Expression of progastrin-releasing peptide and gastrin-releasing peptide receptor mRNA transcripts in tumor cells of patients with small cell lung cancer.

PURPOSE: Small cell lung cancer (SCLC) is a rapidly growing neoplasm accounting for approximately 20% of patients with lung cancer. Progastrin-releasing peptide (proGRP) is produced in about two-thirds of SCLC tumors and is used as a specific marker for SCLC. Although GRP is known to have a variety of biological functions, only limited information is available concerning expression of proGRP mRNA and protein, and that of the receptor for GRP (GRPR) in SCLC tumors. METHODS: In individuals with SCLC, the levels of serum proGRP(31-98) were measured by enzyme-linked immunosorbent assay. Expression of proGRP as well as GRPR mRNA in SCLC tumor tissues was investigated by reverse transcription-nested polymerase chain reaction (PCR) amplification. The proportions of alternatively spliced proGRP mRNA transcripts were analyzed in proGRP-producing tumors by nested and competitive PCR amplification. Finally, production of proGRP protein in SCLC tumor was evaluated by using immunohistochemical staining with a polyclonal human anti-proGRP antibody. RESULTS: ProGRP mRNA transcripts could be detected only in tumor tissues recovered from individuals with high serum proGRP levels. The proportions of mRNA subtypes in each case were nearly the same, revealing type I of 55.4+/-7.6%, type II with 21-b deletion of 1.8+/-3.6%, and type III with 19-b deletion of 42.8+/-4.3%, respectively. ProGRP protein production was demonstrated in tumor tissues exclusively from individuals exhibiting high serum proGRP levels. In contrast, GRPR mRNA transcripts were detectable in cancer cells from two of five proGRP-expressing tumor tissues. CONCLUSIONS: ProGRP mRNA expression is closely related with the synthesis of proGRP protein which is eventually released into the blood. It is suggested GRP may function as an autocrine growth factor for cancer cells in a subgroup of SCLC patients through, at least in part, upregulation of GRPR expression.

Detection of tumor specific gene expression in bone marrow and peripheral blood from patients with small cell lung carcinoma.

BACKGROUND: Small cell lung carcinoma (SCLC) has the propensity to grow rapidly and metastasize extensively. Detection of micro-dissemination of SCLC may have clinical relevance. For its detection, tumor-specific gene expressions were examined in peripheral blood and bone marrow aspirate from patients with SCLC. METHODS: Expression of prepro-gastrin-releasing peptide (preproGRP), neuromedin B receptor (NMB-R) and gastrin-releasing peptide receptor (GRP-R) were examined by reverse transcriptase polymerase chain reaction (RT-PCR) in peripheral blood and bone marrow aspirate from 40 untreated patients with SCLC. Control samples consisted of peripheral blood samples from 5 patients with nonsmall cell lung cancer (NSCLC) and 20 healthy volunteers. RESULTS: Positive rates of preproGRP, NMB-R, and GRP-R in bone marrow aspirate of patients with SCLC were 23% (9/40), 8% (3/40), and 10% (4/40), respectively. Those rates in peripheral blood were 11% (4/38), 5% (2/38), and 29% (11/38), respectively. Although GRP-R expression was detected in patients with NSCLC and in healthy volunteers, preproGRP and NMB-R expressions were not detected in patients with NSCLC and in healthy volunteers. All three gene expressions in bone marrow were more frequently observed in patients with bone marrow metastasis, accessed by biopsy, than in patients without. PreproGRP gene expression in bone marrow was also more frequent in patients with bone metastasis, accessed by bone scintigram, than in patients without, and was related to poorer survival. CONCLUSIONS: Micro-dissemination of SCLC was detectable by RT-PCR of preproGRP and NMB-R, both specific for SCLC. These gene expressions in bone marrow may be related to disease extent and prognosis.