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Myeloma

The hypoxia target adrenomedullin is aberrantly expressed in multiple myeloma and promotes angiogenesis

Leukemia volume 27, pages 1729–1737 (2013)Cite this article

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Abstract

In multiple myeloma (MM), angiogenesis is strongly correlated to disease progression and unfavorable outcome, and may be promoted by bone marrow hypoxia. Employing gene-expression profiling, we here identified the pro-angiogenic factor adrenomedullin (AM) as the most highly upregulated gene in MM cells exposed to hypoxia. Malignant plasma cells from the majority of MM patients, belonging to distinct genetic subgroups, aberrantly express AM. Already under normoxic conditions, a subset of MM highly expressed and secreted AM, which could not be further enhanced by hypoxia or cobalt chloride-induced stabilization of hypoxia-inducible factor (HIF)1α. In line with this, expression of AM did not correlate with expression of a panel of established hypoxia-/HIF1α-target genes in MM patients. We demonstrate that MM-driven promotion of endothelial cell proliferation and tube formation is augmented by inducible expression of AM and strongly repressed by inhibition of endogenous and hypoxia-induced AM activity. Together, our results demonstrate that MM cells, both in a hypoxia-dependent and -independent fashion, aberrantly express and secrete AM, which can mediate MM-induced angiogenesis. Thus, AM secretion can be a major driving force for the angiogenic switch observed during MM evolution, which renders AM a putative target for MM therapy.

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Acknowledgements

We thank Dr Cuttitta for kindly providing AM inhibitors.

Author Contributions

KAK designed the research, performed experiments, analyzed the data, designed the figures, and wrote the manuscript; AdHK and HvA performed experiments. MJK provided MM patient samples and reviewed the manuscript. KM and RV. performed experiments and analyzed data. STP and MS designed the research, supervised the study, analyzed the data, and wrote and revised the manuscript.

Disclaimer

The study involving human biopsy samples was conducted in accordance with the Declaration of Helsinki and approved by the local ethics committee of the University of Amsterdam, AIEC (Algemene Instellingsgebonden Ethische Commissie). Patients gave written informed consent for the sample collection.

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Author notes

  1. K A Kocemba and H van Andel: These authors contributed equally to this work.

  2. M Spaargaren and S T Pals: These authors share last authorship.

Authors and Affiliations

  1. Department of Pathology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands

    K A Kocemba, H van Andel, A de Haan-Kramer, K Mahtouk, M Spaargaren & S T Pals

  2. Department of Human Genetics, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands

    R Versteeg

  3. Department of Hematology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands

    M J Kersten

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Kocemba, K., van Andel, H., de Haan-Kramer, A. et al. The hypoxia target adrenomedullin is aberrantly expressed in multiple myeloma and promotes angiogenesis. Leukemia 27, 1729–1737 (2013). https://doi.org/10.1038/leu.2013.76

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