Skip to main content

Advertisement

Log in

Immunohistochemical location of the p75 neurotrophin receptor (p75NTR) in oral leukoplakia and oral squamous cell carcinoma

  • Original Article
  • Published:
International Journal of Clinical Oncology Aims and scope Submit manuscript

Abstract

Background

Recent studies have demonstrated that the p75 neurotrophin receptor (p75NTR) is a useful marker of keratinocyte stem cells. Although the stem cell markers of original normal tissue have been used to identify cancer stem cells in a variety of cancers, the expression and function of p75NTR have been poorly understood in oral squamous cell carcinoma (OSCC). The objective of this study is, thus, to examine p75NTR expression immunohistochemically in oral leukoplakia (OL), the most frequent precancerous lesion, and OSCC, and to reveal the usefulness of p75NTR as a marker for undifferentiated cancer cells and a novel prognostic factor for OSCC patients.

Methods

In this study immunohistochemical expression of p75NTR, Ki-67, cytokeratin (CK) 5, and CK14 was examined in 112 cases of OL and 81 of OSCC. The labeling indices (LIs) of p75NTR and Ki-67 were calculated, and the association of these LIs with histopathologic characteristics was then evaluated.

Results

In the normal oral epithelium and OL, p75NTR was expressed only in the basal layer, and its LI was invariant, irrespective of the extent of epithelial dysplasia. In OSCC, however, p75NTR-LI was significantly increased in association with upgrading of histologic grade and mode of tumor invasion. Furthermore, the prognosis of the high p75NTR-LI group (LI ≥ 53.1%) was poorer than that of the low p75NTR-LI group (LI < 53.1%).

Conclusions

These results suggest that p75NTR is expressed in undifferentiated cell populations in OL and OSCC. Furthermore, p75NTR is possibly involved in invasion and poor prognosis in OSCC.

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

Access this article

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

Instant access to the full article PDF.

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

Similar content being viewed by others

References

  1. Parkin DM, Bray F, Ferlay J et al (2001) Estimating the world cancer burden: Globocan 2000. Int J Cancer 94:153–156

    Article  PubMed  CAS  Google Scholar 

  2. Parkin DM, Bray F, Ferlay J et al (2005) Global cancer statistics, 2002. CA Cancer J Clin 55:74–108

    Article  PubMed  Google Scholar 

  3. Breakhuis BJM, Brakenhoff RH, Leemans CR (2005) Second field tumors: a new opportunity for cancer prevention? Oncologist 10:493–500

    Article  Google Scholar 

  4. Bonnet D, Dick JE (1997) Human acute myeloid leukemia is organized as a hierarchy that originates from a primitive hematopoietic cell. Nat Med 3:730–737

    Article  PubMed  CAS  Google Scholar 

  5. Al-Haji M, Wicha MS, Benito-Herandez A et al (2003) Prospective identification of tumorigenic breast cancer cells. Proc Natl Acad Sci USA 100:3983–3988

    Article  Google Scholar 

  6. Singh SK, Hawkins C, Clarke ID et al (2004) Identification of human brain tumour initiating cells. Nature 432:396–401

    Article  PubMed  CAS  Google Scholar 

  7. Hemmati HD, Nakano I, Lazareff JA et al (2003) Cancerous stem cells can arise from pediatric brain tumors. Proc Natl Acad Sci USA 100:15178–15183

    Article  PubMed  CAS  Google Scholar 

  8. Ma S, Chan KW, Hu L et al (2007) Identification and characterization of tumorigenic liver cancer stem/progenitor cells. Gastroenterology 132:2542–2556

    Article  PubMed  CAS  Google Scholar 

  9. Zen Y, Fujii T, Yoshikawa S et al (2007) Histological and culture studies with respect to ABCG2 expression support the existence of a cancer cell hierarchy in human hepatocellular carcinoma. Am J Pathol 170:1750–1762

    Article  PubMed  CAS  Google Scholar 

  10. Singh SK, Clarke ID, Tearasaki M et al (2003) Identification of a cancer stem cell in human brain tumors. Cancer Res 63:5821–5828

    PubMed  CAS  Google Scholar 

  11. Liu S, Dontsu G, Mantle ID et al (2006) Hedgehog signaling and Bmi-1 regulate self-renewal of normal and malignant human mammary stem cells. Cancer Res 66:6063–6071

    Article  PubMed  CAS  Google Scholar 

  12. Seo DC, Sung JM, Cho HJ et al (2007) Gene expression profiling of cancer stem cell in human lung adenocarcinoma A549 cells. Mol Cancer 6:75

    Article  PubMed  Google Scholar 

  13. Ricci-Vitiani L, Lombardi DG, Pilozzi E et al (2007) Identification and expansion of human colon-cancer-initiating cells. Nature 445:111–115

    Article  PubMed  CAS  Google Scholar 

  14. Li C, Heidt DG, Dalerba P et al (2007) Identification of pancreatic cancer stem cells. Cancer Res 67:1030–1037

    Article  PubMed  CAS  Google Scholar 

  15. Mitsutake N, Iwao A, Nagai K et al (2007) Characterization of side population in thyroid cancer cell lines: cancer stem-like cells are enriched partly but not exclusively. Endocrinology 148:1797–1803

    Article  PubMed  CAS  Google Scholar 

  16. Bao S, Wu Q, McLendon RE et al (2006) Glioma stem cells promote radioresistence by preferential activation of the DNA damage response. Nature 444:756–760

    Article  PubMed  CAS  Google Scholar 

  17. Liu G, Yuan X, Zeng Z et al (2006) Analysis of gene expression and chemoresistance of CD133+ cancer stem cells in glioblastoma. Mol Cancer 5:67

    Article  PubMed  Google Scholar 

  18. Prince ME, Sivanandan R, Kaczorowski A et al (2007) Identification of a subpopulation of cells with cancer stem cell properties in head and neck squamous cell carcinoma. Proc Natl Acad Sci USA 104:973–978

    Article  PubMed  CAS  Google Scholar 

  19. Chikamatsu K, Takahashi G, Sakakura K et al (2010) Immunoregulatory properties of CD44+ cancer stem-like cells in squamous cell carcinoma of the head and neck. Head Neck (in press)

  20. Zhang P, Zhang Y, Mao L et al (2009) Side population in oral squamous cell carcinoma possesses tumor stem cell phenotypes. Cancer lett 277:227–234

    Article  PubMed  CAS  Google Scholar 

  21. Harper LJ, Piper K, Common J et al (2007) Stem cell patterns in cell lines derived from head and neck squamous cell carcinoma. J Oral Pathol Med 36:594–603

    Article  PubMed  Google Scholar 

  22. Dean M, Fojo T, Bates S (2005) Tumor stem cells and drug resistance. Nat Rev Cancer 5:275–284

    Article  PubMed  CAS  Google Scholar 

  23. Okumura T, Shimada Y, Imamura M et al (2003) Neurotrophin receptor p75NTR characterizes human esophageal keratinocyte stem cells in vitro. Oncogene 22:4017–4026

    Article  PubMed  CAS  Google Scholar 

  24. Nakamura T, Endo K, Kinoshita S (2007) Identification of human oral keratinocyte stem/progenitor cells by neurotrophin receptor p75 and the role of neurotrophin/p75 signaling. Stem cells 25:628–638

    Article  PubMed  CAS  Google Scholar 

  25. Rodriguez-Tebar A, Dechant G, Gotz R et al (1992) Binding of neurotrophin-3 to its neuronal receptors and interactions with nerve growth factor and brain-derived neurotrophic factor. EMBO J 11:917–922

    PubMed  CAS  Google Scholar 

  26. Wang X, Bauer JH, Li Y et al (2001) Characterization of a p75(NTR) apoptotic signaling pathway using a novel cellular model. J Biol Chem 276:33812–33820

    Article  PubMed  CAS  Google Scholar 

  27. Krygier S, Djakiew D (2002) p75 suppresses growth and NGF mediated metastasis of human prostate cancer cells. Int J Cancer 98:1–7

    Article  PubMed  CAS  Google Scholar 

  28. Khwaja F, Djakiew D (2003) Inhibition of cell-cycle effectors of proliferation in bladder tumor epithelial cells by the p75NTR tumor suppressor. Mol Carcinog 36:153–160

    Article  PubMed  CAS  Google Scholar 

  29. Pflug BR, Onoda M, Lynch JH et al (1992) Reduced expression of the low affinity nerve growth factor receptor in benign and malignant human prostate tissue and loss of expression in four human metastatic prostate tumor cell lines. Cancer Res 52:5403–5406

    PubMed  CAS  Google Scholar 

  30. Gale N, Pilch BZ, Sindramsky D et al (2005) World Health Organization classification of tumors. Pathology and genetics of head and neck tumors. Iarc Press, Lyon, pp 177–179

  31. Sobin LH, Witte Sobin LH, Wittekind Ch (eds) (2002) TNM classification of malignant tumors. Wiley-Liss, Inc., New York

  32. Yamamoto E, Miyakawa A, Kohama G et al (1984) Mode of invasion and lymph node metastasis in squamous cell carcinoma of the oral cavity. Head Neck Surg 6:938–947

    Article  PubMed  CAS  Google Scholar 

  33. Lehrer MS, Sun TT, Lavker RM (1998) Strategies of epithelial repair: modulation of stem cell and transit amplifying cell proliferation. J Cell Sci 111:2867–2875

    PubMed  CAS  Google Scholar 

  34. Morris RJ, Potten CS (1994) Slowly cycling (label-retaining) epidermal cells behave like clonogenic stem cells in vitro. Cell Prolif 27:279–289

    Article  PubMed  CAS  Google Scholar 

  35. Takeda T, Sugihara K, Hirayama Y et al (2006) Immunohistological evaluation of Ki-67, p63, CK19 and p53 expression in oral epithelial dysplasias. J Oral Pathol Med 35:369–375

    Article  PubMed  CAS  Google Scholar 

  36. Okumura T, Tsunoda S, Mori Y et al (2006) The biological role of the low-affinity p75 neurotrophin receptor in esophageal squamous cell carcinoma. Clin Cancer Res 12:5096–5103

    Article  PubMed  CAS  Google Scholar 

  37. Søland TM, Brusevold IJ, Koppang HS et al (2008) Nerve growth factor receptor (p75NTR) and pattern of invasion predict poor prognosis in oral squamous cell carcinoma. Histopahology 53:62–67

    Article  Google Scholar 

  38. Tsunoda S, Okumura T, Ito T et al (2006) Significance of nerve growth factor overexpression and its autocrine loop in oesophageal squamous cell carcinoma. Br J cancer 95:322–330

    Article  PubMed  CAS  Google Scholar 

  39. Dang C, Zhang Y, Ma Q et al (2006) Expression of nerve growth factor receptors is correlated with progression and prognosis of human pancreatic cancer. J Gastroenterol Hepatol 21:850–858

    Article  PubMed  CAS  Google Scholar 

  40. Roux PP, Barker PA (2002) Neurotrophin signaling through the p75 neurotrophin receptor. Prog Neurobiol 67:203–233

    Article  PubMed  CAS  Google Scholar 

  41. Barker P, Shooter E (1994) Disruption of NGF binding to the low affinity neurotrophin receptor p75NTR reduces NGF binding to TrkA on PC12 cells. Neuron 13:203–215

    Article  PubMed  CAS  Google Scholar 

  42. Lee KF, Bachman K, Landis S et al (1994) Dependence on p75 for innervation of some sympathetic targets. Science 263:1447–1449

    Article  PubMed  CAS  Google Scholar 

  43. Van der Zee CE, Ross GM, Riopelle RJ et al (1996) Survival of cholinergic forebrain neurons in the developing p75 (NGFR) deficient mice. Science 274:1729–1732

    Article  PubMed  Google Scholar 

  44. Dolle L, Adriaenssens E, EI-Yazidi-Belkoura I et al (2004) Nerve growth factor receptors and signaling in breast cancer. Curr Cancer Drug Targets 4:463–470

    Article  PubMed  CAS  Google Scholar 

  45. Descamps S, Toillon RA, Adriaenssens E et al (2001) Nerve growth factor stimulates proliferation and survival of human breast cancer cells through two distinct signaling pathways. J Biol Chem 276:17864–17870

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

The work was supported by a Grant-in-Aid (no. 20791531) from the Japanese Ministry of Education, Culture, Science, Sports and Technology of Japan

Conflict of interest

The authors declare that they have no conflict of interest.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Shintaro Kawano.

About this article

Cite this article

Kiyosue, T., Kawano, S., Matsubara, R. et al. Immunohistochemical location of the p75 neurotrophin receptor (p75NTR) in oral leukoplakia and oral squamous cell carcinoma. Int J Clin Oncol 18, 154–163 (2013). https://doi.org/10.1007/s10147-011-0358-4

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10147-011-0358-4

Keywords

Navigation