Oral Oncology
Volume 46, Issue 1 , Pages 19-24 , January 2010

Biological pathways involved in the aggressive behavior of the keratocystic odontogenic tumor and possible implications for molecular oriented treatment – An overview

  • Rui Amaral Mendes

      Affiliations

    • Department of Oral Surgery, Faculty of Dental Medicine, University of Porto, Porto, Portugal
    • Instituto Superior de Ciências da Saúde – Norte, Porto, Portugal
    • Corresponding Author InformationCorresponding author. Address: Rua Garcia de Resende, 238 – 3° Esq. Frt., 4400-163 Vila Nova de Gaia, Portugal. Tel: +351 93 2805962.
    • ,
  • João FC Carvalho

      Affiliations

    • Department of Oral Surgery, Faculty of Dental Medicine, University of Porto, Porto, Portugal
    • ,
  • Isaac van der Waal

      Affiliations

    • Head, Department of Oral and Maxillofacial Surgery/Oral Pathology, VU University Medical Center/ACTA, Amsterdam, The Netherlands

Received 28 September 2009 ,Revised 26 October 2009 ,Accepted 26 October 2009.

References 

  1. Philipsen HP. Om keratocystedr (Kolesteratomer) and kaeberne. Tandlaegebladet. 1956;60:963–971
  2. Barnes L, Eveson JW, Reichart P, et al., editors. World health organization classification of tumors. Pathology and genetics of head and neck tumors. Lyon: IARC Press; 2005.
  3. Shear M, Speight PM, editors. Cysts of the oral and maxillofacial regions. 4th ed. Oxford: Blackwell Munksgaard; 2007.
  4. Agaram NP, Collins BM, Barnes L, Lomago D, Aldeeb D, Swalsky P, et al. Molecular analysis to demonstrate that odontogenic keratocysts are neoplastic. Arch Pathol Lab Med. 2004;128:313–317
  5. Kolár Z, Geierová M, Bouchal J, Pazdera J, Zboril V, Tvrdý P. Immunohistochemical analysis of the biological potential of odontogenic keratocysts. J Oral Pathol Med. 2006;35:75–80
  6. Regezi JA. Odontogenic cysts, odontogenic tumors, fibroosseous, and giant cell lesions of the jaws. Mod Pathol. 2002;15:331–341
  7. Makowski GJ, McGuff S, Van Sickels JE. Squamous cell carcinoma in a maxillary odontogenic keratocyst. J Oral Maxillofac Surg. 2001;59:76–80
  8. Anand VK, Arrowood JP, Krolls SO. Malignant potential of the odontogenic keratocyst. Otolaryngol Head Neck Surg. 1994;111:124–129
  9. Shear M. The aggressive nature of the odontogenic keratocyst: is it a benign cystic neoplasm? Part 1. Clinical and early experimental evidence of aggressive behaviour. Oral Oncol. 2002;38:219–226
  10. Madras J, Lapointe H. Keratocystic odontogenic tumour: reclassification of the odontogenic keratocyst from cyst to tumour. J Can Dent Assoc. 2008;74:165–165h.
  11. Meara JG, Shah S, Li KK, Cunningham MJ. The odontogenic keratocyst: a 20-year clinicopathologic review. Laryngoscope. 1998;108:280–283
  12. Kuroyanagi N, Sakuma H, Miyabe S, Machida J, Kaetsu A, Yokoi M, et al. Prognostic factors for keratocystic odontogenic tumor (odontogenic keratocyst): analysis of clinico-pathologic and immunohistochemical findings in cysts treated by enucleation. J Oral Pathol Med. 2009;38:386–392
  13. Shear M. The aggressive nature of the odontogenic keratocyst: is it a benign cystic neoplasm? Part 2: proliferation and genetic studies. Oral Oncol. 2002;38:323–331
  14. Myoung H, Hong SP, Hong SD, et al. Odontogenic keratocyst: review of 256 cases for recurrence and clinicopathologic parameters. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 2001;91:328–333
  15. Stoelinga PJ. Long-term follow-up on keratocysts treated according to a defined protocol. Int J Oral Maxillofac Surg. 2001;30:14–25
  16. Kubota Y, Oka S, Nakagawa S, Shirasuna K. Interleukin-1alpha enhances type I collagen-induced activation of matrix metalloproteinase-2 in odontogenic keratocyst fibroblasts. J Dent Res. 2002;81:23–27
  17. Oliveira MD, Souza LB, Pinto LP, Freitas RA. Immunohistochemical study of components of the basement membrane in odontogenic cysts. Pesqui Odontol Bras. 2002;16:157–162
  18. de Paula AM, Carvalhais JN, Domingues MG, Barreto DC, Mesquita RA. Cell proliferation markers in the odontogenic keratocyst: effect of inflammation. J Oral Pathol Med. 2000;29:477–482
  19. Piattelli A, Fioroni M, Santinelli A, Rubini C. P53 protein expression in odontogenic cysts. J Endod. 2001;27:459–461
  20. Vogelstein B, Fearon ER, Hamilton SR, et al. Genetic alterations during colorectal-tumor development. N Engl J Med. 1988;319:525–532
  21. Fearon ER, Vogelstein B. A genetic model for colorectal tumorigenesis. Cell. 1990;61:759–767
  22. Liotta LA, Stetler-Stevenson WG. Tumor invasion and metastasis: an imbalance of positive and negative regulation. Cancer Res. 1991;51:5054s–5059s
  23. Stetler-Stevenson WG, Aznavoorian S, Liotta LA. Tumor cell interactions with the extracellular matrix during invasion and metastasis. Annu Rev Cell Biol. 1993;9:541–573
  24. Tucker AS, Sharpe PT. Molecular genetics of tooth morphogenesis and patterning: the right shape in the right place. J Dent Res. 1999;78:826–834
  25. Jernvall J, Thesleff I. Reiterative signaling and patterning during mammalian tooth morphogenesis. Mech Dev. 2000;92:19–29
  26. Stass SA, Mixson J. Oncogenes and tumor suppressor genes: therapeutic implications. Clin Cancer Res. 1997;3:2687–2695
  27. Weinberg RA. Tumor suppressor genes. Science. 1991;254:1138–1146
  28. Knudson AG. Antioncogenes and human cancer. Proc Natl Acad Sci USA. 1993;90:10914–10921
  29. Knudson AG. Mutation and cancer: statistical study of retinoblastoma. Proc Natl Acad Sci USA. 1971;68:820–823
  30. Barreto DC, Bale AE, De Marco L, Gomez RS. Immunolocalization of PTCH protein in odontogenic cysts and tumors. J Dent Res. 2002;81:757–760
  31. Kumamoto H, Ohki K, Ooya K. Expression of Sonic Hedgehog (SHH) signaling molecules in ameloblastomas. J Oral Pathol Med. 2004;33:185–190
  32. Kumamoto H. Molecular pathology of odontogenic tumors. J Oral Pathol Med. 2006;35:65–74
  33. Zhang YD, Chen Z, Song YQ, Liu C, Chen YP. Making a tooth: growth factors, transcription factors, and stem cells. Cell Res. 2005;15:301–316
  34. Ingham PW, Taylor AM, Nakano Y. Role of the drosophila patched gene in positional signalling. Nature. 1991;353:184–187
  35. Hardcastle Z, Hui CC, Sharpe PT. The SHH signalling pathway in early tooth development. Cell Mol Biol. 1999;45:567–568
  36. Dassule HR, Lewis P, Bei M, Maas R, McMahon AP. Sonic Hedgehog regulates growth and morphogenesis of the tooth. Development. 2000;127:4775–4785
  37. Cobourne MT, Miletich I, Sharpe PT. Restriction of Sonic Hedgehog signalling during early tooth development. Development. 2004;131:2875–2885
  38. McMahon AP. More surprises in the Hedgehog signalling pathway. Cell. 2000;100:185–188
  39. Ingham PW. McMahon AP: Hedgehog signalling in animal development: paradigms and principles. Genes Dev. 2001;12:3059–3087
  40. Thayer SP, di Magliano MP, Heiser PW, Nielsen CM, Roberts GY, Lauwers GY, et al. Hedgehog is an early and late mediator of pancreatic cancer tumorigenesis. Nature. 2003;425:851–856
  41. Nishimaki H, Kasai K, Kozaki K, Takeo T, Ikeda H, Saga S, et al. Role of activated Sonic Hedgehog signaling for the cellular proliferation of oral squamous cell carcinoma cell line. Biochem Biophys Res Commun. 2004;314:313–320
  42. Barnes EA, Heidtman KJ, Donoghue DJ. Constitutive activation of the shh–ptc1 pathway by a patched1 mutation identified in BCC. Oncogene. 2005;24:902–915
  43. Thievessen I, Wolter M, Prior A, Seifert HH, Schulz WA. Hedgehog signaling in normal urothelial cells and in urothelial carcinoma cell lines. J Cell Physiol. 2005;203:372–377
  44. Levanat S, Musani V, Komar A, Oreskovic S. Role of the Hedgehog/patched signaling pathway in oncogenesis: a new polymorphism in the PTCH gene in ovarian fibroma. Ann NY Acad Sci. 2004;1030:134–143
  45. Oniscu A, James RM, Morris RG, Bader S, Malcomson RD, Harrison DJ. Expression of Sonic Hedgehog pathway genes is altered in colonic neoplasia. J Pathol. 2004;203:909–917
  46. Shiotani A, Iishi H, Uedo N, Ishiguro S, Tatsuta M, Nakae Y, et al. Evidence that loss of Sonic Hedgehog is an indicator of helicobater pylori-induced atrophic gastritis progressing to gastric cancer. Am J Gastroenterol. 2005;100:581–587
  47. Sanchez P, Hernandez AM, Stecca B, Kahler AJ, DeGueme A, Barrett A, et al. Inhibition of prostate cancer proliferation by interference with Sonic Hedgehog-GLI1 signaling. Proc Natl Acad Sci USA. 2004;101:12561–12566
  48. Cengel KA. Targeting Sonic Hedgehog: a new way to move down pancreatic cancer?. Cancer Biol Ther. 2004;3:165–166
  49. Ohki K, Kumamoto H, Ichinohasama R, Sato T, Takahashi N, Ooya K, et al. PTC, SMO and GLI-1 in odontogenic keratocysts. Int J Oral Maxillofac Surg. 2004;33:584–592
  50. Yagyuu T, Kirita T, Sasahira T, Moriwaka Y, Yamamoto K, Kuniyasu H. Recurrence of keratocystic odontogenic tumor: clinicopathological features and immunohistochemical study of the Hedgehog signaling pathway. Pathobiology. 2008;75:171–176
  51. Farndon PA, Del Mastro RG, Evans DG, Kilpatrick MW. Location of gene for Gorlin syndrome. Lancet. 1992;339:581–582
  52. Lench NJ, High AS, Markham AF, Hume WJ, Robinson PA. Investigation of chromosome 9q22.3-q31 DNA marker loss in odontogenic keratocysts. Eur J Cancer B Oral Oncol. 1996;32B:202–206
  53. Lench NJ, Telford EA, High AS, Markham AF, Wicking C, Wainwright BJ. Characterization of human patched germ line mutations in nevoid basal cell carcinoma syndrome. Hum Genet. 1997;100:497–502
  54. Barreto DC, Gomez RS, Bale AE, Boson WL, De Marco L. PTCH gene mutation in odontogenic keratocysts. J Dent Res. 2000;79:1418–1422
  55. Reis A, Kuster W, Linss G, Gebel E, Hamm H, Fuhrmann W, et al. Localisation of gene for naevoid basal cell carcinoma syndrome. Lancet. 1992;339:617
  56. Levanat S, Gorlin RJ, Fallet S, Johnson DR, Fantasia JE, Bale AE. A two-hit model for developmental defects in Gorlin syndrome. Nat Genet. 1996;12:85–87
  57. Lo Muzio L, Staibanot S, Pannone G, et al. Expression of cell cycle and apoptosis-related proteins in sporadic odontogenic keratocysts and odontogenic keratocysts associated with the nevoid basal cell carcinoma syndrome. J Dent Res. 1999;78:1345–1353
  58. Yamamoto K, Yoshihashi H, Furuya N, Adachi M, Ito S, Tanaka Y, et al. Further delineation of 9q22 deletion syndrome associated with basal cell nevus (Gorlin) syndrome: report of two cases and review of the literature. Congenit Anom (Kyoto). 2009;49:8–14
  59. Brellier F, Bergoglio V, Valin A, Barnay S, Chevallier-Lagente O, Vielh P, et al. Heterozygous mutations in the tumor suppressor gene PATCHED provoke basal cell carcinoma-like features in human organotypic skin cultures. Oncogene. 2008;27:6601–6606
  60. Santarosa M, Ashworth A. Haploinsufficiency for tumour suppressor genes: when you don’t need to go all the way. Biochim Biophys Acta. 2004;1654:105–122
  61. Li TJ, Browne RM, Matthews JB. Expression of epidermal growth factor receptors by odontogenic jaw cysts. Virchows Arch A Pathol Anat Histopathol. 1993;423:137–144
  62. Li TJ, Browne RM, Matthews JB. Immunocytochemical expression of growth factors by odontogenic jaw cysts. Mol Pathol. 1997;50:21–27
  63. Kumamoto H, Yoshida M, Ooya K. Immunohistochemical detection of hepatocyte growth factor, transforming growth factor-b and their receptors in epithelial odontogenic tumors. J Oral Pathol Med. 2002;31:539–548
  64. Folkman J. Angiogenesis in cancer, vascular, rheumatoid and other disease. Nat Med. 1995;1:27–31
  65. Toi M, Taniguchi T, Yamamoto Y, Kurisaki T, Suzuki H, Tominaga T. Clinical significance of the determination of angiogenic factors. Eur J Cancer. 1996;32A:2513–2519
  66. Ferrara N, Davis-Smyth T. The biology of vascular endothelial growth factor. Endocr Rev. 1997;18:4–25
  67. Kumamoto H, Ohki K, Ooya K. Association between vascular endothelial growth factor (VEGF) expression and tumor angiogenesis in ameloblastomas. J Oral Pathol Med. 2002;31:28–34
  68. Ogden GR, Chisholm DM, Kiddie RA, Lane DP. P53 protein in odontogenic cysts: increased expression in some odontogenic keratocysts. J Clin Pathol. 1992;45:1007–1010
  69. Slootweg PJ. P53 protein and Ki-67 reactivity in epithelial odontogenic lesions. An immunohistochemical study. J Oral Pathol Med. 1995;24:393–397
  70. Lombardi T, Odelll EW, Morgan PR. P53 immunohistochemistry of odontogenic keratocysts in relation to recurrence, basal cell budding and basal-cell naevus syndrome. Arch Oral Biol. 1995;40:1081–1084
  71. Li TJ, Browne RM, Prime SS, Paterson IC, Matthews JB. P53 expression in odontogenic keratocyst epithelium. J Oral Pathol Med. 1996;25:245–255
  72. El Murtadi A, Grehan D, Toner M, Mc Cartan BE. Proliferating cell nuclear antigen staining in syndrome and nonsyndrome odontogenic keratocysts. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 1996;81:217–220
  73. Piattelli A, Fioroni M, Santinelli A, Rubini C. Expression of proliferating cell nuclear antigen in ameloblastomas and odontogenic cysts. Oral Oncol. 1998;34:408–412
  74. Kimi K, Kumamoto H, Ooya K, Motegi K. Analysis of apoptosis-related factors and apoptotic cells in lining epithelium of odontogenic keratocysts. Oral Med Pathol. 2000;5:35–40
  75. Kimi K, Kumamoto H, Ooya K, Motegi K. Immunohistochemical analysis of cell-cycle- and apoptosis-related factors in lining epithelium of odontogenic keratocysts. J Oral Pathol Med. 2001;30:434–442
  76. Kim DK, Ahn SG, Kim J, Yoon JH. Comparative Ki-67 expression and apoptosis in the odontogenic keratocyst associated with or without an impacted tooth in addition to unilocular and multilocular varieties. Yonsei Med J. 2003;44:841–846
  77. Kichi E, Enokiya Y, Muramatsu T, Hashimoto S, Inoue T, Abiko Y, et al. Cell proliferation, apoptosis and apoptosis-related factors in odontogenic keratocysts and in dentigerous cysts. J Oral Pathol Med. 2005;34:280–286
  78. Schmitt CA, Lowe SW. Apoptosis and therapy. J Pathol. 1999;187:127–137
  79. Li TJ, Browne RM, Matthews JB. Quantification of PCNA+ cells within odontogenic jaw cyst epithelium. J Oral Pathol Med. 1994;23:184–189
  80. González-Moles MA, Mosqueda-Taylor A, Delgado-Rodríguez M, Martínez-Mata G, Gil-Montoya JA, Díaz-Franco MA, et al. Analysis of p53 protein by PAb240, Ki-67 expression and human papillomavirus DNA detection in different types of odontogenic keratocyst. Anticancer Res. 2006;26:175–181
  81. Li TJ, Browne RM, Matthews JB. Epithelial cell proliferation in odontogenic keratocysts: immunocytochemical study of Ki67 in simple, recurrent and basal cell naevus syndrome (BCNS)-associated lesions. J Oral Pathol Med. 1995;24:221–226
  82. Lu QL, Abel P, Foster CS, Lalani EN. Bcl-2: role in epithelial differentiation and oncogenesis. Human Pathol. 1996;27:102–110
  83. Chylicki K, Ehinger M, Svedberg H, Gullberg U. Characterization of the molecular mechanisms for p53-mediated differentiation. Cell Growth Differ. 2000;11:561–571
  84. Kumamoto H. Detection of apoptosis-related factors and apoptotic cells in ameloblastomas: analysis by immunohistochemistry and an in situ DNA nick end-labelling method. J Oral Pathol Med. 1997;26:419–425
  85. Mitsuyasu T, Harada H, Higuchi Y, et al. Immunohistochemical demonstration of bcl-2 protein in ameloblastoma. J Oral Pathol Med. 1997;26:345–348
  86. Singh BB, Chandler FW, Whitaker SB, Forbes-Nelson AE. Immunohistochemical evaluation of bcl-2 oncoprotein in oral dysplasia and carcinoma. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 1998;85:692–698
  87. Tosios KI, Angelopoulou K, Kapranos N. Immunohistochemical study of bcl-2 protein, Ki-67 antigen and p53 protein in epithelium of glandular odontogenic cysts and dentigerous cysts. J Oral Pathol Med. 2000;29:139–144
  88. Slootweg PJ, De Weger RA. Immunohistochemical demonstration of bcl-2 protein in human tooth germs. Arch Oral Biol. 1994;39:545–550
  89. Vedtofte P, Holmstrup P, Dabelsteen E. Human odontogenic keratocyst transplants in nude mice. Scand J Dent Res. 1982;90:306–314
  90. Kaplan I, Hirshberg A. The correlation between epithelial cell proliferation and inflammation in odontogenic keratocyst. Oral Oncol. 2004;40:985–991
  91. Meghji S, Henderson B, Bando Y, Harris M. Interleukin-1: the principal osteolytic cytokine produced by keratocysts. Arch Oral Biol. 1992;37:935–943
  92. Lader CS, Flanagan AM. Prostaglandin E2, interleukin 1a, and tumor necrosis factor-a increase human osteoclast formation and bone resorption in vitro. Endocrinology. 1998;139:3157–3164
  93. Tani-Ishii N, Tsunoda A, Teranaka T, Umemoto T. Autocrine regulation of osteoclast formation and bone resorption by IL-1α and TNFα. J Dent Res. 1999;78:1617–1623
  94. Dayer J-M, de Rochemonteix B, Burrus B, Demczuk S, Dinarello CA. Human recombinant interleukin 1 stimulates collagenase and prostaglandin E2 production by human synovial cells. J Clin Invest. 1986;77:645–648
  95. Saito S, Ngan P, Rosol T, et al. Involvement of PGE synthesis in the effect of intermittent pressure and interleukin-1β on bone resorption. J Dent Res. 1991;70:27–33
  96. Tewari M, Tuncay OC, Milchman A, et al. Association of interleukin-1-induced, NFΚB DNA-binding activity with collagenase gene expression in human gingival fibroblasts. Arch Oral Biol. 1996;41:461–468
  97. Kusano K, Miyaura C, Inada M, et al. Reguration of matrix metalloproteinase (MMP-2-3-9, and -13) by interleukin-1 and interleukin-6 in mouse calvaria: association of MMP induction with bone resorption. Endocrinology. 1998;139:1338–1345
  98. Kubota Y, Ninomiya T, Oka S, Takenoshita Y, Shirasuna K. Interleukin-1α dependent regulation of matrix metalloproteinase-9 (MMP-9) secretion and activation in the epithelial cells of odontogenic jaw cysts. J Dent Res. 2000;79:1423–1430
  99. Ogata S, Kubota Y, Yamashiro T, Takeuchi H, Ninomiya T, Suyama Y, et al. Signaling pathways regulating IL-1alpha-induced COX-2 expression. J Dent Res. 2007;86:186–191
  100. Meghji S, Qureshi W, Henderson B, Harris M. The role of endotoxin and cytokines in the pathologenesis of odontogenic cysts. Arch Oral Biol. 1996;41:523–531
  101. Maas-Szabowski N, Shimotoyodome A, Fusenig NE. Keratinocyte growth regulation in fibroblast cocultures via a double paracrine mechanism. J Cell Sci. 1999;112:1843–1853
  102. Ninomiya T, Kubota Y, Koji T, Shirasuna K. Marsupialization inhibits interleukin-1alpha expression and epithelial cell proliferation in odontogenic keratocysts. J Oral Pathol Med. 2002;31:526–533
  103. Taipale J, Chen JK, Cooper MK, Wang B, Mann RK, Milenkovic L, et al. Effects of oncogenic mutations in smoothened and patched can be reversed by cyclopamine. Nature. 2000;406:1005–1009
  104. Arad S, Zattra E, Hebert J, Epstein EH, Goukassian DA, Gilchrest BA. Topical thymidine dinucleotide treatment reduces development of ultraviolet-induced basal cell carcinoma in Ptch-1+/− mice. Am J Pathol. 2008;172:1248–1255
  105. Williams JA, Guicherit OM, Zaharian BI, Xu Y, Chai L, Wichterle H, et al. Identification of a small molecule inhibitor of the Hedgehog signaling pathway: effects on basal cell carcinoma-like lesions. Proc Natl Acad Sci USA. 2003;100:4616–4621
  106. Zhang L, Sun ZJ, Zhao YF, Bian Z, Fan MW, Chen Z. Inhibition of SHH signaling pathway: molecular treatment strategy of odontogenic keratocyst. Med Hypotheses. 2006;67:1242–1244
  107. Stolina M, Sharma S, Lin Y, et al. Specific inhibition of cyclooxygenase 2 restores antitumor reactivity by altering the balance of IL-10 and IL-12 synthesis. J Immunol. 2000;164:361–370

PII: S1368-8375(09)00945-2

doi: 10.1016/j.oraloncology.2009.10.009

Oral Oncology
Volume 46, Issue 1 , Pages 19-24 , January 2010

Article Tools

* Image Usage & Resolution