Adrenomedullin Is Expressed in Pancreatic Cancer and Stimulates Cell Proliferation and Invasion in an Autocrine Manner via the Adrenomedullin Receptor, ADMR

Ramachandran, Vijaya; Arumugam, Thiruvengadam; Hwang, Rosa F.; Greenson, Joel K.; Simeone, Diane M.; Logsdon, Craig D.

doi:10.1158/0008-5472.can-06-3362

Cited by 77 publications

(94 citation statements)

References 39 publications

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“…Several AM-overexpressing human carcinoma cell lines exhibit enhanced growth in vitro and in vivo to a varying degree (15,25). A recent report demonstrated that AMA inhibited the proliferation and invasion of pancreatic cancer cells expressing AM receptors in vitro (13). However, we found that neither AM nor AMA affected the growth of OS-RC-2 renal cancer cells in vitro, even though OS-RC2 tumor sizes in mice were clearly reduced by AMA.…”

Section: Discussioncontrasting

confidence: 77%

“…AM gene knockout mice have shown embryonic lethality with severe abnormalities of the vasculature (10) and subcutaneous hemorrhage indicating the significance of AM signaling in vascular development. AM is expressed in a variety of malignant tumor tissues (11,12) and was shown to be mitogenic for human cancer cell lines, including lung, breast, colon, prostate and pancreatic lineages in vitro (12,13). In addition, AM is considered to be angiogenic in tumors.…”

Section: Introductionmentioning

confidence: 99%

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Adrenomedullin antagonist suppresses tumor formation in renal cell carcinoma through inhibitory effects on tumor endothelial cells and endothelial progenitor mobilization

Tsuchiya

Hida²,

Hida³

et al. 2010

Int J Oncol

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Abstract. Adrenomedullin (AM) is a multifunctional 52-amino acid peptide. AM has several effects and acts as a growth factor in several types of cancer cells. Our previous study revealed that an AM antagonist (AMA) suppressed the growth of pancreatic tumors in mice, although its mechanism was not elucidated. In this study, we constructed an AMA expression vector and used it to treat renal cell carcinoma (RCC) in mice. This AMA expression vector significantly reduced tumor growth in mice. In addition, microvessel density was decreased in AMA-treated tumors. To analyze the effect of AMA on tumor angiogenesis in this model, tumor endothelial cells (TECs) were isolated from RCC xenografts. TEC proliferation was stimulated by AM and it was inhibited by AMA significantly. AM induced migration of TECs and it was also blocked by AMA. However, normal ECs (NECs) were not affected by either AM or AMA. These results demonstrate that AMA has inhibitory effects on TECs specifically, not on NEC, thereby inhibiting tumor angiogenesis. Furthermore, we showed that vascular endothelial growth factor-induced mobilization of endothelial progenitor cell (EPC) into circulation was inhibited by AMA. These results suggest that AMA can be considered a good anti-angiogenic reagent that selectively targets TECs and EPC in renal cancer.

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Section: Discussioncontrasting

confidence: 77%

Section: Introductionmentioning

confidence: 99%

Adrenomedullin antagonist suppresses tumor formation in renal cell carcinoma through inhibitory effects on tumor endothelial cells and endothelial progenitor mobilization

Tsuchiya

Hida²,

Hida³

et al. 2010

Int J Oncol

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“…The expression of CGRP receptor components and CGRP activity has been examined in several tumours and tumour-derived cell lines. For example, RAMP1 mRNA expression has been detected in benign and malignant pheochromocytomas (Thouennon et al 2010), Conn's adenoma (Forneris et al 2001) and pancreatic cancers (Ramachandran et al 2007).…”

Section: C5mentioning

confidence: 99%

“…objectIdZ146). Unfortunately, the original misidentification of this protein as an AM receptor continues to confuse a number of workers who refer to an 'ADMR' (AM receptor) based on L1/G10D (Ramachandran et al 2007(Ramachandran et al , 2009. It is particularly regrettable that the official gene name for L1/G10D has until recently been ADMR, perpetuating the unsubstantiated concept that this is a receptor for AM.…”

Section: What Constitutes An Am or A Cgrp Receptor?mentioning

confidence: 99%

Adrenomedullin and calcitonin gene-related peptide receptors in endocrine-related cancers: opportunities and challenges

Hay

Walker²,

Poyner³

2010

Endocrine Related Cancer

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Adrenomedullin (AM), adrenomedullin 2 (AM2/intermedin) and calcitonin gene-related peptide (CGRP) are members of the calcitonin family of peptides. They can act as growth or survival factors for a number of tumours, including those that are endocrine-related. One mechanism through which this occurs is stimulating angiogenesis and lymphangiogenesis. AM is expressed by numerous tumour types and for some cancers, plasma AM levels can be correlated with the severity of the disease. In cancer models, lowering AM content or blocking AM receptors can reduce tumour mass. AM receptors are complexes formed between a seven transmembrane protein, calcitonin receptor-like receptor and one of the two accessory proteins, receptor activity-modifying proteins (RAMPs) 2 or 3 to give the AM 1 and AM 2 receptors respectively. AM also has affinity at the CGRP receptor, which uses RAMP1. Unfortunately, due to a lack of selective pharmacological tools or antibodies to distinguish AM and CGRP receptors, the precise receptors and signal transduction pathways used by the peptides are often uncertain. Two other membrane proteins, RDC1 and L1/G10D (the 'ADMR'), are not currently considered to be genuine CGRP or AM receptors. In order to properly evaluate whether AM or CGRP receptor inhibition has a role in cancer therapy, it is important to identify which receptors mediate the effects of these peptides. To effectively distinguish AM 1 and AM 2 receptors, selective receptor antagonists need to be developed. The development of specific CGRP receptor antagonists suggests that this is now feasible.

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“…Induced by hypoxia, AM involves in tumor angiogenesis, inhibiting apoptosis, immune escape and other processes which seem to have an important role in tumor growth, invasion, metastasis and other biological behaviors (1,2). Recent studies have indicated that AM highly expressed in ovarian cancer and its expression level was an important indicator of invasive ovarian cancer (1).…”

Section: Introductionmentioning

confidence: 99%

Effect of inhibition of the adrenomedullin gene on the growth and chemosensitivity of ovarian cancer cells

et al. 2012

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Abstract. Adrenomedullin (AM), a potent vasodilator peptide, is present in various types of tumors. Here, we constructed short hairpin RNA (shRNA) in order to target the AM gene in vitro using RNA interference (RNAi) technology. HO8910 ovarian cancer cells were transfected, and the effects of AM on proliferation and chemosensitivity of the cells were examined. RT-PCR, real-time PCR and western blot analysis were performed to detect the AM gene and protein expression. The MTT assay was used to observe the effect of AM on proliferation and chemosensitivity of the cells. Also, the protein levels of Bcl-2 and the extracellular regulated protein kinase (ERK) were evaluated by western blot analysis. We found that silencing of the AM gene inhibited the proliferation and increased the chemosensitivity of HO8910 cells, reduced the expression of AM mRNA and protein as well as downregulated Bcl-2 and p-ERK expression. We, therefore, conclude that silencing of the AM gene in HO8910 ovarian cancer cells inhibited the proliferation and increased the chemosensitivity of the cells through downregulation of ERK and Bcl-2 expression. Thus, anti-AM treatment together with suppression of ERK and Bcl-2 expression provides a novel research approach for ovarian cancer.

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Adrenomedullin Is Expressed in Pancreatic Cancer and Stimulates Cell Proliferation and Invasion in an Autocrine Manner via the Adrenomedullin Receptor, ADMR

Cited by 77 publications

References 39 publications

Adrenomedullin antagonist suppresses tumor formation in renal cell carcinoma through inhibitory effects on tumor endothelial cells and endothelial progenitor mobilization

Adrenomedullin antagonist suppresses tumor formation in renal cell carcinoma through inhibitory effects on tumor endothelial cells and endothelial progenitor mobilization

Adrenomedullin and calcitonin gene-related peptide receptors in endocrine-related cancers: opportunities and challenges

Effect of inhibition of the adrenomedullin gene on the growth and chemosensitivity of ovarian cancer cells

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