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Activated Notch1 expression is associated with angiogenesis in cutaneous melanoma

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Abstract

An early event in melanocytic tumor growth is the upregulation of Notch signaling. When an active form of Notch1 is overexpressed in primary human melanocytes, it increases cell growth, survival and invasive properties, promoting melanoma progression. Recent evidence suggested that tumor initiation and growth are driven by a subset of tumor-initiating cells termed cancer stem cells. Notch1 plays a predominant role in the maintenance of melanoblasts, including melanocyte stem cells, by preventing initiation of apoptosis. Moreover, the importance of Notch1 in the regulation of tumor angiogenesis is supported by growing evidence in various cancers. Nestin has been widely used as a marker for melanocyte stem cells as well as an angiogenic marker to evaluate neovascularity of endothelial cells in tumors. To gain an insight into the impact of Notch1 activation on the maintenance of melanocyte stem cells and angiogenesis in melanoma, the expression levels of activated Notch1 and nestin were analyzed by immunohistochemistry in 114 primary cutaneous melanomas and 35 lymph node metastases. Activated Notch1 and nestin expression was also evaluated in four dysplastic melanocytic nevi. This study provides evidence that activated Notch1 is overexpressed in cutaneous melanoma, in tumor cells as well as in microvessel endothelium, and that it can promote tumor angiogenesis. Indeed, the overexpression of activated Notch1 in both tumor and vascular endothelial cells was significantly associated with microvascular density in melanoma samples. Thus, activated Notch1 inhibitors may provide a therapeutic strategy in the treatment of melanoma by blocking tumor-associated vascularization.

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Acknowledgments

This work was supported by grants from Ministero Affari Esteri (MAE) and Fondazione Banco di Sardegna (to PS and MTP). The study was also supported by Regione Autonoma della Sardegna, Master and Back Program (grant to DM). Particular thanks are due to Itala Mosso and Massimo Annis for their expert technical assistance.

Ethical standards

The study protocol was approved by the Research Ethics Committee of our Institutions, and all the patients gave their informed consent prior to their inclusion in the study.

Conflict of interest

None.

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Authors and Affiliations

  1. Section of Cytomorphology, Department of Biomedical Sciences, University of Cagliari, S.S. 554, 09042, Monserrato, CA, Italy

    Daniela Murtas, Franca Piras, Cristina Maxia, Paolo Demurtas, Simone Lai, Michela Corrias, Paola Sirigu & Maria Teresa Perra

  2. Department of Public Health, Clinical and Molecular Medicine, University of Cagliari, Via Turati, 09045, Quartu Sant’Elena, Italy

    Luigi Minerba

  3. Department of Medical Sciences, University of Cagliari, S.S. 554, 09042, Monserrato, CA, Italy

    Caterina Ferreli

  4. Department of Pathologic Anatomy, Oncology Hospital “Businco”, Via Jenner, 09121, Cagliari, Italy

    Ester Mura

  5. Cancer Institute Solca, Av. Del Paraíso y Agustín Landívar, Cuenca, Ecuador

    Paola Sirigu

  6. Cittadella Universitaria, S.S. 554, 09042, Monserrato, CA, Italy

    Daniela Murtas

Authors
  1. Daniela Murtas
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  2. Franca Piras
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  3. Luigi Minerba
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  4. Cristina Maxia
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  5. Caterina Ferreli
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  6. Paolo Demurtas
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  7. Simone Lai
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  8. Ester Mura
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  9. Michela Corrias
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  10. Paola Sirigu
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  11. Maria Teresa Perra
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Corresponding author

Correspondence to Daniela Murtas.

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Murtas, D., Piras, F., Minerba, L. et al. Activated Notch1 expression is associated with angiogenesis in cutaneous melanoma. Clin Exp Med 15, 351–360 (2015). https://doi.org/10.1007/s10238-014-0300-y

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  • DOI: https://doi.org/10.1007/s10238-014-0300-y

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