The hypoxia target adrenomedullin is aberrantly expressed in multiple myeloma and promotes angiogenesis
K A Kocemba1, H van Andel, A de Haan-Kramer
1Department of Pathology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
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.
Insights
Adrenomedullin (AM) is highly expressed in multiple myeloma (MM) cells, promoting angiogenesis. This study reveals AM as a key driver of MM-induced blood vessel growth, making it a potential therapeutic target for this cancer.
Area of Science:
- Oncology
- Molecular Biology
- Angiogenesis Research
Background:
- Angiogenesis in multiple myeloma (MM) correlates with disease progression and poor outcomes.
- Bone marrow hypoxia may promote angiogenesis in MM.
Purpose of the Study:
- To identify key pro-angiogenic factors in hypoxic MM cells.
- To investigate the role of adrenomedullin (AM) in MM-driven angiogenesis.
- To evaluate AM as a potential therapeutic target in MM.
Main Methods:
- Gene-expression profiling of MM cells under hypoxia.
- Analysis of AM expression in MM patient samples across genetic subgroups.
- Assessment of AM's impact on endothelial cell proliferation and tube formation.
- Inhibition studies targeting endogenous and hypoxia-induced AM activity.
Main Results:
- Adrenomedullin (AM) was identified as the most upregulated gene in hypoxic MM cells.
- Aberrant AM expression was observed in malignant plasma cells from most MM patients.
- MM-driven angiogenesis was enhanced by inducible AM and repressed by AM inhibition.
- AM expression in MM did not consistently correlate with hypoxia-inducible factor (HIF)1α target genes.
Conclusions:
- MM cells aberrantly express and secrete AM, mediating MM-induced angiogenesis via hypoxia-dependent and -independent pathways.
- AM plays a significant role in the angiogenic switch during MM evolution.
- AM represents a promising therapeutic target for multiple myeloma.
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