Targeting adrenomedullin receptors with systemic delivery of neutralizing antibodies inhibits tumor angiogenesis and suppresses growth of human tumor xenografts in mice

Kaafarani, Itidal; Fernandez-Sauze, Samantha; Bérenguer, Caroline; Chinot, Olivier; Delfino, Christine; Dussert, Christophe; Métellus, Philippe; Boudouresque, Françoise; Mabrouk, Kamel; Grisoli, F; Figarella‐Branger, Dominique; Martin, Pièrre‐Marie; Ouafik, L’Houcine

doi:10.1096/fj.08-127852

Cited by 63 publications

(95 citation statements)

References 37 publications

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“…Thus, TAM-derived ADM can influence macrophages themselves in an autocrine manner. Inhibition of ADM receptors expression or activities can impair the tumor angiogenesis and growth (20)(21)(22)47). Interestingly, we show that the expression of all ADM receptor components can be upregulated by the B16/F10 CM, suggesting that the autocrine effect of ADM on TAMs is facilitated by the tumor microenvironment.…”

Section: Discussionmentioning

confidence: 68%

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Tumor-Associated Macrophages Promote Angiogenesis and Melanoma Growth via Adrenomedullin in a Paracrine and Autocrine Manner

Chen

Huang

Bong

et al. 2011

Clinical Cancer Research

187

185

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Purpose: Elevated numbers of tumor-associated macrophages (TAM) in the tumor microenvironment are often correlated with poor prognosis in melanoma. However, the mechanisms by which TAMs modulate melanoma growth are still poorly understood. This study was aimed at examining the function and mechanism of TAM-derived adrenomedullin (ADM) in angiogenesis and melanoma growth.Experimental Design: We established in vitro and in vivo models to investigate the relationship between TAMs and ADM in melanoma, the role and mechanism of ADM in TAM-induced angiogenesis and melanoma growth. The clinical significance of ADM and its receptors was evaluated using melanoma tissue microarrays.Results: ADM was expressed by infiltrating TAMs in human melanoma, and its secretion from macrophages was upregulated upon coculture with melanoma cells, or with melanoma cells conditioned media. Meanwhile, TAMs enhanced endothelial cell migration and tubule formation and also increased B16/F10 tumor growth. Neutralizing ADM antibody and ADM receptor antagonist, AMA, attenuated TAM-induced angiogenesis in vitro and melanoma growth in vivo, respectively. Furthermore, ADM promoted angiogenesis and melanoma growth via both the paracrine effect, mediated by the endothelial nitric oxide synthase signaling pathway, and the autocrine effect, which stimulated the polarization of macrophages toward an alternatively activated (M2) phenotype. Finally, immunofluorescence analysis on human melanomas showed that the expression of ADM in TAMs and its receptors was greatly increased compared with adjacent normal skins.Conclusion: Our study reveals a novel mechanism that TAMs enhance angiogenesis and melanoma growth via ADM and provides potential targets for melanoma therapies.

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Section: Discussionmentioning

confidence: 68%

“…Moreover, the plasma ADM level is associated with lymph node metastasis (18). Several in vivo studies have shown a reduction of tumor angiogenesis and growth upon the treatment with neutralizing ADM antibodies (19), ADM receptor antagonist, AMA (20,21), or ADM receptor RNA interference (22).…”

Section: It Is a Multifunctional Molecule That Is Involved Inmentioning

confidence: 99%

Tumor-Associated Macrophages Promote Angiogenesis and Melanoma Growth via Adrenomedullin in a Paracrine and Autocrine Manner

Chen

Huang

Bong

et al. 2011

Clinical Cancer Research

187

185

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“…In a pheochromocytoma cell model, the PC12 cell line, we could confirm the pro-survival effect of AM and SDF1 on tumoral cells, although the mechanisms involved in these effects may differ between rat and human cells. Thus, the data reported in the present study may have interesting therapeutic implications since AM or RDC1 is currently investigated as therapeutic targets in other cancers including breast, lung, glial, and colon neoplasia (Rocchi et al 2001, Miao et al 2007, Kaafarani et al 2009.…”

Section: Discussionmentioning

confidence: 79%

Expression of trophic amidated peptides and their receptors in benign and malignant pheochromocytomas: high expression of adrenomedullin RDC1 receptor and implication in tumoral cell survival

Thouënnon¹,

Aimar²,

Tanguy³

et al. 2010

Endocrine-Related Cancer

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Pheochromocytomas are catecholamine-producing tumors which are generally benign, but which can also present as or develop into malignancy. Molecular pathways of malignant transformation remain poorly understood. Pheochromocytomas express various trophic peptides which may influence tumoral cell behavior. Here, we investigated the expression of trophic amidated peptides, including pituitary adenylate cyclase-activating polypeptide (PACAP), neuropeptide Y (NPY), and adrenomedullin (AM), and their receptors in benign and malignant pheochromocytomas in order to assess their potential role in chromaffin cell tumorigenesis and malignant transformation. PACAP, NPY, and AM are expressed in the majority of pheochromocytomas studied; NPY exhibiting the highest mRNA levels relative to reference genes. Although median gene expression or peptide levels were systematically lower in malignant compared to benign tumors, no statistically significant difference was found. Among all the receptors of these peptides that were analyzed, only the AM receptor RDC1 displayed a differential expression between benign and malignant pheochromocytomas. This receptor exhibited a fourfold higher expression in malignant than in benign tumors. AM and stromal cell-derived factor 1, which has also been described as a ligand for RDC1, increased the number of human pheochromocytoma cells in primary culture and exerted anti-apoptotic activity on rat pheochromocytoma PC12 cells. In addition, RDC1 gene silencing decreased the number of viable PC12 cells. This study shows the expression of several trophic peptides and their receptors in benign and malignant pheochromocytomas, and suggests that AM and its RDC1 receptor could be involved in chromaffin cell tumorigenesis through pro-survival effects. Therefore, AM and RDC1 may represent valuable targets for the treatment of malignant pheochromocytomas.

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“…To assess programmed cell death, tissue sections were evaluated using mAb F7-26 to detect single-strand DNA (ssDNA; Eurobio AbCys). Staining was carried out as detailed previously (17,23).…”

Section: Immunohistochemical Analysismentioning

confidence: 99%

“…Adrenomedullin is widely expressed in a variety of tumor types (10) and was shown to be mitogenic for many human cancer cell lines in vitro (4,(11)(12)(13)(14)(15). Several in vivo studies have shown a reduction of tumor angiogenesis and growth upon the treatment with neutralizing adrenomedullin antibodies (13), adrenomedullin receptor antagonist (16,17), or adrenomedullin receptor interference (14). Others and we have reported the expression of adrenomedullin in human prostate carcinoma and prostate cancer cell lines (11,(18)(19)(20).…”

Section: Introductionmentioning

confidence: 97%

Adrenomedullin Blockade Suppresses Growth of Human Hormone–Independent Prostate Tumor Xenograft in Mice

Berenguer-Daizé

Boudouresque

Bastide

et al. 2013

Clinical Cancer Research

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Purpose: To study the role of the adrenomedullin system [adrenomedullin and its receptors (AMR), CLR, RAMP2, and RAMP3] in prostate cancer androgen-independent growth.Experimental Design: Androgen-dependent and -independent prostate cancer models were used to investigate the role and mechanisms of adrenomedullin in prostate cancer hormone-independent growth and tumor-associated angiogenesis and lymphangiogenesis.Results: Adrenomedullin and AMR were immunohistochemically localized in the carcinomatous epithelial compartment of prostate cancer specimens of high grade (Gleason score >7), suggesting a role of the adrenomedullin system in prostate cancer growth. We used the androgen-independent Du145 cells, for which we demonstrate that adrenomedullin stimulated cell proliferation in vitro through the cAMP/CRAF/MEK/ERK pathway. The proliferation of Du145 and PC3 cells is decreased by anti-adrenomedullin antibody (aAM), supporting the fact that adrenomedullin may function as a potent autocrine/paracrine growth factor for prostate cancer androgen-independent cells. In vivo, aAM therapy inhibits the growth of Du145 androgenindependent xenografts and interestingly of LNCaP androgen-dependent xenografts only in castrated animals, suggesting strongly that adrenomedullin might play an important role in tumor regrowth following androgen ablation. Histologic examination of aAM-treated tumors showed evidence of disruption of tumor vascularity, with depletion of vascular as well as lymphatic endothelial cells and pericytes, and increased lymphatic endothelial cell apoptosis. Importantly, aAM potently blocks tumor-associated lymphangiogenesis, but does not affect established vasculature and lymphatic vessels in normal adult mice.Conclusions: We conclude that expression of adrenomedullin upon androgen ablation in prostate cancer plays an important role in hormone-independent tumor growth and in neovascularization by supplying/amplifying signals essential for pathologic neoangiogenesis and lymphangiogenesis.

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Targeting adrenomedullin receptors with systemic delivery of neutralizing antibodies inhibits tumor angiogenesis and suppresses growth of human tumor xenografts in mice

Cited by 63 publications

References 37 publications

Tumor-Associated Macrophages Promote Angiogenesis and Melanoma Growth via Adrenomedullin in a Paracrine and Autocrine Manner

Tumor-Associated Macrophages Promote Angiogenesis and Melanoma Growth via Adrenomedullin in a Paracrine and Autocrine Manner

Expression of trophic amidated peptides and their receptors in benign and malignant pheochromocytomas: high expression of adrenomedullin RDC1 receptor and implication in tumoral cell survival

Adrenomedullin Blockade Suppresses Growth of Human Hormone–Independent Prostate Tumor Xenograft in Mice

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