Downregulation of transforming growth factor beta type II receptor in laryngeal carcinogenesis

AIMS: To investigate whether anomalies of transforming growth factor beta type II receptor (TGF-beta RII) expression occur in the early stages of laryngeal carcinogenesis and to assess their importance in the development of laryngeal squamous cell carcinoma. TGF-beta RII status was examined in laryngeal premalignant lesions coupled with malignant evolution and compared with a control group of similar lesions without progression to cancer. METHODS: Immunohistochemical staining for TGF-beta RII was performed on 15 paraffin wax embedded biopsies from patients with precancerous laryngeal lesions who subsequently developed invasive squamous cell carcinoma of the larynx, and on 30 control biopsies from patients who did not develop cancer in a comparable follow up period. In addition, DNA extracted from 18 preneoplastic lesions and eight squamous cell carcinomas was amplified by the polymerase chain reaction at the poly A and the poly GT regions of the TGF-beta RII gene. RESULTS: In the group of lesions with progression to carcinoma, 11 of 15 cases showed loss (< 20% of epithelial cells) of TGF-beta RII immunoreactivity, whereas among non-evolved lesions only five of 30 had similar altered expression of the receptor (p < 0.001, two tailed Fisher's exact test). All squamous cell carcinomas showed a degree of receptor expression comparable with that of the corresponding preneoplastic lesion, with the exception of one case, in which loss of the receptor was evident only in invasive cancer. Mutation of the poly A sequence of the TGF-beta RII gene was identified in only one precancerous lesion and in the subsequent squamous cell carcinoma. CONCLUSIONS: These findings indicate that the downregulation of TGF-beta RII is an early event in laryngeal carcinogenesis, which may result in the loss of TGF-beta mediated growth inhibition, thereby facilitating the progression of laryngeal precancerous lesions to squamous cell carcinoma.