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.