GRP and Small Cell Carcinoma
GRP is a bombesin-like peptide present in mammalian tissues. The production of bombesin by lung cancer has been reported, and we have shown that bombesin-like peptide produced by lung cancers is more similar to GRP than bombesin, and that GRP is a very common product of SCLC compared with other peptide hormones. As far as the biologic implications of GRP production by SCLC are concerned, several reported findings indicate that GRP functions as an autocrine growth factor for human SCLC. First, human SCLCs produce bombesin/GRP with high frequency.’ Second, GRP added exogenously has a stimulatory effect on cellular growth and DNA synthesis of SCLC cells in vitro.10 Third, SCLC cell lines sometimes express high-affinity receptors for bombesin. Fourth, a MoAb recognizing the carboxyl terminal portion of bombesin and GRP inhibits the clonal growth of SCLC cells in vitro and the tumor growth of SCLC xenografts in vivo These facts suggest that an autocrine mechanism related to GRP may play a role in the growth of SCLC cells.
From the clinical standpoint, it is possible to speculate that determination of plasma GRP levels could serve as a reliable tumor marker in SCLC patients. With the aim of investigating this possibility, we developed a highly sensitive RIA system for detecting plasma GRP levels by using immunochromatography for plasma extraction, and then measured plasma GRP levels in normal subjects, SCLC patients, and non-SCLC patients. When plasma GRP levels were determined by using 15 ml of plasma as the starting material (minimum concentration detectable, 0.8 pg/ml), the levels in 10 control subjects were (mean ± SD) 1.2 ± 0.27 pg/ml; range, 0.86-1.7 pg/ml. This assay system was applied for the clinical use by using 3 ml of plasma as the starting material (minimum concentration detectable, 4.0 pg/ml). The data on plasma GRP levels and the frequency of plasma GRP elevation in 10 control subjects, 17 untreated SCLC patients, and 21 non-SCLC patients are shown in Figure 2. Here
Plasma GRP levels were undetectable in control subjects and non-SCLC patients. In contrast, levels were elevated from 4.6 to 58 pg/ml in 5/7 SCLC patients (71%) with limited disease and in 8/10 (80%) with extensive disease. Ftother, a change in the level showed excellent correlation with the therapeutic responses determined by imaging diagnostic techniques. These results indicate that plasma GRP level is a useful tumor marker in SCLC patients, and suggest that a possible autocrine growth factor could serve as a reliable tumor marker for cancer patients. Further improvements of the assay system will be required to measure plasma GRP levels more easily in SCLC patients.
Figure 2. Plasma GRP levels and frequency of plasma GRP elevation in control subjects, SCLC patients and non-SCLC patients. In the block for SCLC patients, closed circles (•) indicate patients with extensive disease and open circles (o) indicate patients with limited disease. Ca., carcinoma; UD, undetectable. (Maruno K, et al. Cancer Res 1989; 49:630. Reproduced by permission of Cancer Research.)