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Adrenomedullin promotes formation of xenografted endometrial tumors by stimulation of autocrine growth and angiogenesis

Oncogene volume 21, pages 2815–2821 (2002)Cite this article

Abstract

The angiogenic peptide adrenomedullin (ADM) has been implicated as a mediator of the increased risk of endometrial hyperplasia and cancer resulting from the use of tamoxifen for the treatment and prevention of breast cancer. ADM has been shown to be induced by tamoxifen in the endometrium and to be a growth factor for endometrial endothelial cells in vitro. We have now shown ADM to be strongly angiogenic in the mouse subcutaneous sponge angiogenesis assay. To examine the role of ADM in tumor growth, the ADM cDNA was transfected into endometrial carcinoma cells followed by xenografting into athymic mice. Two endometrial cancer cell lines were employed, those in which transfection and expression of ADM resulted in no effect on growthin vitro (Ishikawa cells) and those in which expressionof exogenous ADM stimulated in vitro growth (RL95.2 cells). A clear enhancement of tumor growth was seen with both cell lines but the effect was far greater with the RL95.2 cells. We conclude that ADM is pro-tumorigenic by stimulating either angiogenesis alone or by stimulating angiogenesis and carcinoma cell growth directly. The combined activities lead to a striking increase in tumor growth. These results provide the first direct evidence of tumorigenic activity of ADM and provide further support for ADMs involvement in tamoxifen induced endometrial neoplasia.

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Abbreviations

adrenomedullin:

ADM

calcitonin receptor-like receptor:

CRLR

receptor activity modifying protein 2:

RAMP-2

tamoxifen:

TAM

hypoxia-inducible transcription factor-1:

HIF-1

vascular endothelial growth factor:

VEGF

erythropoietin:

EPO

ER:

estrogen receptor

human dermal microvascular endothelial cells:

HDMEC

endothelial growth medium:

EGM

chick chorioallantoic membrane assay:

CAM assay

optical density:

OD

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Acknowledgements

The authors acknowledge the excellent technical assistance of Sandra Peak, ICRF Clare Hall Laboratories, London in performing the xenograft and sponge assays, Helen Turley, Department of Cellular Science, University of Oxford for help with immunohistochemistry and cytospins and Mr Daryl Harman, Caligen Foam Ltd, Accrington for help in obtaining sponge implants. Financial support was provided by the Imperial Cancer Research Fund, The Deutsche Forschungsgemeinschaft and The Sir Jules Thorn Charitable Trust.

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Authors and Affiliations

  1. Molecular Angiogenesis Laboratory, Cancer Research UK, Institute of Molecular Medicine, John Radcliffe Hospital, University of Oxford, Oxford, OX3 9DS, UK

    Martin K Oehler, Stephen Hague & Roy Bicknell

  2. Nuffield Department of Obstetrics and Gynaecology, John Radcliffe Hospital, University of Oxford, Oxford, OX3 9DS, UK

    Martin K Oehler, Stephen Hague & Margaret CP Rees

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  1. Martin K Oehler
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Correspondence to Roy Bicknell.

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Oehler, M., Hague, S., Rees, M. et al. Adrenomedullin promotes formation of xenografted endometrial tumors by stimulation of autocrine growth and angiogenesis. Oncogene 21, 2815–2821 (2002). https://doi.org/10.1038/sj.onc.1205374

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