Expression of neuropeptide hormone receptors in human adrenal tumors and cell lines: Antiproliferative effects of peptide analogues

Ziegler, Christian; Brown, Jacqueline; Schally, Andrew V.; Erler, A.; Gebauer, Leonie; Treszl, Andrea; Young, Louise; Fishman, Lawrence M.; Engel, Jörg B.; Willenberg, Holger S.; Petersenn, Stephan; Eisenhofer, Graeme; Ehrhart‐Bornstein, Monika; Bornstein, Stefan R.

doi:10.1073/pnas.0907843106

Cited by 52 publications

(56 citation statements)

References 42 publications

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“…Adrenocortical cells express receptors for both LHRH and retinoic acid (18,19). The LHRH agonist [D-Trp6]LHRH is clinically approved for the treatment of hormone-dependent cancers, predominantly prostate cancer.…”

Section: Impact Of Lhrh Agonist [D-trp6]lhrh and Retinoic Acid On Enbmentioning

confidence: 99%

Transplantation of bovine adrenocortical cells encapsulated in alginate

Balyura

Gelfgat

Ehrhart‐Bornstein

et al. 2015

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

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Current treatment options for adrenal insufficiency are limited to corticosteroid replacement therapies. However, hormone therapy does not replicate circadian rhythms and has unpleasant side effects especially due to the failure to restore normal function of the hypothalamic-pituitary-adrenal (HPA) axis. Adrenal cell transplantation and the restoration of HPA axis function would be a feasible and useful therapeutic strategy for patients with adrenal insufficiency. We created a bioartificial adrenal with 3D cell culture conditions by encapsulation of bovine adrenocortical cells (BACs) in alginate (enBACs). We found that, compared with BACs in monolayer culture, encapsulation in alginate significantly increased the life span of BACs. Encapsulation also improved significantly both the capacity of adrenal cells for stable, long-term basal hormone release as well as the response to pituitary adrenocorticotropic hormone (ACTH) and hypothalamic luteinizing hormone-releasing hormone (LHRH) agonist, [D-Trp6]LHRH. The enBACs were transplanted into adrenalectomized, immunodeficient, and immunocompetent rats. Animals received enBACs intraperitoneally, under the kidney capsule (free cells or cells encapsulated in alginate slabs) or s.c. enclosed in oxygenating and immunoisolating βAir devices. Graft function was confirmed by the presence of cortisol in the plasma of rats. Both types of grafted encapsulated cells, explanted after 21-25 d, preserved their morphology and functional response to ACTH stimulation. In conclusion, transplantation of a bioartificial adrenal with xenogeneic cells may be a treatment option for patients with adrenocortical insufficiency and other stress-related disorders. Furthermore, this model provides a microenvironment that ensures 3D cell-cell interactions as a unique tool to investigate new insights into cell biology, differentiation, tissue organization, and homeostasis.adrenal | alginate encapsulation | cell transplantation | LHRH A drenal insufficiency is the failure of adrenocortical cells to produce adequate amounts of glucocorticoids and/or mineralocorticoids. These steroid hormones play a central role in the body's homeostasis of energy, salt, and fluid; thus, adrenal insufficiency is a potentially life-threatening condition. The most relevant causes of adrenal insufficiency are autoimmune disorders (up to 80%); infectious diseases; hereditary factors; traumatic, metabolic, or neoplastic conditions; or surgical bilateral adrenalectomy, sometimes due to a compulsory therapeutic strategy in the treatment of adrenal tumors or congenital adrenal hyperplasia

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Section: Impact Of Lhrh Agonist [D-trp6]lhrh and Retinoic Acid On Enbmentioning

confidence: 99%

Transplantation of bovine adrenocortical cells encapsulated in alginate

Balyura

Gelfgat

Ehrhart‐Bornstein

et al. 2015

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

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“…Such peptides and their receptors may represent valuable tools to develop effective therapies for chromaffin cell neoplasia (Ziegler et al 2009). In particular, pituitary adenylate cyclase-activating polypeptide (PACAP), neuropeptide Y (NPY), and adrenomedullin (AM) are trophic and secretion-stimulating peptides that have been characterized in normal adrenomedullary as well as pheochromocytoma cells (Ichiki et al 1994, deS Senanayake et al 1995, Turquier et al 2001, Isobe et al 2003, Conconi et al 2006, Zeng et al 2006.…”

Section: Introductionmentioning

confidence: 99%

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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“…GHRH and GHRH receptors of pituitary type and splice variants thereof are expressed in many human tissues (39). Recently, we have shown splice variant-1 expression of GHRH receptor in rat insulinoma INS-1 cells, as well as in rat and human pancreatic islets (40,41). We have also analyzed the effect of a synthetic agonist of GHRH JI-38 on betacell survival and cell proliferation in vitro and in vivo (42).…”

mentioning

confidence: 99%

Improvement of islet function in a bioartificial pancreas by enhanced oxygen supply and growth hormone releasing hormone agonist

Ludwig

Rotem

Schmid

et al. 2012

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

169

129

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Islet transplantation is a feasible therapeutic alternative for metabolically labile patients with type 1 diabetes. The primary therapeutic target is stable glycemic control and prevention of complications associated with diabetes by reconstitution of endogenous insulin secretion. However, critical shortage of donor organs, gradual loss in graft function over time, and chronic need for immunosuppression limit the indication for islet transplantation to a small group of patients. Here we present a promising approach to address these limitations by utilization of a macrochamber specially engineered for islet transplantation. The s.c. implantable device allows for controlled and adequate oxygen supply and provides immunological protection of donor islets against the host immune system. The minimally invasive implantable chamber normalized blood glucose in streptozotocin-induced diabetic rodents for up to 3 mo. Sufficient graft function depended on oxygen supply. Pretreatment with the growth hormone-releasing hormone (GHRH) agonist, JI-36, significantly enhanced graft function by improving glucose tolerance and increasing β-cell insulin reserve in rats thereby allowing for a reduction of the islet mass required for metabolic control. As a result of hypervascularization of the tissue surrounding the device, no relevant delay in insulin response to glucose changes has been observed. Consequently, this system opens up a fundamental strategy for therapy of diabetes and may provide a promising avenue for future approaches to xenotransplantation. treatment of diabetes | immune isolation | beta cells

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Expression of neuropeptide hormone receptors in human adrenal tumors and cell lines: Antiproliferative effects of peptide analogues

Cited by 52 publications

References 42 publications

Transplantation of bovine adrenocortical cells encapsulated in alginate

Transplantation of bovine adrenocortical cells encapsulated in alginate

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

Improvement of islet function in a bioartificial pancreas by enhanced oxygen supply and growth hormone releasing hormone agonist

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