1. ¹Division of Otorhinolaryngology, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan
2. ²Division of Nephro-Urology, Department of Translational Medical Science, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan
3. ³Division of Histology and Cell Biology, Department of Developmental and Reconstructive Medicine, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan
4. ⁴Department of Otorhinolaryngology, Tohoku University Graduate School of Medicine, Sendai, Japan

Correspondence: Dr. Takehiko Koji, Department of Histology and Cell Biology, Nagasaki University School of Medicine, 1–12–4 Sakamoto, Nagasaki 852–8523, Japan. E-mail: tkoji@net.nagasaki-u.ac.jp

Received 30 October 2002.

Abstract

Middle-ear cholesteatoma is characterized by enhanced proliferation of epithelial cells and granular tissue formation. However, the molecular mechanism underlying these pathological changes is largely unknown. Keratinocyte growth factor (KGF) is a mesenchymal cell-derived paracrine growth factor that specifically stimulates epithelial cell proliferation. In the present study, we investigated the possible involvement of KGF and its receptor, KGFR, in the pathogenesis of cholesteatoma using in situ hybridization and immunohistochemistry, respectively. We examined 56 cholesteatoma specimens, and 8 normal skin areas as control. KGF and KGFR expression was examined by immunohistochemistry using rabbit anti-human KGF and anti-human KGFR polyclonal antisera raised in our laboratories against synthetic peptides corresponding to parts of human KGF and KGFR, respectively. KGF protein and mRNA were detected exclusively in stromal fibroblasts and infiltrating T lymphocytes in 80% of cholesteatoma cases, whereas KGFR protein and mRNA were localized in the epithelium in 72% of cases. Assessment of the proliferative activity of cholesteatoma using the labeling index for Ki-67 showed a significantly higher Ki-67 labeling index (66%) in KGF+/KGFR+ cases than other cases. There was a significant correlation between KGF+/KGFR+ expression and recurrence. Our results indicate the possible involvement of both KGF and KGFR in enhanced epithelial cell proliferative activity and recurrence of cholesteatoma.