Reduced expression of transforming growth factor-beta receptor type III in high stage neuroblastomas

Transforming growth factor beta (TGF-beta) is a powerful inhibitor of cell proliferation and a potent inducer of differentiation. Resistance to TGF-beta action is a characteristic of many malignancies and has been attributed to alterations of TGF-beta receptors as well as disturbance of downstream transduction pathways. To analyse the TGF-beta response in neuroblastoma, the expression of TGF-beta1 and TGF-beta type I, II and III receptor genes was investigated in 61 cancer samples by means of reverse transcription polymerase chain reaction. The specimens analysed belong to different stages, namely nine samples of stage 1, ten of stage 2, nine of stage 3 and 28 of stage 4. Moreover, five samples were of stage 4S, which represents a tumour form undergoing spontaneous regression. The results obtained show that TGF-beta1 and TGF-beta type I and II receptor genes appear to be almost equally expressed in neuroblastomas of all stages. Conversely, TGF-beta type III receptor gene expression, which is required for an efficacious TGF-beta binding and function, is strongly reduced exclusively in neuroblastomas of stages 3 and 4. These findings were directly confirmed by immunohistochemical analyses of ten neuroblastoma specimens. Our results suggest the occurrence of an altered TGF-beta response in advanced neuroblastomas which might be an important mechanism for escaping growth control and for developing invasiveness. Moreover, our findings allow the proposal of a novel mechanism, namely down-regulation of TGF-beta type III receptor gene expression, to avoid TGF-beta inhibitory activity.