Disease relevance of GRP

• GRP receptors were detected, often in high density, in 30 of 30 invasive prostatic carcinomas and also in 26 of 26 cases of prostatic intraepithelial proliferative lesions, corresponding mostly to prostatic intraepithelial neoplasias [1].
• The lymph node metastases (n = 33) from those primary carcinomas expressing GRP receptors were all positive, whereas surrounding lymphoreticular tissue was negative [2].
• GRP receptors were detected, often in high density, in neoplastic epithelial mammary cells in 29 of 46 invasive ductal carcinomas, in 11 of 17 ductal carcinomas in situ, in 1 of 4 invasive lobular carcinomas, in 1 of 2 lobular carcinomas in situ, and in 1 mucinous and 1 tubular carcinoma [2].
• In addition, the proliferative effect of GRP on neuroblastoma cells (SK-N-SH, IMR-32, SH-SY5Y, LAN-1) was determined [3].
• Cultures of HBE cells from four of the five subjects with severe obstructive lung disease gave a positive response to GRP and NMB in proliferation assays, compared to five of fifteen without severe obstructive lung disease, but this difference was not significant (p = 0.13) [4].

Psychiatry related information on GRP

• We conclude that BN-related peptides play an important role in the control of food intake, and may contribute to ingestive disruptions associated with anorexia (anorexia nervosa, AIDS and cancer anorexia), bulimia, obesity and depression [5].
• Total body images were acquired in patients and normal volunteers 1 and 3 h after 99mTc BN acquisition [6].
• METHODS: To explore further the role of GRP in humans, its effects on satiety and eating behavior were investigated by infusion of GRP into healthy men at three dosages (10, 40, and 160 pmol/kg per hour) and compared with saline infusions [7].
• When bulls were in GRP and tested first on test days, more (P <0.05) copulations were distributed to the first three females encountered compared with either the fourth female (P <0.05) or to each of the other females in SEQ (P <0.05) [8].
• Gastrin-releasing peptide: an identity crisis at 30 [9]?

High impact information on GRP

• Bombesin and bombesin-like peptides (BLPs) such as gastrin-releasing peptide (GRP) cause various physiological responses in mammals, including stimulation of proliferation of 3T3 mouse fibroblasts and normal human bronchial epithelial cells in vitro and induction of gastrin cell hyperplasia and increased pancreatic DNA content in vivo in rats [10].
• We used neutralizing GRP monoclonal antibody 2A11 to block the GRP-GRPR interaction in SCCHN cell lines and xenografts and assessed the antibody's effect on proliferation by counting cultured cells or measuring xenograft tumor volume in vivo [11].
• Neutralizing GRP monoclonal antibody 2A11 inhibited SCCHN cell proliferation in vitro and in vivo [11].
• Within the gastrointestinal tract, GRP receptors (GRP-R) are not normally expressed by mucosal epithelial cells except for those lining the gastric antrum [12].
• By RNA blot analysis, GRP mRNA was first detectable in fetal monkey lung at 63 days gestation, reached highest levels at 80 days gestation, and then declined to near adult levels by 120 days gestation; a pattern closely paralleling GRP expression in human fetal lung [13].

Chemical compound and disease context of GRP

• This suggests that the bombesin/GRP family of neuropeptides may play a regulatory role in the biology of androgen-independent prostate cancer [14].
• BACKGROUND: Gastrin releasing peptide (GRP) and neuromedin B are bombesin (BN)-like peptides involved in regulating motility and inflammation in the gastrointestinal tract, which may be useful in treating inflammatory bowel disease (IBD) [15].
• Our results suggest that somatostatin analog RC-160 and bombesin/GRP antagonist RC-3095 can inhibit the growth of androgen-independent prostate cancer when the therapy is started at an early stage of tumor development [16].
• There was no effect of sepsis on GRP or substance P levels [17].
• MS-275 had little effect on the expression of lung cancer cellular GRP or GRP receptors, but increased expression of transforming growth factor-beta receptor II (TGF-beta RII) [18].

Biological context of GRP

• These findings suggest that an inhibition of the tumor suppressor gene PTEN may be an important regulatory mechanism involved in GRP-induced cell proliferation in neuroblastomas [19].
• An increase in GRP binding capacity was confirmed in GRP-R overexpressing cells, which demonstrated an accelerated constitutive cell growth rate [19].
• However, the effects of GRP on expression of the tumor suppressor gene PTEN have not been elucidated in neuroblastomas [19].
• RESULTS: Of the 80 specimens of primary prostate cancer examined by receptor binding assays, 50 ( approximately 63%) showed high-affinity, low-capacity binding sites for bombesin/GRP, and 12 of these 50 receptor-positive specimens also showed a second binding site [20].
• Specific [125I-Tyr0]NMB binding was inhibited with high affinity by NMB (IC50 = 1 nM) and moderate affinity by bombesin, GRP and [D-Arg1, D-Pro2, D-Trp7,9, Leu11]substance P ([APTTL]SP) but not GRP1-16 (IC50 = 50, 100, 1,000 and > 10,000 nM, respectively) [21].

Anatomical context of GRP

• Therapy with RC-3095 decreased the concentration of BN/GRP receptors on H-128 SCLC tumor membranes [22].
• Conversely, GRP receptors were identified in only a few hyperplastic prostates and were localized in very low density in glandular tissue and, focally, in some stromal tissue [1].
• GRP treatment resulted in intracellular calcium [Ca2+]i mobilization in two cell lines (SK-N-SH, LAN-1) [3].
• RESULTS: Normal uterine tissues expressed GRP receptors (GRP-Rs) in the myometrium, in subsets of secretory endometrial glands, and in subsets of endometrial blood vessels of the late proliferative and the secretory phase [23].
• Furthermore, expression of GRP receptors, neurokinin (NK)1 receptors, VIP type2-receptors and sst2 receptors was found in the mucosa-directed margin of the circular smooth muscle where the interstitial cells of Cajal are located [24].

Associations of GRP with chemical compounds

• In all of the cases, the receptors corresponded to the GRP receptor subtype of bombesin receptors, having high affinity for GRP and bombesin and lower affinity for neuromedin B [1].
• In addition to TGF-alpha release, GRP induced amphiregulin, but not EGF, secretion into HNSCC cell culture medium, an effect that was blocked by the MMP inhibitor marimastat [25].
• The affinities of various agonists for binding to the huGRP-R were Bn (Ki = 1.4 +/- 0.2 nM) = 4 x GRP = 300 x NMB [26].
• GRP also induced the labeling of a large percentage (53%) of the cells with bromodeoxyuridine [27].
• Both agents markedly inhibited the degradation of GRP, indicating that this process involves a lysosomal pathway and a phosphoramidon-sensitive pathway, possibly involving the EC 3.4.24.11 enzyme [28].

Physical interactions of GRP

• The bombesin-related peptides neuromedin B (NMB) and phyllolitorin also bound to GRP receptors with Ki values of 22.7 and 59.1 nM respectively [28].
• These data support the hypothesis that GRP interacts with VIP and PHI within the SCN to induce phase shifts of circadian rhythms [29].

Co-localisations of GRP

• Gastrin-releasing peptide-containing cell bodies also colocalized with a subgroup of somatostatin cell bodies [30].

Regulatory relationships of GRP

• NMB induced a larger percent change in alkaline phosphatase secretion than GRP with a half maximal response at less than 1 nM NMB [31].
• All actions of bombesin were blocked by BME (D-Phe(6)-bombesin-(6-13)-methylester), a selective GRP receptor antagonist, but not by the NMB receptor antagonist BIM-23127 (D-Nal-cyclo[Cys-Tyr-D-Trp-Orn-Val-Cys]-Nal-NH(2)).We conclude that HPAF cells express mRNA for GRP receptors and that functional receptors are present in the cell membrane [32].
• Thus this study demonstrates that GRP receptors are expressed on airway epithelial cells in developing fetal lung and that the interaction of GRP with the GRP receptor stimulates airway development [13].
• Gastrin-releasing peptide mediates its morphogenic properties in human colon cancer by upregulating intracellular adhesion protein-1 (ICAM-1) via focal adhesion kinase [33].
• Although we have shown that these processes are mediated by focal adhesion kinase (FAK), the downstream target(s) of GRP-induced FAK activation are not known [33].

Other interactions of GRP

• To further elucidate the mechanism of activation of EGFR by GRP in HNSCC, we investigated the role of Src family kinases [25].
• Invasion and growth assays showed that c-Src was required for GRP-induced proliferation or invasion of HNSCC cells [25].
• Lung tissue GRP, CGRP, and PYY levels appeared to decrease gradually with time, perhaps as a result of the positive pressure ventilation procedure [34].
• GRP concentrations increased during hypoglycaemia (p < 0.01) while a reduction in AVP occurred at the start of hypoglycaemia (p < 0.001) [35].
• Levels of gastrin-releasing peptide and substance P in synovial fluid and serum correlate with levels of cytokines in rheumatoid arthritis [36].

Analytical, diagnostic and therapeutic context of GRP

• In the present study, we have evaluated the expression of GRP receptors in human nonneoplastic and neoplastic prostate tissues using in vitro receptor autoradiography on tissue sections with 125I-Tyr4-bombesin as radio-ligand [1].
• Apart from suggesting a role of GRP in breast physiology, these data represent the molecular basis for potential clinical applications of GRP analogs such as GRP receptor scintigraphy, radiotherapy, or chemotherapy [2].
• METHODS: Sections of paraffin-embedded neuroblastomas from 33 patients were analyzed for GRP and GRP-R protein expression by immunohistochemistry [3].
• Sequence-specific radioimmunoassay demonstrated the presence of substantial amounts of fully processed amidated GRP in the ovine renal cortex and medulla [37].
• GRP mRNA was detected in rat kidney from embryonic day 19 to postnatal day 30 by RT-PCR [37].

References