Molecular Medicine

, Volume 14, Issue 5–6, pp 318–326 | Cite as

Expression of Odontogenic Ameloblast-Associated Protein (ODAM) in Dental and Other Epithelial Neoplasms

  • Daniel P. Kestler
  • James S. Foster
  • Sallie D. Macy
  • Charles L. Murphy
  • Deborah T. Weiss
  • Alan Solomon
Research Article


We previously have communicated our discovery that the amyloid associated with calcifying epithelial odontogenic tumors is composed of N-terminal fragments of the structurally novel odontogenic ameloblast-associated protein designated ODAM. Subsequently, it was shown by other investigators that ODAM is expressed in rodent enamel organ and is likely involved in dental development. We now report that this molecule also is found in certain human tissues, principally the salivary gland and trachea, as evidenced by RNA array analysis and immunohistochemistry-utilizing antibodies prepared against synthetic ODAM-related peptides and recombinant protein. Notably, these reagents immunostained normal and malignant ameloblasts and other types of human neoplastic cells, including those of gastric, lung, and breast origin where the presence in the latter was confirmed by in situ hybridization using gene-specific molecular probes. Moreover, significant titers of anti-ODAM IgG antibodies were detected in the sera of patients with these malignancies. Our studies have provided the first evidence in humans for the cellular expression of ODAM in normal and diseased states. Based on our findings, we posit that ODAM is a developmental antigen that has an essential role in tooth maturation and in the pathogenesis of certain odontogenic and other epithelial neoplasms; further, we suggest that ODAM may serve as a novel prognostic biomarker, as well as a potential diagnostic and therapeutic target for patients with breast and other epithelial forms of cancer.



We thank P Seim for furnishing the CEOT/ameloblastoma specimen, J T Wright for the mouse dental tissue, J Hudson for the supernummary tooth follicle, Elliot K. Swab for technical assistance, and Keira Clark for manuscript preparation. This work was supported, in part, by USPHS Research Grant CA-10056 from the National Cancer Institute and the University of Tennessee Medical Center’s Physician’s Medical and Education Research Foundation.


  1. 1.
    Moffatt P, Smith CE, Sooknanan R, St-Arnaud R, Nanci A. (2006) Identification of secreted and membrane proteins in the rat incisor enamel organ using a signal-trap screening approach. Eur. J. Oral Sci. 114(Suppl 1):139–46.CrossRefPubMedGoogle Scholar
  2. 2.
    Kawasaki K, Weiss KM. (2003) Mineralized tissue and vertebrate evolution: the secretory calcium-binding phosphoprotein gene cluster. Proc. Natl. Acad. Sci. U.S.A. 100:4060–5.CrossRefPubMedPubMedCentralGoogle Scholar
  3. 3.
    Park JC, et al. (2007) The amyloid protein APin is highly expressed during enamel mineralization and maturation in rat incisors. Eur. J. Oral Sci. 115:153–60.CrossRefPubMedGoogle Scholar
  4. 4.
    Moffatt, P. Smith, CE, St-Arnaud R, Nanci A. (2008) Characterization of APin, a secreted protein highly expressed in tooth-associated epithe-lia. J. Cell Biochem. 103:941–60.CrossRefPubMedGoogle Scholar
  5. 5.
    Rosty C, et al. (2005) Clinical and biological characteristics of cervical neoplasias with FGFR3 mutation. Mol. Cancer. 4:15.CrossRefPubMedPubMedCentralGoogle Scholar
  6. 6.
    Aung PP, et al. (2006) Systematic search for gastric cancer-specific genes based on SAGE data: melanoma inhibitory activity and matrix metallo-proteinase-10 are novel prognostic factors in patients with gastric cancer. Oncogene. 25:2546–57.CrossRefPubMedGoogle Scholar
  7. 7. HomoloGene: 49511 Gene conserved in Eutheria. Updated April 4, 2008.
  8. 8.
    Solomon A, Murphy CL, Weaver K, et al. (2003) Calcifying epithelial odontogenic (Pindborg) tumor-associated amyloid consists of a novel human protein. J. Lab. Clin. Med. 142:348–55.CrossRefPubMedGoogle Scholar
  9. 9.
    Sugano S, et al. 2000. Hypothetical protein FLJ20513 (FLJ20513 mRNA), Accession AK000520, Updated September 12, 2008.
  10. 10.
    Sekiguchi M, Sakakibara K, Fujii G. (1978) Establishment of cultured cell lines derived from a human gastric carcinoma. Jpn. J. Exp. Med. 48:61–8.PubMedGoogle Scholar
  11. 11.
    Murphy CL et al. (2008) Odontogenic ameloblast-associated protein nature of the amylid found in calcifying epithelial odontogenic tumors and unerupted tooth follicles. Amyloid 15:89–95.CrossRefPubMedGoogle Scholar
  12. 12.
    Seim P, Regezi JA, O’Ryan F. (2005) Hybrid ameloblastoma and calcifying epithelial odonto-genic tumor: case report. J. Oral Maxillofac. Surg. 63:852–5.CrossRefPubMedGoogle Scholar
  13. 13.
    Kestler DP, Hill M, Agarwal S, Hall RE. (2000) Use of bidirectional blots in differential display analysis. Anal. Biochem. 280:216–20.CrossRefPubMedGoogle Scholar
  14. 14.
    Foster JS, Henley DC, Bukovsky A, Seth P, Wimalasena J. (2001) Multifaceted regulation of cell cycle progression by estrogen: regulation of Cdk inhibitors and Cdc25A independent of cyclin D1-Cdk4 function. Mol. Cell Biol. 21:794–810.CrossRefPubMedPubMedCentralGoogle Scholar
  15. 15.
    Solomon A et al. (2006) Amyloid contained in the knee joint meniscus is formed from apolipoprotein A-I. Arthritis Rheum. 54:3545–50.CrossRefPubMedGoogle Scholar
  16. 16.
    Tchaikovskaya T et al. (2005) Glutathione S-transferase hGSTM3 and ageing-associated neurodegeneration: relationship to Alzheimer’s disease. Mech. Ageing Dev. 126:309–15.CrossRefPubMedGoogle Scholar
  17. 17.
    Gengozian N, Foster JS, Kestler DP. (2005) Characterization of a monoclonal antibody identifying a CD45RA antigen on feline leukocytes. Vet. Immunol. Immunopathol. 108:253–64.CrossRefPubMedGoogle Scholar
  18. 18.
    Philipsen HP, Reichart PA. (2000) Calcifying epithelial odontogenic tumor: biological profile based on 181 cases from the literature. Oral Oncol. 36:17–26.CrossRefPubMedGoogle Scholar
  19. 19.
    Nakamura S et al. (2005) Identification of genes preferentially expressed in periodontal ligament: specific expression of a novel secreted protein, FDC-SP. Biochem. Biophys. Res. Commun. 338:1197–203.CrossRefPubMedGoogle Scholar
  20. 20.
    Matalova E, Antonarakis GS, Sharpe PT, Tucker AS. (2005) Cell lineage of primary and secondary enamel knots. Dev. Dyn. 233:754–9.CrossRefPubMedGoogle Scholar
  21. 21.
    Jernvall J, Thesleff I. (2000) Reiterative signaling and patterning during mammalian tooth morphogenesis. Mech. Dev. 92:19–29.CrossRefPubMedGoogle Scholar
  22. 22.
    Kawasaki K, Weiss KM. (2006) Evolutionary genetics of vertebrate tissue mineralization: the origin and evolution of the secretory calcium-binding phosphoprotein family. J. Exp. Zoolog. B. Mol. Dev. Evol. 306:295–316.CrossRefGoogle Scholar
  23. 23.
    Iwasaki K et al. (2005) Amelotin-a Novel Secreted, Ameloblast-specific protein. J. Dent. Res. 84:1127–32.CrossRefPubMedGoogle Scholar
  24. 24.
    Huq NL, Cross KJ, Ung M, Reynolds EC. (2005) A review of protein structure and gene organisation for proteins associated with mineralised tissue and calcium phosphate stabilisation encoded on human chromosome 4. Arch. Oral Biol. 50:599–609.CrossRefPubMedGoogle Scholar
  25. 25.
    Ozyildirim AM, Wistow GJ, Gao J, Wang J, Dickinson DP, Frierson HF Jr, Laurie GW. (2005) The lacrimal gland transcriptome is an unusually rich source of rare and poorly characterized gene transcripts. Invest. Ophthalmol. Vis. Sci. 46:1572–80.CrossRefPubMedGoogle Scholar
  26. 26.
    Rijnkels M, Elnitski L, Miller W, Rosen JM. (2003) Multispecies comparative analysis of a mammalian-specific genomic domain encoding secretory proteins. Genomics. 82:417–32.CrossRefPubMedGoogle Scholar
  27. 27. UniGene: Hs. 143811 Homo sapiens ODAM expression profile. Updated February 11, 2008.
  28. 28.
    Adachi J et al. (2000) Direct submission, Accession AK009298, Updated February 11, 2008.
  29. 29.
    Sire JY, Davit-Bela T, Delgado S, Gu X. (2007) The origin and evolution of enamel mineralization genes. Cells Tissues Organs. 186:25–48.CrossRefPubMedGoogle Scholar
  30. 30.
    Ravindranath RM, Devarajan A, Uchida T. (2007) Spatiotemporal expression of ameloblastin isoforms during murine tooth development J. Biol. Chem. 282:36370–76.CrossRefPubMedGoogle Scholar
  31. 31.
    Moffatt P, Smith CE, St-Arnaud R, Simmons D, Wright JT, Nanci A. (2006) Cloning of rat amelotin and localization of the protein to the basal lamina of maturation stage ameloblasts and junctional epithelium. Biochem. J. 399:37–46.CrossRefPubMedPubMedCentralGoogle Scholar
  32. 32.
    Noh SJ, Lee K, Paik H, Hur CG. (2006) TISA: tissue-specific alternative splicing in human and mouse genes. DNA Res. 13:229–43.CrossRefPubMedGoogle Scholar
  33. 33.
    Aung PP et al. (2006) Systematic search for gastric cancer-specific genes based on SAGE data: melanoma inhibitory activity and matrix metalloproteinase-10 are novel prognostic factors in patients with gastric cancer. Oncogene. 25:2546–57.CrossRefPubMedGoogle Scholar
  34. 34.
    Zucchi I et al. (2004) Gene expression profiles of epithelial cells microscopically isolated from a breast-invasive ductal carcinoma and a nodal metastasis. Proc. Natl. Acad. Sci. U.S.A. 101:18147–52.CrossRefPubMedPubMedCentralGoogle Scholar
  35. 35.
    Liu R et al. (2007) The prognostic role of a gene signature from tumorigenic breast-cancer cells. N. Engl. J. Med. 356:217–26.CrossRefPubMedGoogle Scholar
  36. 36.
    Kita H et al. (2006) Differential gene expression between flat adenoma and normal mucosa in the colon in a microarray analysis. J. Gastroenterol. 41:1053–63.CrossRefPubMedGoogle Scholar
  37. 37.
  38. 38.
    Cross SS, Hamdy FC, Deloulme JC, Rehman I. (2005) Expression of S100 proteins in normal human tissues and common cancers using tissue microarrays: S100A6, S100A8, S100A9, and S100A11 are all overexpressed in common cancers. Histopathology. 46:256–69.CrossRefPubMedGoogle Scholar
  39. 39.
    Deryugina EI, Quigley JP. (2006) Matrix metalloproteinases and tumor metastasis. Cancer Metastasis Rev. 25:9–34.CrossRefPubMedGoogle Scholar
  40. 40.
    Zhang L et al. (2006) Epithelial expression of SHH signaling pathway in odontogenic tumors. Oral Oncol. 42:398–408.CrossRefPubMedGoogle Scholar
  41. 41.
    Ma X et al. (2005) Frequent activation of the hedgehog pathway in advanced gastric adenocarcinomas. Carcinogenesis. 26:1698–705.CrossRefPubMedGoogle Scholar
  42. 42.
    Mukherjee S et al. (2006) Hedgehog signaling and response to cyclopamine differ in epithelial and stromal cells in benign breast and breast cancer. Cancer Biol. Ther. 5:674–83.CrossRefPubMedPubMedCentralGoogle Scholar
  43. 43.
    Hatsell S, Frost AR. (2007) Hedgehog signaling in mammary gland development and breast cancer. J. Mammary Gland Biol. Neoplasia. 12:163–73.CrossRefPubMedGoogle Scholar
  44. 44.
    Lemjabbar-Alaoui H et al. (2006) Wnt and hedgehog are critical mediators of cigarette smoke-induced lung cancer. PLoS ONE. 1:e93.CrossRefPubMedPubMedCentralGoogle Scholar
  45. 45.
    Soussi T. (2000) Antibodies in the sera of patients with various types of cancer: a review. Cancer Res. 60:1777–88.PubMedGoogle Scholar
  46. 46.
    Fernandez MF. (2005) Autoantibodies in breast cancer sera: candidate biomarkers and reporters of tumorigenesis. Cancer Lett. 230:187–98.CrossRefGoogle Scholar
  47. 47.
    Toubi E, Shoenfeld Y. (2007) Protective autoimmunity in cancer (review). Oncol. Rep. 17:245–51.PubMedGoogle Scholar
  48. 48.
    Lacroix M. (2006) Significance, detection and markers of disseminated breast cancer cells. Endocr. Relat. Cancer. 13:1033–67.CrossRefPubMedGoogle Scholar
  49. 49.
    Fabre-Lafay S, Monville F, Garrido-Urbani S. (2007) Nectin-4 is a new histological and serological tumor associated marker for breast cancer. BMC Cancer. 7:73.CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Feinstein Institute for Medical Research 2008

Authors and Affiliations

  • Daniel P. Kestler
    • 1
  • James S. Foster
    • 1
  • Sallie D. Macy
    • 1
  • Charles L. Murphy
    • 1
  • Deborah T. Weiss
    • 1
  • Alan Solomon
    • 1
  1. 1.Human Immunology and Cancer Program, Department of MedicineUniversity of Tennessee Graduate School of MedicineKnoxvilleUSA

Personalised recommendations