Neuroendocrine dysdifferentiation and bombesin production in carcinogen-induced hepatocellular rat tumours

Primary rat hepatocellular tumours, induced by a combination of diethylnitrosamine and 2-acetylaminofluorene, were examined for the presence of neuroendocrine peptides by immunocytochemical methods. Two-thirds of the tumours showed positive immunostaining for either neuron-specific enolase (NSE), protein S-100 or bombesin. NSE was commonly observed both in hepatocarcinomas and in neoplastic nodules, whereas protein S-100 was more frequently seen in carcinomas (49% positive) than in nodules (13% positive). Bombesin, previously shown to function as an autocrine growth factor in small-cell carcinoma of the lung, was present in neurosecretory granules in 13% of the nodules and 29% of the carcinomas. Normal, preneoplastic and peritumorous liver tissue, including the frequent atypical foci present in the latter two categories, was uniformly negative for all neuroendocrine markers. The foci, like the nodules and carcinomas, generally stained positively for the liver tumour marker glutathione S-transferase type P (GSTP). The results suggest that dysdifferentiation of altered hepatocytes in a neuroendocrine direction may be a common, late event in liver carcinogenesis which could possibly contribute to tumour formation, e.g. by establishing autocrine or paracrine circuits.