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Neuronal system-dependent facilitation of tumor angiogenesis and tumor growth by calcitonin gene-related peptide.

ABSTRACT: A neuropeptide, calcitonin gene-related peptide (CGRP), is widely distributed in neuronal systems and exhibits numerous biological activities. Using CGRP-knockout mice (CGRP(-/-)), we examined whether or not endogenous CGRP facilitates angiogenesis indispensable to tumor growth. CGRP increased tube formation by endothelial cells in vitro and enhanced sponge-induced angiogenesis in vivo. Tumor growth and tumor-associated angiogenesis in CGRP(-/-) implanted with Lewis lung carcinoma (LLC) cells were significantly reduced compared with those in wild-type (WT) mice. A CGRP antagonist, CGRP8-37 or denervation of sciatic nerves (L(1-5)) suppressed LLC growth in the sites of denervation compared with vehicle infusion or sham operation. CGRP precursor mRNA levels in the dorsal root ganglion in LLC-bearing WT were increased compared with those in non-LLC-bearing mice. This increase was abolished by denervation. The expression of VEGF in tumor stroma was down-regulated in CGRP(-/-). These results indicate that endogenous CGRP facilitates tumor-associated angiogenesis and tumor growth and suggest that relevant CGRP may be derived from neuronal systems including primary sensory neurons and may become a therapeutic target for cancers.

SUBMITTER: Toda M

PROVIDER: S-EPMC2527353 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Promotion of corneal angiogenesis by sensory neuron-derived calcitonin gene-related peptide.

Project description:The normal cornea has no blood vessels but has abundant innervation. There is emerging evidence that sensory nerves, originated from the trigeminal ganglion (TG) neurons, play a key role in corneal angiogenesis. In the current study, we examined the role of TG sensory neuron-derived calcitonin gene-related peptide (CGRP) in promoting corneal neovascularization (CNV). We found that CGRP was expressed in the TG and cultured TG neurons. In the cornea, minimal CGRP mRNA was detected and CGRP immunohistochemical staining was exclusively co-localized with corneal nerves, suggesting corneal nerves are likely the source of CGRP in the cornea. In response to intrastromal suture placement and neovascularization in the cornea, CGRP expression was increased in the TG. In addition, we showed that CGRP was potently pro-angiogenic, leading to vascular endothelial cell (VEC) proliferation, migration, and tube formation in vitro and corneal hemangiogenesis and lymphangiogenesis in vivo. In a co-culture system of TG neurons and VEC, blocking CGRP signaling in the conditioned media of TG neurons led to decreased VEC migration and tube formation. More importantly, subconjunctival injection of a CGRP antagonist CGRP8-37 reduced suture-induced corneal hemangiogenesis and lymphangiogenesis in vivo. Taken together, our data suggest that TG sensory neuron and corneal nerve-derived CGRP promotes corneal angiogenesis.

| S-EPMC9428938 | biostudies-literature

Sensory Neurotransmitter Calcitonin Gene-Related Peptide Modulates Tumor Growth and Lymphocyte Infiltration in Oral Squamous Cell Carcinoma.

Project description:Head and neck squamous cell carcinoma are highly innervated by peripheral sensory neurons. Local neurotransmitter release (e.g., calcitonin gene-related peptide (CGRP)) from sensory neurons innervating cancer is linked to tumorigenesis. CGRP-immunoreactive nerve presence comprised 9.53±1.9% of total nerve area across 11 HNSCC patients. A syngeneic tongue tumor transplant mouse model of oral cancer and a global Calca knockout mouse (CGRPKO ) are used to investigate the impact of CGRP signaling on tumor growth and the associated immune response in vivo. In tumor-bearing CGRPKO mice, there is a significant reduction in tumor size over time compared to wildtype mice using two different mouse oral cancer cell lines. Furthermore, tumor tissue from CGRPKO mice had a significant increase in tumor-infiltrating CD4+ T cells, cytotoxic CD8+ T cells, and NK1.1+ NK cells compared to wildtype. Fluorescent-activated cell sorting and real-time qPCR are used to confirm that CD4+ T cells are isolated from tumor-bearing wildtype mice containing a high expression of Ramp1 compared to sham mice. These data suggest that sensory neurotransmitter CGRP may modulate oral cancer progression via tumor immunosurveillance. Understanding the relationship between sensory neurons and cancer will aid in repurposing clinically available nervous system drugs for the treatment of cancer.

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The Calcitonin/Calcitonin Gene-Related Peptide Family in Invertebrate Deuterostomes.

Project description:Calcitonin (CT)/CT gene-related peptide (CGRP) family peptides (CT/CGRP family peptides) including CT, CGRP, adrenomedullin, amylin, and CT receptor-stimulating peptide have been identified from various vertebrates and perform a variety of important physiological functions. These peptides bind to two types of receptors including CT receptor (CTR) and CTR-like receptor (CLR). Receptor recognition of CT/CGRP family peptides is determined by the heterodimer between CTR/CLR and receptor activity-modifying protein (RAMP). Comparative studies of the CT/CGRP family have been exclusively performed in vertebrates from teleost fishes to mammals and strongly manifest that the CGRP family system containing peptides, their receptors, and RAMPs was derived from a common ancestor. In addition, CT/CGRP family peptides and their receptors are also identified and inferred from various invertebrate species. However, the evolutionary process of the CT/CGRP family from invertebrates to vertebrates remains enigmatic. In this review, I principally summarize the CT/CGRP family peptides and their receptors in invertebrate deuterostomes, highlighting the study of invertebrate chordates including ascidians and amphioxi. The CT/CGRP family peptide that shows similar molecular structure and function with that of vertebrate CT has been identified from ascidian, Ciona intestinalis. Amphioxus, Branchiostoma floridae also possessed three CT/CGRP family peptides, one CTR/CLR receptor, and three RAMP-like proteins. The molecular function of the receptor complex formed by amphioxus CTR/CLR and a RAMP-like protein was clarified. Moreover, CT/CGRP family peptides have been identified in the superphylum Ambulacraria, which is close to Chordata. Finally, this review provides potential hypotheses of the evolution of CGRP family peptides and their receptors from invertebrates to vertebrates.

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Solution structures of calcitonin-gene-related-peptide analogues of calcitonin-gene-related peptide and amylin.

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Calcitonin gene-related peptide: physiology and pathophysiology.

Project description:Calcitonin gene-related peptide (CGRP) is a 37-amino acid neuropeptide. Discovered 30 years ago, it is produced as a consequence of alternative RNA processing of the calcitonin gene. CGRP has two major forms (α and β). It belongs to a group of peptides that all act on an unusual receptor family. These receptors consist of calcitonin receptor-like receptor (CLR) linked to an essential receptor activity modifying protein (RAMP) that is necessary for full functionality. CGRP is a highly potent vasodilator and, partly as a consequence, possesses protective mechanisms that are important for physiological and pathological conditions involving the cardiovascular system and wound healing. CGRP is primarily released from sensory nerves and thus is implicated in pain pathways. The proven ability of CGRP antagonists to alleviate migraine has been of most interest in terms of drug development, and knowledge to date concerning this potential therapeutic area is discussed. Other areas covered, where there is less information known on CGRP, include arthritis, skin conditions, diabetes, and obesity. It is concluded that CGRP is an important peptide in mammalian biology, but it is too early at present to know if new medicines for disease treatment will emerge from our knowledge concerning this molecule.

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Structure-activity relationships for ?-calcitonin gene-related peptide.

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