PCR display identifies tamoxifen induction of the novel angiogenic factor adrenomedullin by a non estrogenic mechanism in the human endometrium

Yuan, Zhao; Hague, Stephen J.; Manek, Sanjiv; Zhang, Lyna; Bicknell, Roy; Rees, Margaret

doi:10.1038/sj.onc.1201768

Cited by 126 publications

(124 citation statements)

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“…Adverse effects of TAM on the endometrium include hyperplasia, malignancy and uterine bleeding all of which involve angiogenesis. We have examined the expression of a number of well characterized angiogenic factors in the endometrium of pre-and postmenopausal women receiving TAM therapy, namely aFGF, bFGF, TP, VEGF and ADM. Apart from ADM (Zhao et al, 1998), previous studies have mainly examined carcinoma lines or rodent uteri but not human tissues and not in relation to menopausal status. From the work described here, it appears TAM is capable of modulating the expression of these angiogenic factors, both in terms of the expression level and profile with aFGF, bFGF and ADM being upregulated especially in premenopausal tissue.…”

Section: Discussionmentioning

confidence: 99%

“…Immunohistochemistry was carried out as previously described (Zhao et al, 1998). Briefly, slides were incubated with 5% goat serum (Dako) to reduce non-specific background staining, followed by 1 out of 800 anti-adrenomedullin (Peninsula Laboratories, Liverpool, UK).…”

Section: Adrenomedullin Immunohistochemical Stainingmentioning

confidence: 99%

“…We have previously shown by differential PCR display that TAM, but not oestrogen induces expression of adrenomedullin (ADM) in endometrial isolates (Zhao et al, 1998). ADM stimulates angiogenesis in the chick chorioallantoic membrane assay (Zhao et al, 1998).…”

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confidence: 99%

“…ADM stimulates angiogenesis in the chick chorioallantoic membrane assay (Zhao et al, 1998). ADM is also an autocrine growth factor for human endometrial endothelial cells and is clearly involved in endometrial angiogenesis (Nikitenko et al, 2000).…”

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Tamoxifen induction of angiogenic factor expression in endometrium

et al. 2002

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Tamoxifen is the current therapy of choice for patients with oestrogen receptor positive breast cancer, and it is currently under evaluation as a prophylactic for women at high risk of developing the disease. However, tamoxifen is also known to induce proliferative changes in the endometrium increasing the risk of developing endometrial hyperplasia, polyps and carcinoma. Angiogenesis is an intimate part of this process. For this reason, we have examined the expression of several well characterized angiogenic factors, namely, acidic and basic fibroblast growth factor, thymidine phosphorylase, vascular endothelial growth factor and adrenomedullin in both normal and tamoxifen exposed pre-and postmenopausal endometrium. Vascular density and endothelial proliferation index were also quantified. We found increased expression of acidic and basic fibroblast growth factor and adrenomedullin after treatment with tamoxifen mainly in premenopausal tissue. Vascular density was significantly increased in pre-but not post-menopausal endometrium (P=0.0018) following tamoxifen treatment. These results support the notion that angiogenesis is integral to the response to tamoxifen exposure, and is a potential target with which to block these side effects of tamoxifen.

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Section: Discussionmentioning

confidence: 99%

Section: Adrenomedullin Immunohistochemical Stainingmentioning

confidence: 99%

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Tamoxifen induction of angiogenic factor expression in endometrium

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“…In 1998, we first showed ADM to be potently angiogenic using the chick chorioallantoic membrane assay (Zhao et al, 1998), and it has subsequently been shown to be protumorigenic by a number of groups employing both xenograft studies Oehler et al, 2002) and blocking antibodies (Ouafik et al, 2002). Adrenomedullin and cancer have recently been reviewed (Zudaire et al, 2003).…”

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Tissue and plasma expression of the angiogenic peptide adrenomedullin in breast cancer

et al. 2003

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Adrenomedullin (ADM) is an angiogenic factor that has also been shown to be a mitogen and a hypoxia survival factor for tumour cells. These properties point to ADM as a potential promoter of human malignancies, but little data are available concerning the expression of ADM in human breast cancer. In the present work, we have examined ADM peptide expression in a series of malignant breast tumours by immunohistochemistry using a newly developed anti-ADM monoclonal antibody. In addition, ADM plasma concentrations in breast cancer patients and healthy controls were determined by radioimmunoassay. Of the examined breast cancer samples, 27/33 (82%) showed a moderate to strong staining intensity. ADM-peptide expression in breast tumours was significantly correlated with axillary lymph node metastasis (P ¼ 0.030). Analysis of ADM plasma concentrations showed no significant difference between the circulating ADM levels of breast cancer patients and healthy controls. However, a significant positive correlation was found between tumour size and plasma ADM levels (r ¼ 0.641, P ¼ 0.017). Moreover, ADM levels in breast cancer patients correlated with the presence of lymph node metastasis (P ¼ 0.002). In conclusion, we have shown for the first time that ADM peptide is widely expressed in breast cancer and that the degree of expression is associated with lymph node metastasis. ADM peptide in plasma of breast cancer patients reflects the size of the primary tumour, but is unlikely to be a useful tumour marker for the detection of breast cancer. Plasma ADM might represent an independent predictor of lymph node metastasis. The clinical implications of these findings remain to be evaluated.

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RETRACTED: Expression of adrenomedullin in human colorectal tumors and its role in cell growth and invasion in vitro and in xenograft growth in vivo

et al. 2013

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Adrenomedullin (AM) is a multifunctional peptide vasodilator that transduces its effects through calcitonin receptor-like receptor/receptor activity-modifying protein-2 and -3 (CLR/RAMP2 and CLR/RAMP3). In this study, real-time quantitative reverse transcription demonstrated a significant expression of AM mRNA in tumor samples from colorectal cancer (CRC) patients in clinical stage II, III, and IV when compared with normal colorectal tissue. AM, CLR, RAMP2, and RAMP3 proteins were immunohistochemically localized in the carcinomatous epithelial compartment of CRC tissue. Tissue microarray analysis revealed a clear increase of AM, CLR, RAMP2, and RAMP3 staining in lymph node and distant metastasis when compared with primary tumors. The human colon carcinoma cells HT-29 expressed and secreted AM into the culture medium with a significant increase under hypoxia. Treatment of HT-29 cells with synthetic AM stimulated cell proliferation and invasion in vitro. Incubation with anti-AM antibody (αAM), anti-AM receptors antibodies (αAMR), or AM antagonist AM22–52 inhibited significantly basal levels of proliferation of HT-29 cells, suggesting that AM may function as an autocrine growth factor for CRC cells. Treatment with αAM significantly suppressed the growth of HT-29 tumor xenografts in vivo. Histological examination of αAM-treated tumors showed evidence of disruption of tumor vascularity with decreased microvessel density, depletion of endothelial cells and pericytes, and increased tumor cell apoptosis. These findings highlight the potential importance of AM and its receptors in the progression of CRC and support the conclusion that αAM treatment inhibits tumor growth by suppression of angiogenesis and tumor growth, suggesting that AM may be a useful therapeutic target.

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PCR display identifies tamoxifen induction of the novel angiogenic factor adrenomedullin by a non estrogenic mechanism in the human endometrium

Cited by 126 publications

References 22 publications

Tamoxifen induction of angiogenic factor expression in endometrium

Tamoxifen induction of angiogenic factor expression in endometrium

Tissue and plasma expression of the angiogenic peptide adrenomedullin in breast cancer

RETRACTED: Expression of adrenomedullin in human colorectal tumors and its role in cell growth and invasion in vitro and in xenograft growth in vivo

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