To elucidate the biosynthetic processing of the precursor for
vasoactive intestinal peptide (prepro-VIP) in tumours producing VIP we have used newly developed radioimmunoassays directed against the five functional domains of the VIP precursor molecule:
preproVIP 22-79,
peptide histidine methionine (PHM),
preproVIP 111-122, VIP and
preproVIP 156-170 in combination with HPLC to identify and quantify the
peptides in tumour specimen and plasma from patients with the watery diarrhoea syndrome. Elevated quantities of all the five
peptides were found in the 13 tumours (nine neurogenic tumours, one
pheochromocytoma, three
pancreatic carcinomas) examined. The
preproVIP derived
peptides were expressed in non-equimolar amounts and the relative proportion of the various
peptides differed markedly from tumour to tumour. The
pheochromocytoma was the only tumour type which contained large amounts of
preproVIP 156-170 in comparison with the other
peptides. A proportion of the VIP precursor which varied from 7% to 73% followed a pathway in which the dibasic conversion site after PHM was uncleaved as evidenced by the presence of PHV, a C-terminally extended form of PHM. It was also found that unlike normal tissue a fraction of the C-terminal VIP precursor
peptide,
preproVIP 156-170, was having its C-terminal
lysine residue removed during processing. The findings indicate that various post-translational processing pathways of
preproVIP exist. All the
peptide sequences produced in the tumour tissue were secreted as evidenced by their presence in plasma in elevated concentrations. The plasma levels of
preproVIP 22-79,
preproVIP 111-122 and PHV exceeded those of the remaining
preproVIP-derived
peptides suggesting that determination of these
peptides in patients with VIP-secreting tumours may be better markers than VIP.