Expression of transforming growth factor alpha and its receptor in human neuroendocrine tumours

Transforming growth-factor-α (TGF-α) is a 50-amino-acid polypeptide that binds to the epidermal growth factor (EGF) receptor and stimulates cell growth. It has been suggested that enhanced production of TGF-α and EGF receptors by tumour cells promote tumour-cell growth by autocrine mechanisms. In the present study we have investigated the expression of TGF-α and EGF receptors in human neuroendocrine tumours, including midgut carcinoid tumours, phaeochromocytomas and medullary thyroid carcinomas. TGF-α expression was demonstrated in biopsies of all tumours examined (n = 30) and EGF receptors in a majority of tumours by Northern analysis and/or immunocy-tochemistry. Expression of TGF-α and EGF receptors was also demonstrated in primary cultures of tumour cells. Carcinoid tumours and phaeochromocytomas in culture secreted detectable amounts of TGF-α into the culture medium (400–700 pM). The amount of secreted TGF-α could be suppressed by octreotide treatment in individual tumours. Administration of exogenous TGF-α stimulated carcinoid tumour growth in vitro as determined by the DNA contents of cell cultures. The growth-stimulatory effect of TGF-α could be partially blocked by the use of neutralizing anti-EGF receptor monoclonal antibodies (MAbs). In conclusion, several human neuroendocrine tumours express both TGF-α and EGF receptors in in vivo and in vitro, suggesting that TGF-α may regulate tumour-cell growth by autocrine mechanisms.