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Journal of Nuclear Medicine : Official... Oct 2014Receptors for some regulatory peptides are highly expressed in tumors. Selective radiolabeled peptides can bind with high affinity and specificity to these receptors and... (Review)
Review
Receptors for some regulatory peptides are highly expressed in tumors. Selective radiolabeled peptides can bind with high affinity and specificity to these receptors and exhibit favorable pharmacologic and pharmacokinetic properties, making them suitable agents for imaging or targeted therapy. The success encountered with radiolabeled somatostatin analogs is probably the first of a long list, as multiple peptide receptors are now recognized as potential targets. This review focuses on 3 neuropeptide receptor systems (bombesin, neurotensin, and neuropeptide-Y) that offer high potential in the field of nuclear oncology. The underlying biology of these peptide/receptor systems, their physiologic and pathologic roles, and their differential distribution in normal and tumoral tissues are described with emphasis on breast, prostate, and lung cancers. Radiolabeled analogs that selectively target these receptors are highlighted.
Topics: Breast Neoplasms; Female; Humans; Lung Neoplasms; Male; Peptides; Positron-Emission Tomography; Prostatic Neoplasms; Receptors, Bombesin; Receptors, Neuropeptide Y; Receptors, Neurotensin; Tomography, X-Ray Computed
PubMed: 25189338
DOI: 10.2967/jnumed.114.142000 -
The Journal of Endocrinology Jan 2016The incretin hormones glucagon-like peptide-1 (GLP1) and glucose-dependent insulinotropic polypeptide (GIP) are secreted from intestinal endocrine cells, the so-called...
The incretin hormones glucagon-like peptide-1 (GLP1) and glucose-dependent insulinotropic polypeptide (GIP) are secreted from intestinal endocrine cells, the so-called L- and K-cells. The cells are derived from a common precursor and are highly related, and co-expression of the two hormones in so-called L/K-cells has been reported. To investigate the relationship between the GLP1- and GIP-producing cells more closely, we generated a transgenic mouse model expressing a fluorescent marker in GIP-positive cells. In combination with a mouse strain with fluorescent GLP1 cells, we were able to estimate the overlap between the two cell types. Furthermore, we used primary cultured intestinal cells and isolated perfused mouse intestine to measure the secretion of GIP and GLP1 in response to different stimuli. Overlapping GLP1 and GIP cells were rare (∼5%). KCl, glucose and forskolin+IBMX increased the secretion of both GLP1 and GIP, whereas bombesin/neuromedin C only stimulated GLP1 secretion. Expression analysis showed high expression of the bombesin 2 receptor in GLP1 positive cells, but no expression in GIP-positive cells. These data indicate both expressional and functional differences between the GLP1-producing 'L-cell' and the GIP-producing 'K-cell'.
Topics: Animals; Calcium; Cell Separation; Cells, Cultured; Enteroendocrine Cells; Female; Flow Cytometry; Fluorescent Dyes; Gastric Inhibitory Polypeptide; Glucagon-Like Peptide 1; Integrases; Male; Mice; Mice, Inbred C57BL; Mice, Transgenic; Receptors, Bombesin
PubMed: 26483393
DOI: 10.1530/JOE-15-0247 -
The Journal of Neuroscience : the... Nov 2020The neurokinin-1 receptor (NK1R; encoded by ) is expressed in spinal dorsal horn neurons and has been suggested to mediate itch in rodents. However, previous studies...
The neurokinin-1 receptor (NK1R; encoded by ) is expressed in spinal dorsal horn neurons and has been suggested to mediate itch in rodents. However, previous studies relied heavily on neurotoxic ablation of NK1R spinal neurons, which limited further dissection of their function in spinal itch circuitry. To address this limitation, we leveraged a newly developed mouse line to characterize the role of NK1R spinal neurons in itch. We show that pharmacological activation of spinal NK1R and chemogenetic activation of spinal neurons increases itch behavior in male and female mice, whereas pharmacological inhibition of spinal NK1R suppresses itch behavior. We use fluorescence hybridization (FISH) to characterize the endogenous expression of throughout the superficial and deeper dorsal horn (DDH), as well as the lateral spinal nucleus (LSN), of mouse and human spinal cord. Retrograde labeling studies in mice from the parabrachial nucleus (PBN) show that less than 20% of superficial dorsal horn neurons are spinal projection neurons, and thus the majority of are local interneurons. We then use a combination of hybridization and two-photon Ca imaging of the mouse spinal cord to establish that NK1R and the gastrin-releasing peptide receptor (GRPR) are coexpressed within a subpopulation of excitatory superficial dorsal horn (SDH) neurons. These findings are the first to suggest a role for NK1R interneurons in itch and extend our understanding of the complexities of spinal itch circuitry. The spinal cord is a critical hub for processing somatosensory input, yet which spinal neurons process itch input and how itch signals are encoded within the spinal cord is not fully understood. We demonstrate neurokinin-1 receptor (NK1R) spinal neurons mediate itch behavior in mice and that the majority of NK1R spinal neurons are local interneurons. These NK1R neurons comprise a subset of gastrin-releasing peptide receptor (GRPR) interneurons and are thus positioned at the center of spinal itch transmission. We show NK1R mRNA expression in human spinal cord, underscoring the translational relevance of our findings in mice. This work is the first to suggest a role for NK1R interneurons in itch and extends our understanding of the complexities of spinal itch circuitry.
Topics: Adult; Animals; Behavior, Animal; Brachial Plexus; Female; Humans; Interneurons; Male; Mice, Inbred C57BL; Middle Aged; Nerve Net; Pain; Posterior Horn Cells; Pruritus; Receptors, Bombesin; Receptors, Neurokinin-1; Spinal Cord
PubMed: 33051347
DOI: 10.1523/JNEUROSCI.1832-20.2020 -
EMBO Reports Oct 2023A11 dopaminergic neurons regulate somatosensory transduction by projecting from the diencephalon to the spinal cord, but the function of this descending projection in...
A11 dopaminergic neurons regulate somatosensory transduction by projecting from the diencephalon to the spinal cord, but the function of this descending projection in itch remained elusive. Here, we report that dopaminergic projection neurons from the A11 nucleus to the spinal dorsal horn (dopaminergic ) are activated by pruritogens. Inhibition of these neurons alleviates itch-induced scratching behaviors. Furthermore, chemogenetic inhibition of spinal dopamine receptor D1-expressing (DRD1 ) neurons decreases acute or chronic itch-induced scratching. Mechanistically, spinal DRD1 neurons are excitatory and mostly co-localize with gastrin-releasing peptide (GRP), an endogenous neuropeptide for itch. In addition, DRD1 neurons form synapses with GRP receptor-expressing (GRPR ) neurons and activate these neurons via AMPA receptor (AMPAR). Finally, spontaneous itch and enhanced acute itch induced by activating spinal DRD1 neurons are relieved by antagonists against AMPAR and GRPR. Thus, the descending dopaminergic pathway facilitates spinal itch transmission via activating DRD1 neurons and releasing glutamate and GRP, which directly augments GRPR signaling. Interruption of this descending pathway may be used to treat chronic itch.
Topics: Humans; Receptors, Bombesin; Gastrin-Releasing Peptide; Spinal Cord; Glutamic Acid; Dopamine; Pruritus; Dopaminergic Neurons; Receptors, AMPA
PubMed: 37522391
DOI: 10.15252/embr.202256098 -
Annals of Oncology : Official Journal... 2001In the prostate, the importance of sex hormones for its normal development and function is well known. However, it has been proposed that various neuroendocrine (NE)... (Review)
Review
BACKGROUND
In the prostate, the importance of sex hormones for its normal development and function is well known. However, it has been proposed that various neuroendocrine (NE) hormones and growth factors may be involved in the pathogenesis of prostatic carcinoma (CaP). Neuroendocrine differentiation appears to be associated with tumour progression and the androgen-independent state, for which there is currently no successful therapy. Therefore, we need to improve our understanding of NE cells, their regulatory products and influence on the prostate gland. Finally, new therapeutic protocols need to be developed.
METHODS
Information is presented on prostatic NE cells and neuroendocrine differentiation (NED) in prostatic carcinoma. Neuroendocrine secretory products and interactions with epithelial prostate cells are investigated in order to understand their significance for the pathogenesis of the prostate gland, prognosis and therapy.
RESULTS
Recent research suggests that NE-secreted products. such as serotonin, somatostatin and bombesin, may influence growth, invasiveness, metastatic processes and angiogenesis in CaP. During recent years. new experimental models for NED have been developed to provide evidence that NE products may promote proliferation and confer antiapoptotic capabilities on non-neuroendocrine cells in close proximity to NE cells. Cancerous epithelial cells may become more responsive to NE factors by upregulation of receptors for neuropeptides, or may induce NE cells to upregulate the secretion and synthesis of NE factors. In the androgen independent state, neuropeptides and their intracellular signals may activate the androgen receptor. Furthermore, androgen ablation may lead to downregulation of neural endopeptidase 24.11 (a zinc-dependent metalloproteinase) and PSA, which would lead to increased levels of NE products becoming available. These studies confirm that NE cells and NED may have a significant impact on prostate cancer, especially in the androgen independent state.
CONCLUSIONS
Recent developments in molecular biology and pathophysiology of prostate cancer have increased our understanding of the NE regulatory mechanisms. Hopefully, this will lead to the development of entirely new therapeutic modalities. For example, somatostatin agonists may suppress angiogenesis and proliferation, and simultaneously promote apoptosis in prostate cancer cells. Somatostatin may thus have an important role in tumour biology, and in the future there may be a potential role for somatostatin analogues in the treatment of prostate cancer, but also for serotonin and bombesin receptor antagonists. However, a review of the accumulated knowledge in this field suggests that we still need to improve our understanding of NE cells and their regulatory products and influence on the prostate gland. and that clinical trials are needed, to test drugs based on neuroendocrine hormones and their agonists/antagonists.
Topics: Adenocarcinoma; Androgens; Cell Differentiation; Disease Progression; Humans; Male; Neovascularization, Pathologic; Neuropeptides; Neurosecretory Systems; Prostatic Neoplasms
PubMed: 11762343
DOI: 10.1093/annonc/12.suppl_2.s145 -
Pharmacological Reviews Mar 2008The mammalian bombesin receptor family comprises three G protein-coupled heptahelical receptors: the neuromedin B (NMB) receptor (BB(1)), the gastrin-releasing peptide... (Review)
Review
International Union of Pharmacology. LXVIII. Mammalian bombesin receptors: nomenclature, distribution, pharmacology, signaling, and functions in normal and disease states.
The mammalian bombesin receptor family comprises three G protein-coupled heptahelical receptors: the neuromedin B (NMB) receptor (BB(1)), the gastrin-releasing peptide (GRP) receptor (BB(2)), and the orphan receptor bombesin receptor subtype 3 (BRS-3) (BB(3)). Each receptor is widely distributed, especially in the gastrointestinal (GI) tract and central nervous system (CNS), and the receptors have a large range of effects in both normal physiology and pathophysiological conditions. The mammalian bombesin peptides, GRP and NMB, demonstrate a broad spectrum of pharmacological/biological responses. GRP stimulates smooth muscle contraction and GI motility, release of numerous GI hormones/neurotransmitters, and secretion and/or hormone release from the pancreas, stomach, colon, and numerous endocrine organs and has potent effects on immune cells, potent growth effects on both normal tissues and tumors, potent CNS effects, including regulation of circadian rhythm, thermoregulation; anxiety/fear responses, food intake, and numerous CNS effects on the GI tract as well as the spinal transmission of chronic pruritus. NMB causes contraction of smooth muscle, has growth effects in various tissues, has CNS effects, including effects on feeding and thermoregulation, regulates thyroid-stimulating hormone release, stimulates various CNS neurons, has behavioral effects, and has effects on spinal sensory transmission. GRP, and to a lesser extent NMB, affects growth and/or differentiation of various human tumors, including colon, prostate, lung, and some gynecologic cancers. Knockout studies show that BB(3) has important effects in energy balance, glucose homeostasis, control of body weight, lung development and response to injury, tumor growth, and perhaps GI motility. This review summarizes advances in our understanding of the biology/pharmacology of these receptors, including their classification, structure, pharmacology, physiology, and role in pathophysiological conditions.
Topics: Animals; Disease; Humans; Receptors, Bombesin; Signal Transduction; Terminology as Topic
PubMed: 18055507
DOI: 10.1124/pr.107.07108 -
Oncogene Mar 2015Small cell lung carcinoma (SCLC) often features the upregulation of the Sonic hedgehog (Shh) pathway leading to activation of Gli transcription factors. SCLC cells...
Small cell lung carcinoma (SCLC) often features the upregulation of the Sonic hedgehog (Shh) pathway leading to activation of Gli transcription factors. SCLC cells secrete bombesin (BBS)-like neuropeptides that act as autocrine growth factors. Here, we show that SCLC tumor samples feature co-expression of Shh and BBS-cognate receptor (gastrin-releasing peptide receptor (GRPR)). We also demonstrate that BBS activates Gli in SCLC cells, which is crucial for BBS-mediated SCLC proliferation, because cyclopamine, an inhibitor of the Shh pathway, hampered the BBS-mediated effects. BBS binding to GRPR stimulated Gli through its downstream Gαq and Gα₁₂/₁₃ GTPases, and consistently, other Gαq and Gα₁₃ coupled receptors (such as muscarinic receptor, m1, and thrombin receptor, PAR-1) and constitutively active GαqQL and Gα₁₂/₁₃QL mutants stimulated Gli. By using cells null for Gαq and Gα₁₂/₁₃, we demonstrate that these G proteins are strictly necessary for Gli activation by BBS. Moreover, by using constitutively active Rho small G-protein (Rho QL) as well as its inhibitor, C3 toxin, we show that Rho mediates G-protein-coupled receptor (GPCR)-, Gαq- and Gα₁₂/₁₃-dependent Gli stimulation. At the molecular level, BBS caused a significant increase in Shh gene transcription and protein secretion that was dependent on BBS-induced GPCR/Gαq-₁₂/₁₃/Rho mediated activation of nuclear factor κB (NFκB), which can stimulate a NF-κB response element in the Shh gene promoter. Our data identify a novel molecular network acting in SCLC linking autocrine BBS and Shh circuitries and suggest Shh inhibitors as novel therapeutic strategies against this aggressive cancer type.
Topics: Animals; Bombesin; Boronic Acids; Bortezomib; Cisplatin; GTP-Binding Protein alpha Subunits, G12-G13; GTP-Binding Protein alpha Subunits, Gq-G11; HEK293 Cells; Hedgehog Proteins; Humans; Lung Neoplasms; Mice; NIH 3T3 Cells; Oncogene Proteins; Pyrazines; Receptors, Bombesin; Signal Transduction; Small Cell Lung Carcinoma; Trans-Activators; Zinc Finger Protein GLI1
PubMed: 24747971
DOI: 10.1038/onc.2014.104 -
American Journal of Physiology. Lung... Jan 2004Bombesin-peptide (BLP) immunoreactivity occurs at high levels in fetal lung. Previous studies showed that bombesin promotes fetal lung development. To test the...
Bombesin-peptide (BLP) immunoreactivity occurs at high levels in fetal lung. Previous studies showed that bombesin promotes fetal lung development. To test the hypothesis that such effects are mediated by known mammalian bombesin receptors [gastrin-releasing peptide (GRP)/bombesin-preferring receptor (GRPR), neuromedin B (NMB) receptor (NMBR), and the orphan bombesin receptor subtype-3 (BRS-3)], we analyzed the ontogeny of GRPR, NMBR, and BRS-3 gene expression in mouse lung. We examined the regulation of these three genes by dexamethasone and bombesin, which modulate lung development. Using incorporation of [3H]thymidine and [3H]choline, we then assessed whether GRP, NMB, and Leu8-phyllolitorin modulate lung growth and maturation in fetal lung explants. GRPR gene expression was detected predominantly in utero, whereas NMBR and BRS-3 genes were expressed from embryonic days 13-16 and on multiple postnatal days. All three mRNAs are present in airway epithelium and mesenchymal cells but occur in different relative patterns. These genes were regulated differently. Dexamethasone and bombesin increased GRPR mRNA, bombesin downregulated NMBR, and neither agent affected BRS-3. GRP increased incorporation of [3H]thymidine and [3H]choline in explants, whereas NMB induced cell proliferation and Leu8-phyllolitorin yielded variable results. Cumulative data suggest the involvement of multiple BLP receptors, including novel molecules, and argue against simple functional redundancy within this gene family during lung development.
Topics: Amino Acid Sequence; Animals; Bombesin; Cell Differentiation; Cell Division; Choline; Dexamethasone; Female; Gene Expression Regulation, Developmental; Glucocorticoids; In Situ Hybridization; Lung; Mice; Molecular Sequence Data; Organ Culture Techniques; Pregnancy; RNA, Messenger; Receptors, Bombesin; Thymidine; Tritium
PubMed: 12959933
DOI: 10.1152/ajplung.00436.2002 -
Annals of Medicine Dec 2024This comprehensive review aims to explore the potential applications of Gastrin-releasing peptide receptor (GRPR) in the diagnosis and treatment of prostate cancer.... (Review)
Review
This comprehensive review aims to explore the potential applications of Gastrin-releasing peptide receptor (GRPR) in the diagnosis and treatment of prostate cancer. Additionally, the study investigates the role of GRPR in prognostic assessment for individuals afflicted with prostate cancer. The review encompasses a thorough examination of existing literature and research studies related to the upregulation of GRPR in various tumor types, with a specific focus on prostate. The review also evaluates the utility of GRPR as a molecular target in prostate cancer research, comparing its significance to the well-established Prostate-specific membrane antigen (PSMA). The integration of radionuclide-targeted therapy with GRPR antagonists is explored as an innovative therapeutic approach for individuals with prostate cancer. Research findings suggest that GRPR serves as a promising molecular target for visualizing low-grade prostate cancer. Furthermore, it is demonstrated to complement the detection of lesions that may be negative for PSMA. The integration of radionuclide-targeted therapy with GRPR antagonists presents a novel therapeutic paradigm, offering potential benefits for individuals undergoing treatment for prostate cancer. In conclusion, this review highlights the emerging role of GRPR in prostate cancer diagnosis and treatment. Moreover, the integration of radionuclide-targeted therapy with GRPR antagonists introduces an innovative therapeutic approach that holds promise for improving outcomes in individuals dealing with prostate cancer. The potential prognostic value of GRPR in assessing the disease's progression adds another dimension to its clinical significance in the realm of urology.
Topics: Male; Humans; Receptors, Bombesin; Prostatic Neoplasms; Biomarkers; Up-Regulation; Radioisotopes
PubMed: 38442298
DOI: 10.1080/07853890.2024.2320301 -
Cancer Imaging : the Official... Nov 2006The fact that a number of common human tumours, including those of breast and prostate, express increased levels of the gastrin-releasing peptide receptor (GRP-R) means... (Review)
Review
The fact that a number of common human tumours, including those of breast and prostate, express increased levels of the gastrin-releasing peptide receptor (GRP-R) means that this receptor is a potential target for peptide receptor mediated scintigraphy and targeted radionuclide therapy. Although clinical application is yet in its infancy, there is a considerable literature on preclinical studies aimed at developing suitable radioligands for potential clinical application. This brief review provides an overview of this research and also describes some of the limited clinical studies that have been published.
Topics: Animals; Bombesin; Humans; Male; Prostatic Neoplasms; Radionuclide Imaging; Radiopharmaceuticals; Receptors, Bombesin
PubMed: 17098646
DOI: 10.1102/1470-7330.2006.0025