Human lung small-cell carcinoma contains bombesin.

Abstract

The presence of immunoreactive bombesin in a human lung small-cell carcinoma grown in nude mice was established by several criteria: (i) Radioimmunoassay of tissue extracts for bombesin revealed approximately 6.5 pmol/g of tissue; (ii) bombesin was found in 12-14% of the tumor cells by immunohistochemical localization; (iii) gel filtration ofsmall-cell carcinoma extract on Sephadex G-75 and Bio-Gel P-4 gave only a single peak ofimmunoreactivity, which occurred at the elution volume ofbombesin; and (iv) reverse-phase HPLC of acid-solubilized extracts separated the immunoreactive material into three discrete peaks, one of which eluted with a retention time identical to that of synthetic bombesin. Small oat-cell carcinoma accounts for 10-25% of identifiable human lung cancers (1). This neoplasm is characterized by a rapid growth rate and a propensity to metastasize (1) and is frequently a source for "ectopic" hormone production (1-7). Many of the clinical symptoms manifested by patients with small-cell carcinoma (SCC) can be attributed to increased levels ofectopic hormones (5-7). For example, the syndrome of inappropriate secretion of antidiuretic hormone is apparently due to [Arg]vasopressin (5,6,8), whereas Cushing syndrome is considered to be caused by ectopic adrenocorticotropin (ACTH) formation and secretion, which is nonsuppressible by dexamethasone (3, 5, 7). Other symptoms may be due to the presence ofpresently unknown or undiscovered peptide hormones. In this regard, bombesin, a tetradecapeptide from anuran skin, elicits numerous physiological and pharmacological responses (9, 10) that resemble some of the clinical symptoms observed for SCC.(5, 11). Bombesin-like immunoreactivity was detected in numerous mammalian tissues (12-20), including human fetal and neonatal lung, but is apparently absent from adult lung (21). Because many immunological and enzymological changes that appear in tumors resemble those normally associated with fetal tissues, it seemed reasonable to evaluate the presence of bombesin in a lung neoplasm noted for ectopic hormone production. Bombesin in a human lung SCC grown in nude mice was demonstrated by (i) immunohistochemical localization of this peptide in the tumor, (ii) its quantitation in extracts by radioimmunoassay, and (iii) analysis by gel-filtration chromatography and reverse-phase HPLC. MATERIALS AND METHODSTumor. A SCC resected from a 51-year-old man with few apparent clinical endocrinopathies was propagated subcutaneously in athymic (nude) mice by Reid et al. (22) and generously supplied by G. Sato (University of California, San Diego). Tumors from two separate passages were analyzed separately. The tumors, 8.71 and 6.36 g wet weight, were removed and sectioned for histology, and the remainders of each were minced at 10C. They were homogenized in 5 ml of ice-cold 0.01 M sodium phosphate buffer, pH 6.8, containing 1 mM phenylmethylsulfonyl fluoride. The homogenate was slowly added to 25 ml of boiling water, boiled 30 min, and cooled on ice; then formic acid was ad...

Protein kinase C-mediated negative-feedback inhibition of unstimulated and bombesin-stimulated polyphosphoinositide hydrolysis in Swiss-mouse 3T3 cells

“…Since human SCCL and SCCL-derived cell lines are known to synthesize and secrete bombesin-like peptides (Erisman et al, 1982;Moody et al, 1983;Sorenson et al, 1982), it is possible that these peptides may function as autocrine growth factors involved in the abnormal growth of the tumours. Evidence in favour of this proposition has been reported by Cuttitta et al (1985), who showed that a highly specific monoclonal antibody against bombesin markedly suppressed the growth of SCCL cells both in vitro and in nude mice.…”

Pro-gastrin-releasing peptide(31-98) as a tumour marker of small-cell lung cancer: comparative evaluation with neuron-specific enolase

“…Spindel et al (1984) prepared and cloned cDNAs derived from mRNA from a human pulmonary carcinoid tumour that had strong immunoreactivity to GRP. A number of investigators have reported that immunoreactive GRP is present in the fetal and neonatal lung (Wharton' et al, 1978;Yamaguchi et al, 1983) and in primary lung cancer, especially in SCLC (Erisman et al, 1982;Moody et al, 1981;Wharton et al, 1978). Additionally, immunohistochemical analysis (Cuttitta et al, 1988) of ProGRP fragments (GGAPs) was also reported to immunostain both GRP and GGAP in SCLC cell lines and human SCLC tumours.…”

[D-Arg1,D-Phe5,D-Trp7,9,Leu11]substance P, a potent bombesin antagonist in murine Swiss 3T3 cells, inhibits the growth of human small cell lung cancer cells in vitro

“…SCLC is known to secrete bombesin-like peptides (20)(21)(22) that might act as autocrine growth factors (2,25). Thus it was plausible but not proven that an antagonist to bombesin/GRP would inhibit SCLC growth, so we tested the effects of peptides A and D on SCLC cells in vitro.…”

“…SCLC constitutes 25% of lung cancers and is, therefore, of major clinical and economic importance. Evidence that bombesin-like peptides, which are secreted by these tumors (20)(21)(22), can act as autocrine growth factors (25) has prompted the search for clinically useful GRP antagonists. We have presented evidence that two peptides that are antagonists of GRP and vasopressin profoundly inhibit the growth of SCLC cells in vitro although the participation of other growthpromoting peptides cannot be excluded.…”

“…Bombesin-like peptides are present in high concentrations in small cell lung cancer (SCLC) (20)(21)(22). They can stimulate the growth of SCLC cells in vitro (23,24) and may act as autocrine growth factors (2,25).…”