Biochemistry, Bombesin

Andrew LaPelusa; Arif Jan

Biochemistry, Bombesin

Free Review Questions

Introduction

Bombesin (BBS, BB), is a 14-amino acid neurohormone polypeptide, derived initially from amphibians with a wide range of physiological effects in the brain, lungs, and GI tract. Bombesin regulates gastrointestinal hormone release and gastrointestinal motility.[1] Recently, studies have evaluated the role of bombesin in tumor growth, cellular proliferation, and inflammation.[2] Research has also discovered several peptides structurally related to bombesin.[3] Two well-studied homologs are called neuromedin B and gastrin-releasing peptide (GRP).[1] The gastrin-releasing peptide is biologically and immunologically equivalent to bombesin, making GRP the mammalian equivalent. In addition to gastric neurohormonal impacts on the GI tract, the BN-like peptides have also been shown to modulate satiety, thermoregulation, glucose homeostasis, and circadian rhythms.[4][5]

Fundamentals

Bombesin receptors (BBR) are G-protein-coupled receptors. These receptors classify into three different types.

Neuromedin-B receptor ([NMB] also known as bombesin receptor 1 [BRS1, BB1, BBR-1])
Gastrin-releasing peptide receptor ([GRPR] also known as bombesin receptor 2 [BRS1, BB2, BBR-2]).
- GRPR is expressed in the pancreas and at lower levels in the colon, breast, prostate, and skin.
- Bombesin binding sites in the pancreas have a higher affinity for GRP and bombesin than compared to its other analog neuromedin B. This compares to the bombesin binding sites in the esophagus, which have a higher affinity to neuromedin B and bombesin than compared to GRP; this suggests that although bombesin has mammalian analogs, their true functions are not identical. The GRP-preferring binding sites were called "BB2" while the NMB-preferring binding sites were called "BB1". GRP has a higher affinity for BBR-2 than for BBR-1, making it a promising target for directed cancer therapies.[6]
Orphan receptor ([OR], also known as bombesin receptor 3 [BRS3, BB3, or BBR-3]).[7]
- The bombesin receptor-3 (BBR-3): The synthetic Bn peptide analog can be radiolabeled and used for binding studies in human tissues because it has a high affinity for human BRS-3.[8][9][10]

Bombesin has no known antagonist capability (i.e., receptor blocking effects). The area of the bombesin molecule that controls essential physiological activity also determines the affinity of the peptide toward its receptors. That is, the difference in potency amongst various derivatives and analogs of bombesin correlates with the variety in their receptor affinities. Of the segments and analogs of bombesin examined, none have been observed to occupy the bombesin receptor without causing a full biological response. Therefore, there remain no bombesin-related peptides that operate as a bombesin receptor antagonist.

As a stimulatory peptide, bombesin's effects do have variable potency in their impacts. The essential physiological effect of bombesin-related peptides is attributed to the carboxy-terminal portion of the molecule.[11][12] Shortened carboxy-terminal variants of bombesin still maintain full inherent biological response, but their influences are less than that of primary bombesin.[11][12][13][14] Bombesin receptors (and their analogs) are found in higher prevalence within breast, colon, lung, ovarian, urinary bladder, skin, and prostate tumors. Knowing this, researchers have attempted to target these receptors by using synthetic analogs of bombesin that are modified to contain chemotherapy agents (i.e., targeted chemotherapy).

Issues of Concern

It bears mentioning that bombesin is not structurally compatible with the biochemical processes because radioactive iodine (i.e., needed for biotech processes) normally binds to a tyrosine residue on the peptide of interest. Bombesin’s primary structure conflicts with the radioactive iodine and hence renders bombesin incapable of creating a radioactive peptide. This fact is important because the radioactive peptide is what researchers use for receptor binding studies. This issue is also true of all peptides structurally related to bombesin, thus potential use in radioactive labeling may not be possible.[15][16]

Cellular Level

Bombesin binds to G protein-coupled receptors, which stimulate adenylate cyclase, increasing intracellular cyclic adenine monophosphate (cAMP) levels and activating intracellular signal cascades. These cascades propagate, leading to calcium, sodium, and potassium fluxes inducing the modulation of growth factor receptors, and expression of the proto-oncogenes c-fos and c-myc.[17]. When bound to G-cells, bombesin signal transduction ultimately produces phosphatidylinositol, which acts as a secondary messenger, mediating intracellular vesicular fusion with the plasma membrane, and therefore regulating gastrin secretion from G-cells in the antrum of the stomach.[18][19]

Bombesin G protein-coupled receptor signal-cascade also results in the activation of protein kinase C (PKC) through the phosphatidylinositol second-messenger system.[17] Bombesin and bombesin-like peptides can activate protein kinase C proteins by endogenous diacylglycerol(DAG) levels; this increases the synthesis of cellular cyclic guanosine monophosphate (cGMP) molecules enabling the mobilization of intracellular calcium. Intracellular calcium activates the intracellular signal cascade mechanism controlling hormone secretion.[6]

Bombesin-associated extracellular events include stimulation of mitogenesis and monocyte chemoattraction.[20] A study showed evidence of bombesin’s mitogenic capabilities was whereby vasopressin caused desensitization to the mitogenic action of bombesin mediated by uncoupling the receptor from its signaling system.[17][20] Therefore the localization of these receptors is preassumed to be positioned on the basolateral side of the cell plasma membrane. There remain no studies that have localized receptors for bombesin or structurally associated peptides.

Function

In the brain, bombesin is known as neuromedin B and is involved in smooth muscle contraction.[21] Bombesin is present in regions of the trachea, bronchus, and within the whole lung at different stages of human fetal development. Bombesin is present in neonates, children, and adults.[22]

Bombesin causes the release of endogenous gastrin, activating sensory neurons located in the gastric fundus responsible for gastric smooth muscle motility and luminal protection. Activation of sensory neurons causes increased production of nitric oxide through activation of constitutive nitric oxide synthase. Activation of nitric oxide synthase leads to an increase in gastric mucosal blood flow and makes the stomach less susceptible to injury from luminal irritants.[23] Bombesin is the most effective promotor of G cell-regulated gastrin release plus subsequent stimulation of gastric acid excretion.[16][24][25][24]

Bombesin is predominantly known to regulate homeostasis within the gastrointestinal tract.[1] When binding to gastrointestinal luminal receptors, bombesin produces adverse effects such as nausea, vomiting, and diarrhea. Bombesin is the major source of negative feedback signals that stop eating behavior second only to cholecystokinin.[26]

Bombesin can function as a growth factor through autocrine or paracrine mechanisms, which may modulate the growth of various benign and neoplastic tissues. Therefore, the problem this protein can address is that of prostate precision. The fact that radiolabeling cannot differentiate between benign hyperplastic prostate cells and malignant carcinoma cells limits their diagnostic value. Hence, there has been much effort put into developing new prostate carcinoma–specific PET tracers with high diagnostic sensitivity and specificity.[27][28]

Mechanism

Bombesin binds to the G-protein receptor. G protein-coupled reaction occurs, which activates a phosphorylation cascade. Phosphorylation cascade cleaves PIP2. PIP2 separates into inosine-monophosphate (IP3) and diacylglycerol (DAG). IP3 and DAG both increase in concentration within the cell. DAG interacts with protein kinase C (PKC). DAG-PKC interaction activates protein kinase C (aPKC). aPKC phosphorylates serine residues on intracellular target proteins.[29] Intracellular target proteins release calcium stores intracellularly. Intracellular calcium levels increase, causing cellular depolarization. Intracellular calcium binds to synapsin, altering its conformation. Altered synapsin causes intracellular vesicle diffusion. Altered synapsin exposes calcium-binding sites on microtubules attached to intracellular vesicles. Calcium activates dynein arms causing efferent microtubules diffusion. Vesicles fuse with the plasma membrane and release their contents into the extracellular environment.[29]

Pathophysiology

Researchers believe that neuropeptides influence feeding, satiety, energy homeostasis, and other parameters associated with weight control.[30] Those involved are bombesin, insulin, and orexins. These peptides exhibit diverse effects upon the hypothalamus by acting as ligands for G protein-coupled receptors within the brain. Some tumors can produce agents such as bombesin and adrenocorticotropic hormone, which can affect caloric processing.[31][32][33] The abnormal intake and utilization of calories contribute to the altered metabolism associated with cachexic states precipitated by tumorigenesis, which leads to a cyclical chain of events in which protein catabolism, glucose intolerance, and lipolysis cannot be augmented by the addition of calories.

Inhalational exposures can precipitate an inflammatory reaction within the airways and alveoli, leading to activated neutrophils, and other inflammatory cells release proteases as part of the inflammatory process. Neutrophil-induced oxidative damage stimulates the release of profibrotic neuropeptide bombesin in the normal process of tissue repair. This mechanism appears to contribute to the pulmonary neuroendocrine cells' promotion of bombesin-like peptide immunoreactivity.[34]

Studies have correlated bombesin-like immunoreactivity with the abnormal inflammatory response seen in bronchopulmonary dysplasia.[35][36] Researchers in a study of 132 infants at 28-weeks gestation or less found that bombesin-like peptide levels elevate in the urine prior to the development of bronchopulmonary dysplasia.[37] Infants who had elevated levels of the bombesin-like peptide in their urine 1 to 4 days after birth were ten times more likely to develop bronchopulmonary dysplasia.[37] Therefore, urine bombesin-like peptide screening might allow for early therapeutic interventions to minimize disease progression.

Eosinophilic granuloma is a fibrotic lung disease almost always seen in adult cigarette smokers. One study showed that the number of pulmonary neuroendocrine cells with bombesin-like immunoreactivity increases in patients with eosinophilic granuloma.[20] Therefore neuroendocrine cell hyperplasia may lead to bombesin-like peptide elevation and subsequent monocyte and fibroblast recruitment, which contribute to granuloma formation; this would be in line with other studies which have shown bombesin to be chemotactic for monocytes and mitogenic for fibroblasts.[20]

Inhibition of Ca ++ influx inhibits the release of neurotransmitters like bombesin, acetylcholine, norepinephrine, serotonin, somatostatin, and substance P. These neurotransmitters mediate pain perception in the spinal cord. Inhibition of release into the synaptic cleft leads to decreased postsynaptic neuronal firing and transmission of nociception.[38]

Tumors of neuronal origin such as medulloblastoma, primitive neuroectodermal tumors, neuroblastoma, pineoblastoma are bombesin positive. Recently it has been suggested that bombesin-related peptides are involved in the autocrine stimulation of human small-cell lung carcinomas The growth and metastatic potential of neuroendocrine tumors. The molecular mechanisms and signaling pathways that are responsible for bombesin-like peptide-induced cell migration and invasion remain unclear.[23][39]

Bombesin exerts a stimulatory effect on the growth of human prostatic cancer cells in vitro.[34] Bombesin also has a role in prostatic epithelium growth; this would support other studies stating that prostatic carcinoma may have an endocrine, autocrine, or paracrine proliferation stimulus within the gland microenvironment.[40][41][42] This important fact provides an objective basis for the development of neuropeptides as therapeutic targets and may be helpful in the treatment of advanced prostatic carcinoma.[43][41]

Clinical Significance

Loss of bombesin receptors correlates with age-dependent obesity, hypertension, glucose intolerance, and high insulin levels. This expanded adipose deposition may, in part, be due to a decline in energy consumption without a shift in eating or movement, which infers that bombesin receptors may signify a plausible target upon which notable advancement can take place in the realm of anti-obesity agents.

Bombesin has the theoretical capability to address prostate cancer screening. Current screening methods include prostate-specific antigen serum testing, followed by a digital rectal examination. Those screening techniques do not yield information on the primary location of the carcinoma cells. Therefore, possible metastases cannot be determined or diagnosed with high accuracy. The fact that radiolabeling cannot differentiate between benign hyperplastic prostate cells and malignant carcinoma cells limits their diagnostic value. BBR and gastrin-releasing peptide receptors are over-expressed in solid malignancies and particularly in prostate cancer.[44] These receptors are over-expressed rarely and, if expressed, then only in low density in benign prostatic hyperplasia and normal prostate tissue.[45] Studies have shown that prostate tissue has a high density of receptors belonging to the bombesin receptor family.[46] This finding has sparked an interest in developing new prostate carcinoma–specific PET tracers, which would provide high diagnostic sensitivity and specificity.

Precision medicine is also known as theranostics, is a medical model that separates people into different groups with medical care tailored to the individual patient based on their predicted response or risk of disease.[47] Gastrin-releasing peptide receptor antagonists have promise in theranostics of several highly incident tumors, including prostate and breast.[48] Bombesin receptors often demonstrate significant expression on a variety of tumors. Therefore, bombesin can chaperone cytotoxic drugs straight to these tumors. A cytotoxic analog of bombesin containing doxorubicin displayed disease stabilization through phase-I clinical trials against ovarian and endometrial carcinomas.[49] It is now undergoing phase-I or phase-II clinical trials in other various malignancies.[4]

Measuring bombesin stimulated gastrin response can serve as a marker for patients who are at very high risk for gastric cancer. Patients with late-onset hypogammaglobulinemia are at very high risk for gastric cancer. Late-onset hypogammaglobulinemia patients have reduced secretion of gastrin after stimulation with bombesin. Stimulated gastrin response can, therefore, be useful as a marker for this type of immunodeficiency. Plasma gastrin responses to stimulation with bombesin correlate with late-onset hypogammaglobulinemia. (72% sensitivity , 100% specificity). Bombesin can help to distinguish late-onset hypogammaglobulinemia from X-linked agammaglobulinemia, early-onset hypogammaglobulinemia, and lymphoproliferative cancer.[50] This differentiation would also help to identify patients with an increased risk for gastric cancer. Plasma gastrin responses to stimulation with bombesin correlate with late-onset hypogammaglobulinemia.

A bombesin/gastrin-releasing peptide antagonist might hold promise as a possible new agent for the treatment of breast cancer.[51]

Details

References

[1]

Anastasi A, Erspamer V, Bucci M. Isolation and amino acid sequences of alytesin and bombesin, two analogous active tetradecapeptides from the skin of European discoglossid frogs. Archives of biochemistry and biophysics. 1972 Feb:148(2):443-6 [PubMed PMID: 4537042]

[2]

Moreno P, Mantey SA, Lee SH, Ramos-Álvarez I, Moody TW, Jensen RT. A possible new target in lung-cancer cells: The orphan receptor, bombesin receptor subtype-3. Peptides. 2018 Mar:101():213-226. doi: 10.1016/j.peptides.2018.01.016. Epub 2018 Feb 2 [PubMed PMID: 29410320]

[3]

McDonald TJ, Jörnvall H, Nilsson G, Vagne M, Ghatei M, Bloom SR, Mutt V. Characterization of a gastrin releasing peptide from porcine non-antral gastric tissue. Biochemical and biophysical research communications. 1979 Sep 12:90(1):227-33 [PubMed PMID: 496973]

[4]

Accardo A, Mannucci S, Nicolato E, Vurro F, Diaferia C, Bontempi P, Marzola P, Morelli G. Easy formulation of liposomal doxorubicin modified with a bombesin peptide analogue for selective targeting of GRP receptors overexpressed by cancer cells. Drug delivery and translational research. 2019 Feb:9(1):215-226. doi: 10.1007/s13346-018-00606-x. Epub [PubMed PMID: 30569349]

[5]

Assimakopoulos SF, Alexandris IH, Scopa CD, Mylonas PG, Thomopoulos KC, Georgiou CD, Nikolopoulou VN, Vagianos CE. Effect of bombesin and neurotensin on gut barrier function in partially hepatectomized rats. World journal of gastroenterology. 2005 Nov 21:11(43):6757-64 [PubMed PMID: 16425380]

[6]

Gonzalez N, Moody TW, Igarashi H, Ito T, Jensen RT. Bombesin-related peptides and their receptors: recent advances in their role in physiology and disease states. Current opinion in endocrinology, diabetes, and obesity. 2008 Feb:15(1):58-64. doi: 10.1097/MED.0b013e3282f3709b. Epub [PubMed PMID: 18185064]

Level 3 (low-level) evidence

[7]

Battey JF, Way JM, Corjay MH, Shapira H, Kusano K, Harkins R, Wu JM, Slattery T, Mann E, Feldman RI. Molecular cloning of the bombesin/gastrin-releasing peptide receptor from Swiss 3T3 cells. Proceedings of the National Academy of Sciences of the United States of America. 1991 Jan 15:88(2):395-9 [PubMed PMID: 1671171]

[8]

Mantey SA, Weber HC, Sainz E, Akeson M, Ryan RR, Pradhan TK, Searles RP, Spindel ER, Battey JF, Coy DH, Jensen RT. Discovery of a high affinity radioligand for the human orphan receptor, bombesin receptor subtype 3, which demonstrates that it has a unique pharmacology compared with other mammalian bombesin receptors. The Journal of biological chemistry. 1997 Oct 10:272(41):26062-71 [PubMed PMID: 9325344]

[9]

Moreno P, Mantey SA, Nuche-Berenguer B, Reitman ML, González N, Coy DH, Jensen RT. Comparative pharmacology of bombesin receptor subtype-3, nonpeptide agonist MK-5046, a universal peptide agonist, and peptide antagonist Bantag-1 for human bombesin receptors. The Journal of pharmacology and experimental therapeutics. 2013 Oct:347(1):100-16. doi: 10.1124/jpet.113.206896. Epub 2013 Jul 26 [PubMed PMID: 23892571]

Level 2 (mid-level) evidence

[10]

Pradhan TK, Katsuno T, Taylor JE, Kim SH, Ryan RR, Mantey SA, Donohue PJ, Weber HC, Sainz E, Battey JF, Coy DH, Jensen RT. Identification of a unique ligand which has high affinity for all four bombesin receptor subtypes. European journal of pharmacology. 1998 Feb 19:343(2-3):275-87 [PubMed PMID: 9570477]

[11]

Deschodt-Lanckman M, Robberecht P, De Neef P, Lammens M, Christophe J. In vitro action of bombesin and bombesin-like peptides on amylase secretion, calcium efflux, and adenylate cyclase activity in the rat pancreas: a comparison with other secretagogues. The Journal of clinical investigation. 1976 Oct:58(4):891-8 [PubMed PMID: 184111]

[12]

Jensen RT, Battey JF, Spindel ER, Benya RV. International Union of Pharmacology. LXVIII. Mammalian bombesin receptors: nomenclature, distribution, pharmacology, signaling, and functions in normal and disease states. Pharmacological reviews. 2008 Mar:60(1):1-42 [PubMed PMID: 18055507]

[13]

Broccardo M, Falconieri Erspamer G, Melchiorri P, Negri L, de Castiglione R. Relative potency of bombesin-like peptides. British journal of pharmacology. 1975 Oct:55(2):221-7 [PubMed PMID: 1201380]

[14]

Lin JT, Coy DH, Mantey SA, Jensen RT. Comparison of the peptide structural requirements for high affinity interaction with bombesin receptors. European journal of pharmacology. 1995 Dec 27:294(1):55-69 [PubMed PMID: 8788416]

[15]

Swope SL, Schonbrunn A. Characterization of ligand binding and processing by bombesin receptors in an insulin-secreting cell line. The Biochemical journal. 1987 Nov 1:247(3):731-8 [PubMed PMID: 2827637]

[16]

Cardona C, Bleehen NM, Reeve JG. Characterization of ligand binding and processing by gastrin-releasing peptide receptors in a small-cell lung cancer cell line. The Biochemical journal. 1992 Jan 1:281 ( Pt 1)(Pt 1):115-20 [PubMed PMID: 1310003]

[17]

Rozengurt E. Bombesin stimulation of mitogenesis. Specific receptors, signal transduction, and early events. The American review of respiratory disease. 1990 Dec:142(6 Pt 2):S11-5 [PubMed PMID: 2174658]

[18]

Campos RV, Buchan AM, Meloche RM, Pederson RA, Kwok YN, Coy DH. Gastrin secretion from human antral G cells in culture. Gastroenterology. 1990 Jul:99(1):36-44 [PubMed PMID: 1971610]

[19]

Buchan AM, Meloche RM. Signal transduction events involved in bombesin-stimulated gastrin release from human G cells in culture. Canadian journal of physiology and pharmacology. 1994 Sep:72(9):1060-5 [PubMed PMID: 7842388]

[20]

Aguayo SM, King TE Jr, Waldron JA Jr, Sherritt KM, Kane MA, Miller YE. Increased pulmonary neuroendocrine cells with bombesin-like immunoreactivity in adult patients with eosinophilic granuloma. The Journal of clinical investigation. 1990 Sep:86(3):838-44 [PubMed PMID: 2394833]

[21]

Minamino N, Sudoh T, Kangawa K, Matsuo H. Neuromedins: novel smooth-muscle stimulating peptides identified in porcine spinal cord. Peptides. 1985:6 Suppl 3():245-8 [PubMed PMID: 3841690]

[22]

Ghatei MA, Sheppard MN, Henzen-Logman S, Blank MA, Polak JM, Bloom SR. Bombesin and vasoactive intestinal polypeptide in the developing lung: marked changes in acute respiratory distress syndrome. The Journal of clinical endocrinology and metabolism. 1983 Dec:57(6):1226-32 [PubMed PMID: 6630415]

[23]

Tell R, Rivera CA, Eskra J, Taglia LN, Blunier A, Wang QT, Benya RV. Gastrin-releasing peptide signaling alters colon cancer invasiveness via heterochromatin protein 1Hsβ. The American journal of pathology. 2011 Feb:178(2):672-8. doi: 10.1016/j.ajpath.2010.10.017. Epub [PubMed PMID: 21281799]

[24]

Delle Fave G, Annibale B, de Magistris L, Severi C, Bruzzone R, Puoti M, Melchiorri P, Torsoli A, Erspamer V. Bombesin effects on human GI functions. Peptides. 1985:6 Suppl 3():113-6 [PubMed PMID: 3913904]

[25]

Ladenheim EE, Moore KA, Salorio CF, Mantey SA, Taylor JE, Coy DH, Jensen RT, Moran TH. Characterization of bombesin binding sites in the rat stomach. European journal of pharmacology. 1997 Jan 29:319(2-3):245-51 [PubMed PMID: 9042597]

[26]

Erspamer V, Improta G, Melchiorri P, Sopranzi N. Evidence of cholecystokinin release by bombesin in the dog. British journal of pharmacology. 1974 Oct:52(2):227-32 [PubMed PMID: 4451817]

[27]

Sherman SK, Carr JC, Wang D, O'Dorisio MS, O'Dorisio TM, Howe JR. Gastric inhibitory polypeptide receptor (GIPR) is a promising target for imaging and therapy in neuroendocrine tumors. Surgery. 2013 Dec:154(6):1206-13; discussion 1214. doi: 10.1016/j.surg.2013.04.052. Epub [PubMed PMID: 24238043]

[28]

Rick FG, Abi-Chaker A, Szalontay L, Perez R, Jaszberenyi M, Jayakumar AR, Shamaladevi N, Szepeshazi K, Vidaurre I, Halmos G, Krishan A, Block NL, Schally AV. Shrinkage of experimental benign prostatic hyperplasia and reduction of prostatic cell volume by a gastrin-releasing peptide antagonist. Proceedings of the National Academy of Sciences of the United States of America. 2013 Feb 12:110(7):2617-22. doi: 10.1073/pnas.1222355110. Epub 2013 Jan 28 [PubMed PMID: 23359692]

[29]

Kim HJ, Evers BM, Guo Y, Banker NA, Hellmich MR, Townsend CM Jr. Bombesin-mediated AP-1 activation in a human gastric cancer (SIIA). Surgery. 1996 Aug:120(2):130-6; discussion 136-7 [PubMed PMID: 8751574]

[30]

Arora S, Anubhuti. Role of neuropeptides in appetite regulation and obesity--a review. Neuropeptides. 2006 Dec:40(6):375-401 [PubMed PMID: 16935329]

[31]

Tsuchihashi T, Yamaguchi K, Abe K, Yanaihara N, Saito S. Production of immunoreactive corticotropin-releasing hormone in various neuroendocrine tumors. Japanese journal of clinical oncology. 1992 Aug:22(4):232-7 [PubMed PMID: 1359172]

[32]

Travis WD, Linnoila RI, Tsokos MG, Hitchcock CL, Cutler GB Jr, Nieman L, Chrousos G, Pass H, Doppman J. Neuroendocrine tumors of the lung with proposed criteria for large-cell neuroendocrine carcinoma. An ultrastructural, immunohistochemical, and flow cytometric study of 35 cases. The American journal of surgical pathology. 1991 Jun:15(6):529-53 [PubMed PMID: 1709558]

Level 3 (low-level) evidence

[33]

Jackson JA, Raju BU, Fachnie JD, Mellinger RC, Janakiraman N, Lloyd RV, Vinik AI. Malignant somatostatinoma presenting with diabetic ketoacidosis. Clinical endocrinology. 1987 May:26(5):609-21 [PubMed PMID: 2822297]

[34]

Johnson DE, Wobken JD, Landrum BG. Changes in bombesin, calcitonin, and serotonin immunoreactive pulmonary neuroendocrine cells in cystic fibrosis and after prolonged mechanical ventilation. The American review of respiratory disease. 1988 Jan:137(1):123-31 [PubMed PMID: 3337452]

[35]

Subramaniam M, Bausch C, Twomey A, Andreeva S, Yoder BA, Chang L, Crapo JD, Pierce RA, Cuttitta F, Sunday ME. Bombesin-like peptides modulate alveolarization and angiogenesis in bronchopulmonary dysplasia. American journal of respiratory and critical care medicine. 2007 Nov 1:176(9):902-12 [PubMed PMID: 17585105]

[36]

Subramaniam M, Sugiyama K, Coy DH, Kong Y, Miller YE, Weller PF, Wada K, Wada E, Sunday ME. Bombesin-like peptides and mast cell responses: relevance to bronchopulmonary dysplasia? American journal of respiratory and critical care medicine. 2003 Sep 1:168(5):601-11 [PubMed PMID: 12807697]

[37]

Cullen A, Van Marter LJ, Allred EN, Moore M, Parad RB, Sunday ME. Urine bombesin-like peptide elevation precedes clinical evidence of bronchopulmonary dysplasia. American journal of respiratory and critical care medicine. 2002 Apr 15:165(8):1093-7 [PubMed PMID: 11956050]

[38]

Zhao ZQ, Huo FQ, Jeffry J, Hampton L, Demehri S, Kim S, Liu XY, Barry DM, Wan L, Liu ZC, Li H, Turkoz A, Ma K, Cornelius LA, Kopan R, Battey JF Jr, Zhong J, Chen ZF. Chronic itch development in sensory neurons requires BRAF signaling pathways. The Journal of clinical investigation. 2013 Nov:123(11):4769-80 [PubMed PMID: 24216512]

[39]

Lee S, Qiao J, Paul P, Chung DH. Integrin β1 is critical for gastrin-releasing peptide receptor-mediated neuroblastoma cell migration and invasion. Surgery. 2013 Aug:154(2):369-75. doi: 10.1016/j.surg.2013.04.067. Epub [PubMed PMID: 23889963]

Level 2 (mid-level) evidence

[40]

Ohlsson B, Fredäng N, Axelson J. The effect of bombesin, cholecystokinin, gastrin, and their antagonists on proliferation of pancreatic cancer cell lines. Scandinavian journal of gastroenterology. 1999 Dec:34(12):1224-9 [PubMed PMID: 10636070]

[41]

Robertson JF, Watson SA, Hardcastle JD. Effect of gastrointestinal hormones and synthetic analogues on the growth of pancreatic cancer. International journal of cancer. 1995 Sep 27:63(1):69-75 [PubMed PMID: 7558455]

[42]

Anastasi A, Erspamer V, Bucci M. Isolation and structure of bombesin and alytesin, 2 analogous active peptides from the skin of the European amphibians Bombina and Alytes. Experientia. 1971 Feb 15:27(2):166-7 [PubMed PMID: 5544731]

[43]

Salido M, Vilches J, López A, Roomans GM. Neuropeptides bombesin and calcitonin inhibit apoptosis-related elemental changes in prostate carcinoma cell lines. Cancer. 2002 Jan 15:94(2):368-77 [PubMed PMID: 11900223]

[44]

Lau J, Rousseau E, Zhang Z, Uribe CF, Kuo HT, Zeisler J, Zhang C, Kwon D, Lin KS, Bénard F. Positron Emission Tomography Imaging of the Gastrin-Releasing Peptide Receptor with a Novel Bombesin Analogue. ACS omega. 2019 Jan 31:4(1):1470-1478. doi: 10.1021/acsomega.8b03293. Epub 2019 Jan 16 [PubMed PMID: 30775647]

[45]

Markwalder R, Reubi JC. Gastrin-releasing peptide receptors in the human prostate: relation to neoplastic transformation. Cancer research. 1999 Mar 1:59(5):1152-9 [PubMed PMID: 10070977]

[46]

Bologna M, Festuccia C, Muzi P, Biordi L, Ciomei M. Bombesin stimulates growth of human prostatic cancer cells in vitro. Cancer. 1989 May 1:63(9):1714-20 [PubMed PMID: 2539244]

[47]

Baratto L, Jadvar H, Iagaru A. Prostate Cancer Theranostics Targeting Gastrin-Releasing Peptide Receptors. Molecular imaging and biology. 2018 Aug:20(4):501-509. doi: 10.1007/s11307-017-1151-1. Epub [PubMed PMID: 29256046]

[48]

Gnesin S, Cicone F, Mitsakis P, Van der Gucht A, Baechler S, Miralbell R, Garibotto V, Zilli T, Prior JO. First in-human radiation dosimetry of the gastrin-releasing peptide (GRP) receptor antagonist (68)Ga-NODAGA-MJ9. EJNMMI research. 2018 Dec 12:8(1):108. doi: 10.1186/s13550-018-0462-9. Epub 2018 Dec 12 [PubMed PMID: 30543050]

[49]

Keller G, Schally AV, Nagy A, Halmos G, Baker B, Engel JB. Targeted chemotherapy with cytotoxic bombesin analogue AN-215 can overcome chemoresistance in experimental renal cell carcinomas. Cancer. 2005 Nov 15:104(10):2266-74 [PubMed PMID: 16211544]

[50]

den Hartog G, van der Meer JW, Jansen JB, van Furth R, Lamers CB. Decreased gastrin secretion in patients with late-onset hypogammaglobulinemia. The New England journal of medicine. 1988 Jun 16:318(24):1563-7 [PubMed PMID: 3374528]

[51]

Yano T, Pinski J, Szepeshazi K, Halmos G, Radulovic S, Groot K, Schally AV. Inhibitory effect of bombesin/gastrin-releasing peptide antagonist RC-3095 and luteinizing hormone-releasing hormone antagonist SB-75 on the growth of MCF-7 MIII human breast cancer xenografts in athymic nude mice. Cancer. 1994 Feb 15:73(4):1229-38 [PubMed PMID: 8313327]