Expression of the C-terminal peptide of human pro-bombesin in 361 lung endocrine tumours, a reliable marker and possible prognostic indicator for small cell carcinoma

Abstract

Small cell carcinoma of the lung is a highly malignant tumour. Its known biological products which include bombesin, do not allow the prediction of tumour behaviour. Molecular biology has revealed the amino acid sequence of human pro-bombesin, which consists of a signal peptide, the bioactive bombesin molecule and a C-terminal peptide. We have raised a rabbit antiserum to the first (N-terminal) 21 amino acids of the predicted C-terminal peptide. A total of 505 (361 neuroendocrine) surgically resected pulmonary tumours were evaluated for the presence of immunoreactive bombesin and C-terminal peptide. Strong immunostaining was obtained with the antiserum to the C-terminal peptide of human pro-bombesin in 70% of the small cell carcinomas (175/250), in 63% of atypical (aggressive) carcinoids (31/49) but only in 16% of benign carcinoids (10/62). In contrast, bombesin immunostaining was focal and only moderately strong and the relative proportion of positive cases was quite evenly distributed amongst the neuroendocrine tumours: 35% of carcinoids (22/62), 22% of atypical carcinoids (11/49) and 25% of small cell carcinoma (62/250). None of the squamous, adeno, or large cell undifferentiated carcinomas were immunoreactive for bombesin or the C-terminal peptide. Radioimmunoassay and chromatography of extracts of tumours recovered from wax blocks revealed high concentrations of C-terminal peptide immunoreactivity (241 +/- 66 pmol/g of tissue) in all 12 small cell carcinomas studied, moderate concentrations in carcinoid tumours (50 +/- 7 pmol/g) and none in non-small cell carcinomas. Patients with tumours showing immunoreactivity to the C-terminal peptide of human pro-bombesin had a significantly shorter survival time than those without immunoreactive peptide (185 +/- 16.49 days, mean +/- SEM, and with 1128 +/- 226 days, respectively P greater than 0.02). The apparent presence of the C-terminal peptide of human pro-bombesin in higher concentrations than bombesin in the more malignant class of endocrine tumours, mainly small cell carcinomas associated with the poorest prognosis, suggests that the antiserum to this C-terminal peptide is not only a useful pathological marker but may prove to be of value in investigating the biological behaviour of small cell carcinomas and predicting the clinical course of the disease.