Skip to main content

Advertisement

SpringerLink
Log in

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

  • Published:
Cellular and Molecular Neurobiology Aims and scope Submit manuscript

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 the two tumor suppressor genes: TSC1 or TSC2, encoding hamartin and tuberin, respectively. 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. In this 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.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Similar content being viewed by others

REFERENCES

  • Anderson, A. E., Yang, X., Young, R. H. (2002). Epithelioid angiomyolipoma of the ovary: A case report and literature review. Int. J. Gynecol. Pathol. 21:69–73.

    Article  PubMed  Google Scholar 

  • Bender, B. L., and Yunis, E. J. (1980). Central nervous system pathology of tuberous sclerosis in children. Ultrastruct. Pathol. 1:287–299.

    PubMed  CAS  Google Scholar 

  • 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.

    Article  PubMed  CAS  Google Scholar 

  • 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.

    PubMed  CAS  Google Scholar 

  • 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.

    Article  PubMed  CAS  Google Scholar 

  • 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.

    PubMed  CAS  Google Scholar 

  • 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.

    Article  PubMed  Google Scholar 

  • 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., 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.

    Article  PubMed  CAS  Google Scholar 

  • European Tuberous Sclerosis Consortium (1993). Identification and characterization of the tuberous sclerosis gene on chromosome 16. The European Chromosome 16 Tuberous Sclerosis Consortium. Cell 75:1305–1315.

    Google Scholar 

  • Guha, A. (1998). Ras activation in astrocytomas and neurofibromas. Can. J. Neurol. Sci. 25:267–281.

    PubMed  CAS  Google Scholar 

  • 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.

    PubMed  CAS  Google Scholar 

  • Hall, J. G. (1988). Review and hypotheses: Somatic mosaicism: Observations related to clinical genetics. Am. J. Hum. Genet. 43:355–363.

    PubMed  CAS  Google Scholar 

  • 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.

    PubMed  CAS  Google Scholar 

  • 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.

    PubMed  CAS  Google Scholar 

  • 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.

    PubMed  Google Scholar 

  • 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.

    CAS  Google Scholar 

  • 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.

    Article  PubMed  CAS  Google Scholar 

  • 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.

    PubMed  CAS  Google Scholar 

  • 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.

    Article  PubMed  CAS  Google Scholar 

  • 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.

    CAS  Google Scholar 

  • 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.

    Article  PubMed  CAS  Google Scholar 

  • 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.

    Article  PubMed  CAS  Google Scholar 

  • 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.

    PubMed  Google Scholar 

  • 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.

    Article  PubMed  CAS  Google Scholar 

  • 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.

    PubMed  Google Scholar 

  • 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.

    PubMed  CAS  Google Scholar 

  • Knudson, A. G. (1971). Mutation and cancer: Statistical study of retinoblastoma. Proc. Natl. Acad. Sci. U. S. A. 68:820–823.

    Article  PubMed  Google Scholar 

  • 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.

    Article  PubMed  CAS  Google Scholar 

  • Kwiatkowski, D. J. (2003). Tuberous sclerosis: From tubers to mTOR. Ann. Hum. Genet. 67:87–96.

    Article  PubMed  CAS  Google Scholar 

  • 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.

    Article  CAS  Google Scholar 

  • 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.

    Article  PubMed  CAS  Google Scholar 

  • 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.

    Article  PubMed  CAS  Google Scholar 

  • 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.

    Article  PubMed  CAS  Google Scholar 

  • 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.

    Article  PubMed  CAS  Google Scholar 

  • 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.

    PubMed  CAS  Google Scholar 

  • 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.

    Article  PubMed  CAS  Google Scholar 

  • 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.

    Article  Google Scholar 

  • Mizuguchi, M., and Takashima, S. (2001). Neuropathology of tuberous sclerosis. Brain Dev. 23:508–515.

    Article  PubMed  CAS  Google Scholar 

  • 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.

    CAS  Google Scholar 

  • 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.

    Article  PubMed  CAS  Google Scholar 

  • Onda, H., Crino, P. B., Zhang, H., Murphey, R. D., Rastelli, L., and Gould Rothberg, B. E., 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.

    Article  PubMed  CAS  Google Scholar 

  • 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.

    Article  CAS  Google Scholar 

  • 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.

    PubMed  CAS  Google Scholar 

  • 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.

    PubMed  CAS  Google Scholar 

  • Ramesh, V. (2003). Aspects of tuberous sclerosis complex (TSC) protein function in the brain. Biochem. Soc. Trans. 31:579–583.

    Article  PubMed  CAS  Google Scholar 

  • 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.

    Article  PubMed  CAS  Google Scholar 

  • Roberts, P. S., Ramesh, V., Dabora, S., and Kwiatkowski, D. J. (2003). A 34 bp deletion within TSC2 is a rare polymorphism, not a pathogenic mutation. Ann. Hum. Genet. 67:495–503.

    Article  PubMed  CAS  Google Scholar 

  • 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.

    PubMed  CAS  Google Scholar 

  • 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.

    Article  PubMed  CAS  Google Scholar 

  • 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.

    Article  PubMed  CAS  Google Scholar 

  • 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.

    PubMed  CAS  Google Scholar 

  • 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.

    Article  PubMed  Google Scholar 

  • 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.

    Article  PubMed  CAS  Google Scholar 

  • 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.

    Article  PubMed  CAS  Google Scholar 

  • 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.

    Article  PubMed  Google Scholar 

  • 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 

  • Trombley, I. K., and Mirra, S. S. (1981). Ultrastructure of tuberous sclerosis: Cortical tuber and subependymal tumor. Ann. Neurol. 9:174–181.

    Article  PubMed  CAS  Google Scholar 

  • 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.

    Article  PubMed  CAS  Google Scholar 

  • 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.

    Article  PubMed  CAS  Google Scholar 

  • 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 

  • 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.

    Article  PubMed  CAS  Google Scholar 

  • 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.

    Article  PubMed  CAS  Google Scholar 

  • 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.

    Article  CAS  Google Scholar 

  • 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.

    Article  PubMed  CAS  Google Scholar 

  • Yagishita, A., and Arai, N. (1999). Cortical tubers without other stigmata of tuberous sclerosis: Imaging and pathological findings. Neuroradiology 41:428–432.

    Article  PubMed  CAS  Google Scholar 

  • 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.

    Article  PubMed  CAS  Google Scholar 

  • 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.

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Histology and Embryology, Center for Biostructure Research, Medical University of Warsaw ul., Chalubinskiego, 502-004, Warsaw, Poland

    Jaroslaw Jozwiak

  2. Department of Pediatric Neurology, Children’s Memorial Hospital, Warsaw, Poland

    Sergiusz Jozwiak

Authors
  1. Jaroslaw Jozwiak
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Sergiusz Jozwiak
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Jaroslaw Jozwiak.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Jozwiak, J., Jozwiak, S. Giant Cells: Contradiction to Two-Hit Model of Tuber Formation?. Cell Mol Neurobiol 27, 251–261 (2007). https://doi.org/10.1007/s10571-006-9106-0

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10571-006-9106-0

KEY WORDS:

Search

Navigation