Adrenomedullin antagonist suppresses in vivo growth of human pancreatic cancer cells in SCID mice by suppressing angiogenesis

Ishikawa, Takahisa; Chen, Jian; Wang, Jingxin; Okada, Futoshi; Sugiyama, Toshiro; Kobayashi, Takahiko; Shindo, Masanobu; Higashino, Fumihiro; Katoh, Hiroyuki; Asaka, Masahiro; Kondo, Takeshi; Hosokawa, Masuo; Kobayashi, Masanobu

doi:10.1038/sj.onc.1206207

Cited by 73 publications

(107 citation statements)

References 24 publications

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“…The HIF target adrenomedullin was shown to promote physiological and pathological angiogenesis in vitro and in animal models (49)(50)(51). ADM signals angiogenesis by binding calcitonin-receptor-like receptor, which is widely expressed on normal and hypoxic endothelial cells (49,52).…”

Section: Discussionmentioning

confidence: 99%

VEGF is essential for hypoxia-inducible factor-mediated neovascularization but dispensable for endothelial sprouting

Oladipupo¹,

Kovalski³

et al. 2011

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

159

117

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Although our understanding of the molecular regulation of adult neovascularization has advanced tremendously, vascular-targeted therapies for tissue ischemia remain suboptimal. The master regulatory transcription factors of the hypoxia-inducible factor (HIF) family are attractive therapeutic targets because they coordinately up-regulate multiple genes controlling neovascularization. Here, we used an inducible model of epithelial HIF-1 activation, the TetON-HIF-1 mouse, to test the requirement for VEGF in HIF-1 mediated neovascularization. TetON-HIF-1, K14-Cre, and VEGF flox/flox alleles were combined to create TetON-HIF-1:VEGF Δ mice to activate HIF-1 and its target genes in adult basal keratinocytes in the absence of concomitant VEGF. HIF-1 induction failed to produce neovascularization in TetON-HIF-1:VEGF Δ mice despite robust up-regulation of multiple proangiogenic HIF targets, including PlGF, adrenomedullin, angiogenin, and PAI-1. In contrast, endothelial sprouting was preserved, enhanced, and more persistent, consistent with marked reduction in Dll4-Notch-1 signaling. Optical-resolution photoacoustic microscopy, which provides noninvasive, label-free, high resolution, and wide-field vascular imaging, revealed the absence of both capillary expansion and arteriovenous remodeling in serially imaged individual TetON-HIF-1:VEGF Δ mice. Impaired TetON-HIF-1:VEGF Δ neovascularization could be partially rescued by 12- O -tetradecanoylphorbol-13-acetate skin treatment. These data suggest that therapeutic angiogenesis for ischemic cardiovascular disease may require treatment with both HIF-1 and VEGF.

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Section: Discussionmentioning

confidence: 99%

VEGF is essential for hypoxia-inducible factor-mediated neovascularization but dispensable for endothelial sprouting

Oladipupo¹,

Kovalski³

et al. 2011

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

159

117

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“…For example, in some cancers, AM expression is associated with vascular density and endothelial cell proliferation (Hague et al 2000). In vitro studies have shown the AM receptor antagonist AM 22-52 was able to abrogate tumor formation of a pancreatic tumor cell line suggesting a role for AM in this cancer (Ishikawa et al 2003).…”

Section: Introductionmentioning

confidence: 99%

Adrenomedullin increases the expression of calcitonin-like receptor and receptor activity modifying protein 2 mRNA in human microvascular endothelial cells

Schwarz¹,

Renshaw²,

Kapas³

et al. 2006

Journal of Endocrinology

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Adrenomedullin (AM) is a multifunctional peptide hormone, which plays a significant role in vasodilation and angiogenesis, implicating it in hypertension as well as in carcinogenesis. AM exerts its effects via the calcitonin receptor-like receptor (CRLR, now known as CL) complexed with either receptor activity modifying protein (RAMP) 2 or 3. We have investigated the effect of AM on immortalized human microvascular endothelial cells 1, since endothelial cells are a major source as well as a target of AM actions in vivo. Cells treated with AM showed elevated cAMP in a time (5-45 min)-dependent and dose (10 K6 -10 K14 M)-dependent manner. Pre-treatment with the AM receptor antagonist AM 22-52 partially suppressed the AM-induced increase in cAMP levels. An increase in extracellular signal-regulated kinase 1/2 phosphorylation was observed after 5 min of treatment with 10 K8 M AM. This phosphorylation was specific, since we were able to block the AM-induced effect with 1 mM U0126, a specific mitogen-activated protein/extracellular signal-regulated kinase kinase inhibitor. Using realtime PCR, we were able to show for the first time that AM upregulates peptide and mRNA expression of vascular endothelial growth factor (VEGF). However, AM treatment of cells did not result in increased cell proliferation. Instead, we observed that AM and VEGF induced cell migration, which could be inhibited by the AM 22-52 and anti-VEGF antibody respectively. AM also significantly elevated mRNA levels of CL (after 2 and 24 h treatment) and RAMP2 (after 1 and 24 h treatment). The upregulation of the AM receptor at two time points reflects possibly different cellular responses to short-and long-term exposure to AM.

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“…Similar to the studies for vascular endothelial growth factor, the density of blood vessels in the AM antibody-treated tumors was also decreased, supporting the roles for AM in angiogenesis, vasculogenesis and/or vessel stabilization (Zhao et al, 1998;Ouafik et al, 2002;FernandezSauze et al, 2004). In good agreement, Ishikawa et al (2003) demonstrated that the AM antagonist (hAM (22-52)-NH 2 ) inhibited pancreatic cancer cell growth in vivo by suppressing tumor vascular development.…”

Section: Introductionmentioning

confidence: 69%

Identification of secondary structure in the 5′-untranslated region of the human adrenomedullin mRNA with implications for the regulation of mRNA translation

et al. 2006

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Adrenomedullin (AM) is a multifunctional regulatory peptide with important angiogenic and mitogenic properties. Here we identify a region of stable secondary structure in the 5 0 -untranslated region (5 0 UTR) of human AM mRNA. Reverse transcriptase-polymerase chain reaction of the 5 0 UTR consistently resulted, in addition to the product with the expected size of 155 base pair (bp), in a second product with an B65-bp deletion from the central region of the 5 0 UTR, suggesting the presence of a secondary structure. The presence of a stem-loop structure was confirmed by probing the 5 0 UTR with RNases with selectivity for single-or double-stranded RNA. We investigated the role of this stem-loop structure in expression of luciferase reporter gene in cultured cell lines. Reporter assays using a chimeric mRNA that combined luciferase and the 5 0 UTR of AM mRNA demonstrated a dramatic decrease of the reporter activity owing to a decreased translation, whereas the deletion of the stem-loop structure localized between nt þ 31 and þ 95 from the cap site led to the recovery of activity. Gel migration shift assays using cytosolic extracts from mammalian cell lines demonstrate a specific binding of a cytosolic protein to riboprobes containing the 5 0 UTR of AM but not to riboprobes either corresponding to other areas of the message or containing the 5 0 UTR but lacking the region of secondary structure. Although we conclude that the 5 0 UTR of the human AM mRNA can modulate the translation of AM mRNA in vivo, and that the predicted stem-loop structure is necessary for this inhibition, the functional consequences of the cis element-binding activity remain to be determined.

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Adrenomedullin antagonist suppresses in vivo growth of human pancreatic cancer cells in SCID mice by suppressing angiogenesis

Cited by 73 publications

References 24 publications

VEGF is essential for hypoxia-inducible factor-mediated neovascularization but dispensable for endothelial sprouting

VEGF is essential for hypoxia-inducible factor-mediated neovascularization but dispensable for endothelial sprouting

Adrenomedullin increases the expression of calcitonin-like receptor and receptor activity modifying protein 2 mRNA in human microvascular endothelial cells

Identification of secondary structure in the 5′-untranslated region of the human adrenomedullin mRNA with implications for the regulation of mRNA translation

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