Adrenomedullin blockade induces regression of tumor neovessels through interference with vascular endothelial-cadherin signalling

Bendriss, Ghizlane; Dussault, Nadège; Fernandez-Sauze, Samantha; Berenguer-Daizé, Caroline; Sigaud, Romain; Delfino, Christine; Cayol, Mylène; Métellus, Philippe; Chinot, Olivier; Mabrouk, Kamel; Martin, Pièrre‐Marie; Ouafik, L’Houcine

doi:10.18632/oncotarget.3167

Cited by 14 publications

(22 citation statements)

References 57 publications

(65 reference statements)

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“…3a,b). CDX models will also permit putative VM-targeted drug testing, for example, of therapies that inhibit VE-cadherin signalling4142. Mutations in Notch family genes have been recently reported in 25% SCLC29 and whilst these signalling networks are complex, it is notable that inhibitors of Notch signalling are reported to preferentially target ‘stem-like' VM tumour cells434445.…”

Section: Discussionmentioning

confidence: 99%

Vasculogenic mimicry in small cell lung cancer

et al. 2016

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Small cell lung cancer (SCLC) is characterized by prevalent circulating tumour cells (CTCs), early metastasis and poor prognosis. We show that SCLC patients (37/38) have rare CTC subpopulations co-expressing vascular endothelial-cadherin (VE-cadherin) and cytokeratins consistent with vasculogenic mimicry (VM), a process whereby tumour cells form ‘endothelial-like' vessels. Single-cell genomic analysis reveals characteristic SCLC genomic changes in both VE-cadherin-positive and -negative CTCs. Higher levels of VM are associated with worse overall survival in 41 limited-stage patients' biopsies (P<0.025). VM vessels are also observed in 9/10 CTC patient-derived explants (CDX), where molecular analysis of fractionated VE-cadherin-positive cells uncovered copy-number alterations and mutated TP53, confirming human tumour origin. VE-cadherin is required for VM in NCI-H446 SCLC xenografts, where VM decreases tumour latency and, despite increased cisplatin intra-tumour delivery, decreases cisplatin efficacy. The functional significance of VM in SCLC suggests VM regulation may provide new targets for therapeutic intervention.

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Section: Discussionmentioning

confidence: 99%

Vasculogenic mimicry in small cell lung cancer

et al. 2016

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“…Similar effects were observed in lymphatic ECs, in which ADM stimulation caused a reorganization of the tight junction protein ZO-1 (zonula occludens-1) and VE-cadherin in the plasma membrane, thereby tightening the membrane ( 89 ). Other experiments demonstrated barrier disrupting effects of ADM blockade through functional inhibition of the VE-cadherin/β-catenin complex ( 90 ). Underlying mechanisms included induction of Src-dependent VE-cadherin phosphorylation, which prevented binding of β-catenin to the cytoplasmic tail of VE-cadherin, inhibiting cell barrier function.…”

Section: Adm Regulates Endothelial Barrier Functionmentioning

confidence: 99%

“…Furthermore, β-catenin phosphorylation was induced, which targets β-catenin for ubiquitination and proteasomal degradation. Finally, possible involvement of the PI3K/Akt pathway was suggested ( 90 ). These data emphasize that the ADM system is essential for endothelial barrier stabilization.…”

Section: Adm Regulates Endothelial Barrier Functionmentioning

confidence: 99%

Adrenomedullin and Adrenomedullin-Targeted Therapy As Treatment Strategies Relevant for Sepsis

Geven

Kox²,

Pickkers³

2018

Front. Immunol.

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Sepsis remains a major medical challenge, for which, apart from improvements in supportive care, treatment has not relevantly changed over the last few decades. Vasodilation and vascular leakage play a pivotal role in the development of septic shock, with vascular leakage being caused by disrupted endothelial integrity. Adrenomedullin (ADM), a free circulating peptide involved in regulation of endothelial barrier function and vascular tone, is implicated in the pathophysiology of sepsis. ADM levels are increased during sepsis, and correlate with extent of vasodilation, as well as with disease severity and mortality. In vitro and preclinical in vivo data show that administration of ADM exerts anti-inflammatory, antimicrobial, and protective effects on endothelial barrier function during sepsis, but other work suggests that it may also decrease blood pressure, which could be detrimental for patients with septic shock. Work has been carried out to negate ADMs putative negative effects, while preserving or even potentiating its beneficial actions. Preclinical studies have demonstrated that the use of antibodies that bind to the N-terminus of ADM results in an overall increase of circulating ADM levels and improves sepsis outcome. Similar beneficial effects were obtained using coadministration of ADM and ADM-binding protein-1. It is hypothesized that the mechanism behind the beneficial effects of ADM binding involves prolongation of its half-life and a shift of ADM from the interstitium to the circulation. This in turn results in increased ADM activity in the blood compartment, where it exerts beneficial endothelial barrier-stabilizing effects, whereas its detrimental vasodilatory effects in the interstitium are reduced. Up till now, in vivo data on ADM-targeted treatments in humans are lacking; however, the first study in septic patients with an N-terminus antibody (Adrecizumab) is currently being conducted.

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“…By contrast, anti-CGRP and anti-RAMP1 antibodies have been approved as anti-migraine therapies in 2018 [36, 39, 51–56]. On the other hand, because blockage of ADM signaling suppresses tumor xenograft growth and metastasis in animals [26, 29, 43, 47, 49, 57], ADM antagonists are being developed as anti-tumor/angiogenesis therapy [26, 29, 43, 47, 49, 57, 58].…”

Section: Introductionmentioning

confidence: 99%

Development of chimeric and bifunctional antagonists for CLR/RAMP receptors

Chang

Hsu²

2019

PLoS ONE

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CGRP, adrenomedullin (ADM), and adrenomedullin 2 (ADM2) family peptides are important neuropeptides and hormones for the regulation of neurotransmission, vasotone, cardiovascular morphogenesis, vascular integrity, and feto‒placental development. These peptides signal through CLR/RAMP1, 2 and 3 receptor complexes. CLR/RAMP1, or CGRP receptor, antagonists have been developed for the treatment of migraine headache and osteoarthritis pain; whereas CLR/RAMP2, or ADM receptor, antagonists are being developed for the treatment of tumor growth/metastasis. Based on the finding that an acylated chimeric ADM/ADM2 analog potently stimulates CLR/RAMP1 and 2 signaling, we hypothesized that the binding domain of this analog could have potent inhibitory activity on CLR/RAMP receptors. Consistent with this hypothesis, we showed that acylated truncated ADM/ADM2 analogs of 27–31 residues exhibit potent antagonistic activity toward CLR/RAMP1 and 2. On the other hand, nonacylated analogs have minimal activity. Further truncation at the junctional region of these chimeric analogs led to the generation of CLR/RAMP1-selective antagonists. A 17-amino-acid analog (Antagonist 2–4) showed 100-fold selectivity for CLR/RAMP1 and was >100-fold more potent than the classic CGRP receptor antagonist CGRP8-37. In addition, we showed (1) a lysine residue in the Antagonist 2–4 is important for enhancing the antagonistic activity, (2) an analog consisted of an ADM sequence motif and a 12-amino-acid binding domain of CGRP exhibits potent CLR/RAMP1-inhibitory activity, and (3) a chimeric analog consisted of a somatostatin analog and an ADM antagonist exhibits dual activities on somatostatin and CLR/RAMP receptors. Because the blockage of CLR/RAMP signaling prevents migraine pain and suppresses tumor growth/metastasis, further studies of these analogs, which presumably have better access to the tumor microenvironment and nerve endings at the trigeminal ganglion and synovial joints as compared to antibody-based therapies, may lead to the development of better anti-CGRP therapy and alternative antiangiogenesis therapy. Likewise, the use of bifunctional somatostatin-ADM antagonist analogs could be a promising strategy for the treatment of high-grade neuroendocrine tumors by targeting an antiangiogenesis agent to the neuroendocrine tumor microenvironment.

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Adrenomedullin blockade induces regression of tumor neovessels through interference with vascular endothelial-cadherin signalling

Cited by 14 publications

References 57 publications

Vasculogenic mimicry in small cell lung cancer

Vasculogenic mimicry in small cell lung cancer

Adrenomedullin and Adrenomedullin-Targeted Therapy As Treatment Strategies Relevant for Sepsis

Development of chimeric and bifunctional antagonists for CLR/RAMP receptors

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