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Functional implication of BMP4 expression on angiogenesis in malignant melanoma

Abstract

Analyses of malignant melanomas revealed a strong expression of bone morphogenic proteins (BMPs) and their autocrine effect in promoting cell invasion and migration. Here, we report a paracrine effect of BMPs on the vascular network. Both BMP2 and BMP4 induced tube formation as well as the migratory efficiency of microvascular endothelial cells. Melanoma cells with reduced BMP activity attracted less endothelial cells in invasion assays than control cells. Furthermore, reduction of BMPs in melanoma cells had a strong effect on vasculogenic mimicry. Tube formation on matrigel was analysed for melanoma cells as well as in co-cultures of endothelial and melanoma cells. Melanoma cells with reduced BMP activity were not capable of forming cord-like structures by themselves and additionally inhibited tube formation of the endothelial cells. Genes involved in angiogenesis turned out to be strongly downregulated in these cell clones. Tumors derived from cells with impaired BMP activity showed reduced tumor growth or large necrotic areas owing to lack of angiogenesis in in vivo analyses.

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Acknowledgements

We thank Sibylla Lodermeyer, Silvia Haffner and Verena Burger for excellent technical assistance; Dr J Johnson (University of Munich, Germany) for providing the melanoma cell lines; The Centers for Disease Control and Prevention (Atlanta, Georgia, USA) for providing the human microvascular endothelial cell line CDC/EU.-HMEC-1; Theresa E Gratsch and K Sue O'Shea (University of Michigan Medical School) for providing the chordin expression vector. This work was supported by grants from the Deutsche Krebshilfe to AKB and the Deutsche Forschungsgemeinschaft to GE.

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Correspondence to A-K Bosserhoff.

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Rothhammer, T., Bataille, F., Spruss, T. et al. Functional implication of BMP4 expression on angiogenesis in malignant melanoma. Oncogene 26, 4158–4170 (2007). https://doi.org/10.1038/sj.onc.1210182

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