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

Toda, Masaya; Suzuki, Tatsunori; Hosono, Kanako; Hayashi, Izumi; Hashiba, Shinichiro; Onuma, Yuichiro; Aoki, Hideki; Kurihara, Yukiko; Kurihara, Hiroki; Okamoto, Hirotsugu; Hoka, Sumio; Murakami, Masataka

doi:10.1073/pnas.0800767105

Cited by 111 publications

(115 citation statements)

References 28 publications

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“…Compared with pharmacologic therapies that have varied metabolic profiles and excretion rates, local decrease of gene expression enables a defined, clearly targeted therapy that minimizes potential side effects. As CGRP has diverse roles in different tissues (23)(24)(25), a targeted local delivery of dsRNA for CLR or CGRP is preferable. In agreement with previous findings, our dsRNA was not proinflammatory, because it did not alter weight gain or basal levels of intestinal secretion or cytokines and MPO activity (20,26) and, importantly, CLR dsRNA specifically ameliorated TxA-induced ileitis.…”

Section: Discussionmentioning

confidence: 99%

Local injection of dsRNA targeting calcitonin receptor-like receptor (CLR) ameliorates Clostridium difficile toxin A-induced ileitis

Bhargava¹,

Clifton²,

Mhaske³

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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Enteritis caused by Clostridium difficile toxin (Tx) is a nosocomial disease of increasing clinical concern, but the local mediators of C. difficile TxA inflammation are unknown. The potent vasodilator calcitonin gene-related peptide mediates neurogenic inflammation via the calcitonin receptor-like receptor (CLR). Here we examined the ileum-specific effects of reducing CLR on TxA ileitis by local preinjection of double-stranded RNAs. Treatment with CLR dsRNA for 7 d decreased CLR immunoreactivity, whereas treatment with non-CLR dsRNA did not. Subsequent injection of TxA in the same location increased CLR in rats treated with non-CLR dsRNA but not in rats treated with CLR dsRNA, documenting that local injection of dsRNA is effective in preventing the increase in CLR immunoreactivity in response to local TxA. After non-CLR dsRNA pretreatment, TxA induced robust intestinal secretion, myeloperoxidase activity, and histopathologic indications of inflammation including epithelial damage, congestion, neutrophil infiltration, loss of mucin from goblet cells, and increase in mast cell numbers. After CLR dsRNA pretreatment, TxA-induced changes in intestinal secretion and histopathologic inflammation were improved, including normal mucin staining and fewer resident mast cells. Loss of CLR prevented TxA-mediated activation of NF-κB and concomitant increases in pERK1/2 and TNF-α mRNA. Locally produced CLR plays a proinflammatory role in TxA ileitis via MAPK signaling and TNF-α. The results reported here strongly suggest that a local injection of dsRNA targeting CLR could be an effective local therapeutic approach at the inflammation site in the treatment of a growing, clinically relevant hospital-acquired disease, C. difficile infection.

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Section: Discussionmentioning

confidence: 99%

Local injection of dsRNA targeting calcitonin receptor-like receptor (CLR) ameliorates Clostridium difficile toxin A-induced ileitis

Bhargava¹,

Clifton²,

Mhaske³

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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“…In the sponge model, granulation tissues with the property of chronic inflammation were formed around the sponge implants with enough reproducibility, and we can easily determine the active molecules at the site of the chronic inflammation, because rapid sampling and easy extractions of active molecules and mRNA can be performed in the sponge model. The results with this sponge model have been published in some journals, 5,6,26,27,29,[31][32][33][34][35][36][37][38][39][40] and many researchers have a strong interest in this model. In the beginning of this study, we had tried to test this sponge model to clarify the involvement of PGs in lymphangiogenesis during the chronic inflammation, but the detection of newly developed lymphatics was quite difficult in the sponge model.…”

Section: Discussionmentioning

confidence: 99%

Roles of Prostaglandin E ₂ –EP3/EP4 Receptor Signaling in the Enhancement of Lymphangiogenesis During Fibroblast Growth Factor-2–Induced Granulation Formation

Hosono

Suzuki

Tamaki

et al. 2011

ATVB

Self Cite

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Objective— One of the hallmarks of inflammation is lymphangiogesis that drains the interstitial fluids. During chronic inflammation, angiogenesis is induced by a variety of inflammatory mediators, such as prostaglandins (PGs). However, it remains unknown whether they enhance lymphangiogenesis. We examined the roles of cyclooxygenase-2 (COX-2) and PGE 2 receptor signaling in enhancement of lymphangiogenesis during proliferative inflammation. Methods and Results— Lymphangiogenesis estimated by podoplanin/vascular endothelial growth factor (VEGF) receptor-3/LYVE-1 expression was upregulated during proliferative inflammation seen around and into subcutaneous Matrigel plugs containing fibroblast growth factor-2 (125 ng/site). A COX-2 inhibitor (celecoxib) significantly reduced lymphangiogenesis in a dose-dependent manner, whereas topical PGE 2 enhanced lymphangiogenesis. Topical injection of fluorescein isothiocyanate–dextran into the Matrigel revealed that lymphatic flow from the Matrigels was COX-2 dependent. Lymphangiogenesis was suppressed in the granulation tissues of mice lacking either EP3 or EP4, suggesting that these molecules are receptors in response to endogenous PGE 2 . An EP3-selective agonist (ONO-AE-248) increased the expression of VEGF-C and VEGF-D in cultured macrophages, whereas an EP4-selective agonist (ONO-AE1-329) increased VEGF-C expression in cultured macrophages and increased VEGF-D expression in cultured fibroblasts. Conclusion— Our findings suggest that COX-2 and EP3/EP4 signaling contributes to lymphangiogenesis in proliferative inflammation, possibly via induction of VEGF-C and VEGF-D, and may become a therapeutic target for controlling lymphangiogenesis.

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“…4,5 In addition, CGRP and AM both exhibit angiogenic activity. 6,7 As a consequence of the various actions of CGRP and AM and their involvement in several pathophysiological states, their receptors are of interest as drug targets for a variety of disorders including migraine headache, acute myocardial infarction, pulmonary hypertension, preeclampsia, sepsis, and cancer. 4,[8][9][10] The CGRP and AM receptors are heteromeric protein complexes comprised of the calcitonin receptor-like receptor (CLR), a class B/Secretin family G protein-coupled receptor (GPCR), in association with a receptor activity modifying protein (RAMP).…”

Section: Introductionmentioning

confidence: 99%

Selective CGRP and adrenomedullin peptide binding by tethered RAMP‐calcitonin receptor‐like receptor extracellular domain fusion proteins

Moad

Pioszak

2013

Protein Science

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Calcitonin gene-related peptide (CGRP) and adrenomedullin (AM) are related peptides that are potent vasodilators. The CGRP and AM receptors are heteromeric protein complexes comprised of a shared calcitonin receptor-like receptor (CLR) subunit and a variable receptor activity modifying protein (RAMP) subunit. RAMP1 enables CGRP binding whereas RAMP2 confers AM specificity. How RAMPs determine peptide selectivity is unclear and the receptor stoichiometries are a topic of debate with evidence for 1:1, 2:2, and 2:1 CLR:RAMP stoichiometries. Here, we describe bacterial production of recombinant tethered RAMP-CLR extracellular domain (ECD) fusion proteins and biochemical characterization of their peptide binding properties. Tethering the two ECDs ensures complex stability and enforces defined stoichiometry. The RAMP1-CLR ECD fusion purified as a monomer, whereas the RAMP2-CLR ECD fusion purified as a dimer. Both proteins selectively bound their respective peptides with affinities in the low micromolar range. Truncated CGRP(27-37) and AM(37-52) fragments were identified as the minimal ECD complex binding regions. The CGRP C-terminal amide group contributed to, but was not required for, ECD binding, whereas the AM C-terminal amide group was essential for ECD binding. Alanine-scan experiments identified CGRP residues T30, V32, and F37 and AM residues P43, K46, I47, and Y52 as critical for ECD binding. Our results identify CGRP and AM determinants for receptor ECD complex binding and suggest that the CGRP receptor functions as a 1:1 heterodimer. In contrast, the AM receptor may function as a 2:2 dimer of heterodimers, although our results cannot rule out 2:1 or 1:1 stoichiometries.

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

Cited by 111 publications

References 28 publications

Local injection of dsRNA targeting calcitonin receptor-like receptor (CLR) ameliorates Clostridium difficile toxin A-induced ileitis

Local injection of dsRNA targeting calcitonin receptor-like receptor (CLR) ameliorates Clostridium difficile toxin A-induced ileitis

Roles of Prostaglandin E ₂ –EP3/EP4 Receptor Signaling in the Enhancement of Lymphangiogenesis During Fibroblast Growth Factor-2–Induced Granulation Formation

Selective CGRP and adrenomedullin peptide binding by tethered RAMP‐calcitonin receptor‐like receptor extracellular domain fusion proteins

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

Cited by 111 publications

References 28 publications

Local injection of dsRNA targeting calcitonin receptor-like receptor (CLR) ameliorates Clostridium difficile toxin A-induced ileitis

Local injection of dsRNA targeting calcitonin receptor-like receptor (CLR) ameliorates Clostridium difficile toxin A-induced ileitis

Roles of Prostaglandin E 2 –EP3/EP4 Receptor Signaling in the Enhancement of Lymphangiogenesis During Fibroblast Growth Factor-2–Induced Granulation Formation

Selective CGRP and adrenomedullin peptide binding by tethered RAMP‐calcitonin receptor‐like receptor extracellular domain fusion proteins

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Roles of Prostaglandin E ₂ –EP3/EP4 Receptor Signaling in the Enhancement of Lymphangiogenesis During Fibroblast Growth Factor-2–Induced Granulation Formation