossRefPubMedGoogle Scholar
  55. Takahashi, D. K., Dinday, M. T., Barbaro, N. M., and Baraban, S. C. (2004). Abnormal cortical cells and astrocytomas in the Eker rat model of tuberous sclerosis complex. Epilepsia. 45:1525–1530.CrossRefPubMedGoogle Scholar
  56. Telfeian, A. E., Judkins, A., Younkin, D., Pollock, A. N., and Crino, P. (2004). Subependymal giant cell astrocytoma with cranial and spinal metastases in a patient with tuberous sclerosis. Case report. J. Neurosurg. Spine. 100:498–500.Google Scholar
  57. Trombley, I. K., and Mirra, S. S. (1981). Ultrastructure of tuberous sclerosis: Cortical tuber and subependymal tumor. Ann. Neurol. 9:174–181.CrossRefPubMedGoogle Scholar
  58. Uhlmann, E. J., Apicelli, A. J., Baldwin, R. L., Burke, S. P., Bajenaru, M. L., Onda, H., Kwiatkowski, D., and Gutmann, D. H. (2002). Heterozygosity for the tuberous sclerosis complex (TSC) gene products results in increased astrocyte numbers and decreased p27-Kip1 expression in TSC2+/- cells. Oncogene 21:4050–4059.CrossRefPubMedGoogle Scholar
  59. Verhoef, S., Bakker, L., Tempelaars, A. M., Hesseling-Janssen, A. L., Mazurczak, T., Jozwiak, S., Fois, A., Bartalini, G., Zonnenberg, B. A., van Essen, A. J., Lindhout, D., Halley, D. J., and van den Ouweland, A. M. (1999). High rate of mosaicism in tuberous sclerosis complex. Am. J. Hum. Genet. 64:1632–1637.CrossRefPubMedGoogle Scholar
  60. Weeks, D. A., Chase, D. R., and Malott, R. L. (1994). HMB-45 staining in angiomyolipoma, cardiac rhabdomyoma, other mesenchymal processes and tuberous sclerosis associated brain lesions. Int. J. Surg. Pathol. 1:191–198.Google Scholar
  61. Wienecke, R., Konig, A., and DeClue, J. E. (1995). Identification of tuberin, the tuberous sclerosis-2 product. Tuberin possesses specific Rap1GAP activity. J. Biol. Chem. 270:16409–16414.CrossRefPubMedGoogle Scholar
  62. Wilson, P. J., Ramesh, V., Kristiansen, A., Bove, C., Jozwiak, S., Kwiatkowski, D. J., Short, M. P., and Haines, J. L. (1996). Novel mutations detected in the TSC2 gene from both sporadic and familial TSC patients. Hum. Mol. Genet. 5:249–256.CrossRefPubMedGoogle Scholar
  63. Wolf, H. K., Normann, S., Green, A. J., von Bakel, I., Blumcke, I., Pietsch, T., Wiestler, O. D., and von Deimling, A. (1997). Tuberous sclerosis-like lesions in epileptogenic human neocortex lack allelic loss at the TSC1 and TSC2 regions. Acta Neuropathol. (Berl).: 93:93–96.CrossRefGoogle Scholar
  64. Xiao, G. H., Shoarinejad, F., Jin, F., Golemis, E. A., and Yeung, R. S. (1997). The tuberous sclerosis 2 gene product, tuberin, functions as a Rab5 GTPase activating protein (GAP) in modulating endocytosis. J. Biol. Chem. 272:6097–6100.CrossRefPubMedGoogle Scholar
  65. Yagishita, A., and Arai N. (1999). Cortical tubers without other stigmata of tuberous sclerosis: imaging and pathological findings. Neuroradiology 41:428–432.CrossRefPubMedGoogle Scholar
  66. Yamanouchi, H., Jay, V., Rutka, J. T., Takashima, S., and Becker, L. E. (1997). Evidence of abnormal differentiation in giant cells of tuberous sclerosis. Pediatr. Neurol. 17:49–53.CrossRefPubMedGoogle Scholar
  67. Zhang, Y., Gao, X., Saucedo, L. J., Ru, B., Edgar, B. A., and Pan, D. (2003). Rheb is a direct target of the tuberous sclerosis tumour suppressor proteins. Nat. Cell Biol. 5:578–581.CrossRefPubMedGoogle Scholar

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© Springer Science + Business Media, Inc. 2005

Authors and Affiliations

  1. 1.Department of Histology and Embryology, Center for Biostructure ResearchMedical University of WarsawWarsawPoland
  2. 2.Department of Pediatric NeurologyChildren’s Memorial HospitalWarsawPoland
  3. 3.To whom correspondence should be addressed at Department of Histology and Embryology, Center for Biostructure ResearchMedical University of WarsawWarsawPoland

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