Expression of calcitonin receptor-like receptor in human vascular tumours

Hagner, Stefanie; Stahl, U.; Grimm, Tobias; Lang, R.

doi:10.1136/jcp.2005.026930

Cited by 14 publications

(7 citation statements)

References 17 publications

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“…CGRP and its receptor also have been implicated in the pathogenesis of malignant diseases. The expression of CGRP, the closely related peptide CGRP2, and CALCRL was increased in some tumor types compared to the corresponding healthy tissues [3,6,7]. CGRP stimulated proliferation and inhibited apoptosis of both normal and malignant cells [3,6,8,9,10,11], and promoted migration and invasiveness of some carcinoma cell lines [3].…”

Section: Introductionmentioning

confidence: 99%

CGRP Signaling via CALCRL Increases Chemotherapy Resistance and Stem Cell Properties in Acute Myeloid Leukemia

Gluexam

Grandits

Schlerka

et al. 2019

IJMS

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The neuropeptide CGRP, acting through the G-protein coupled receptor CALCRL and its coreceptor RAMP1, plays a key role in migraines, which has led to the clinical development of several inhibitory compounds. Recently, high CALCRL expression has been shown to be associated with a poor prognosis in acute myeloid leukemia (AML). We investigate, therefore, the functional role of the CGRP-CALCRL axis in AML. To this end, in silico analyses, human AML cell lines, primary patient samples, and a C57BL/6-based mouse model of AML are used. We find that CALCRL is up-regulated at relapse of AML, in leukemic stem cells (LSCs) versus bulk leukemic cells, and in LSCs versus normal hematopoietic stem cells. CGRP protects receptor-positive AML cell lines and primary AML samples from apoptosis induced by cytostatic drugs used in AML therapy, and this effect is inhibited by specific antagonists. Furthermore, the CGRP antagonist olcegepant increases differentiation and reduces the leukemic burden as well as key stem cell properties in a mouse model of AML. These data provide a basis for further investigations into a possible role of CGRP-CALCRL inhibition in the therapy of AML.

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Section: Introductionmentioning

confidence: 99%

CGRP Signaling via CALCRL Increases Chemotherapy Resistance and Stem Cell Properties in Acute Myeloid Leukemia

Gluexam

Grandits

Schlerka

et al. 2019

IJMS

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“…[9][10][11] Thus, the SP-receptor, neurokinin 1 (NK 1 ), and the CGRP-receptor, calcitonin-receptor-like receptor (CRLR), including the receptor activity modifying protein (RAMP-1), have been reported to promote angiogenesis and tissue repair by stimulating proliferation of endothelial cells and fibroblasts. [12][13][14][15] In tendons, thus far only the SP-receptor (NK 1 ) has been detected, 16 but none of the SP-(NK 1 ) or the CGRP-(CRLR/RAMP-1) receptors have been analyzed in relation to activity and healing.…”

mentioning

confidence: 99%

Joint immobilization reduces the expression of sensory neuropeptide receptors and impairs healing after tendon rupture in a rat model

Bring

Reno

Renström

et al. 2008

Journal Orthopaedic Research

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Healing after mobilization versus immobilization was assessed in a model of rat Achilles tendon rupture, by RT-PCR at 8 and 17 days and by histological analyses at 14 and 28 days postrupture. The expression of mRNA for extracellular matrix (ECM) molecules (collagen type I and type III, versican, decorin, and biglycan), and the subjective histological maturation of the healing area were analyzed. Effects of immobilization on healing were related to changes in the peripheral expression of substance P (NK 1 )-and calcitonin gene-related peptide (CRLR and RAMP-1)-receptors. At 8 days postinjury, mRNA levels for ECM molecules were equal in both groups. However, by day 17, the ECM mRNA expression in the mobilized group had increased up to $14Â that of the immobilized group, which were comparable to intact tendon values. Histological analysis confirmed a higher regenerating activity in the mobilized group, with an increased amount of blood vessels, fibroblasts, and new collagen. The expression of sensory neuropeptide receptors in the mobilized group exhibited a significant increase from 8 to 17 days postinjury similar to the increased ECM mRNA expression, whereas the immobilized group at 17 days exhibited levels comparable to the intact tendon values. Therefore, immobilization postrupture appears to hamper tendon healing, a process which may prove to be directly linked to a downregulated peripheral sensitivity to sensory neuropeptide stimulation. ß

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“…We also showed for the first time that β-arrestin-mediated ET A R signaling activates two angiogenic/metastatic genes ( Calcrl and Icam2 ), which are inhibited by tumor suppressive Gα s /cAMP/PKA signaling. Notably, these two angiogenic/metastatic genes have been shown to be over-expressed in human vascular tumors [59], uterine leiomyoma [60], glioma [61] and B cell chronic lymphocytic leukemia [62]. Further investigation is warranted to investigate whether these genes are associated with OC progression.…”

Section: Discussionmentioning

confidence: 99%

Endothelin-1/Endothelin A receptor-mediated biased signaling is a new player in modulating human ovarian cancer cell tumorigenesis

Teoh

Wang

et al. 2014

Cellular Signalling

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The endothelin-1 (ET-1)/endothelin A receptor (ETAR, a G protein-coupled receptor) axis confers pleiotropic effects on both tumor cells and the tumor microenvironment, modulating chemo-resistance and other tumor-associated processes by activating Gαq- and β-arrestin-mediated pathways. While the precise mechanisms by which these effects occur remain to be elucidated, interference with ETAR signaling has emerged as a promising antitumor strategy in many cancers including ovarian cancer (OC). However, current clinical approaches using ETAR antagonists in the absence of a detailed knowledge of downstream signaling have resulted in multiple adverse side effects and limited therapeutic efficacy. To maximize the safety and efficacy of ETAR-targeted OC therapy, we investigated the role of other G protein subunits such as Gαs in the ETAR-mediated ovarian oncogenic signaling. In HEY (human metastatic OC) cells where the ET-1/ETAR axis is well-characterized, Gαs signaling inhibits ETAR-mediated OC cell migration, wound healing, proliferation and colony formation on soft agar while inducing OC cell apoptosis. Mechanistically, ET-1/ETAR is coupled to Gαs/cAMP signaling in the same ovarian carcinoma-derived cell line. Gαs/cAMP/PKA activation inhibits ETAR-mediated β-arrestin activation of angiogenic/metastatic Calcrl and Icam2 expression. Consistent with our findings, Gαs overexpression is associated with improved survival in OC patients in the analysis of the Cancer Genome Atlas data. In conclusion, our results indicate a novel function for Gαs signaling in ET-1/ETAR-mediated OC oncogenesis and may provide a rationale for a biased signaling mechanism, which selectively activates Gαs-coupled tumor suppressive pathways while blocking Gαq-/β-arrestin-mediated oncogenic pathways, to improve the targeting of the ETAR axis in OC.

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Expression of calcitonin receptor-like receptor in human vascular tumours

Abstract: CRLR is expressed in vascular tumours and, with adrenomedullin, may have a role in neoplastic vascular growth.

Cited by 14 publications

References 17 publications

CGRP Signaling via CALCRL Increases Chemotherapy Resistance and Stem Cell Properties in Acute Myeloid Leukemia

CGRP Signaling via CALCRL Increases Chemotherapy Resistance and Stem Cell Properties in Acute Myeloid Leukemia

Joint immobilization reduces the expression of sensory neuropeptide receptors and impairs healing after tendon rupture in a rat model

Endothelin-1/Endothelin A receptor-mediated biased signaling is a new player in modulating human ovarian cancer cell tumorigenesis

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