Homotypic and Heterotypic Activation of the Notch Pathway in Multiple Myeloma–Enhanced Angiogenesis: A Novel Therapeutic Target?

Ilaria Saltarella, Maria Antonia Frassanito, Aurelia Lamanuzzi, Arianna Brevi, Patrizia Leone, Vanessa Desantis, Lucia Di Marzo, Matteo Bellone, Daniele Derudas, Domenico Ribatti, Raffaella Chiaramonte, Maria Teresa Palano, Antonino Neri, Maria Addolorata Mariggiò, Ruggiero Fumarulo, Franco Dammacco, Vito Racanelli, Angelo Vacca, Roberto Ria

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Abstract

Interactions of multiple myeloma (MM) cells with endothelial cells (ECs) enhance angiogenesis and MM progression. Here, we investigated the role of Notch signaling in the cross talk between ECs and MM cells enabling angiogenesis. MMECs showed higher expression of Jagged1/2 ligands, of activated Notch1/2 receptors, and of Hes1/Hey1 Notch target genes than ECs from monoclonal gammopathy of undetermined significance patients, suggesting that homotypic activation of Notch pathway occurs in MM. MM cells co-cultured with MMECs triggered Notch activation in these cells through a cell-to-cell contact-dependent way via Jagged1/2, resulting in Hes1/Hey1 overexpression. The angiogenic effect of Notch pathway was analyzed through Notch1/2·siRNAs and the γ-secretase inhibitor MK-0752 by in vitro (adhesion, migration, chemotaxis, angiogenesis) and in vivo (Vk12598/C57B/6 J mouse model) studies. Activated Notch1/2 pathway was associated with the overangiogenic MMEC phenotype: Notch1/2 knockdown or MK-0752 treatment reduced Hes1/Hey1 expression, impairing in vitro angiogenesis of both MMECs alone and co-cultured with MM cells. MM cells were unable to restore angiogenic abilities of treated MMECs, proving that MMEC angiogenic activities closely rely on Notch pathway. Furthermore, Notch1/2 knockdown affected VEGF/VEGFR2 axis, indicating that the Notch pathway interferes with VEGF-mediated control on angiogenesis. MK-0752 reduced secretion of proangiogenic/proinflammatory cytokines in conditioned media, thus inhibiting blood vessel formation in the CAM assay. In the Vk12598/C57B/6 J mouse, MK-0752 treatment restrained angiogenesis by reducing microvessel density. Overall, homotypic and heterotypic Jagged1/2-mediated Notch activation enhances MMECs angiogenesis. Notch axis inhibition blocked angiogenesis in vitro and in vivo, suggesting that the Notch pathway may represent a novel therapeutic target in MM.

Original languageEnglish
Pages (from-to)93-105
Number of pages13
JournalNeoplasia (United States)
Volume21
Issue number1
DOIs
Publication statusPublished - Jan 1 2019

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Multiple Myeloma
Endothelial Cells
Therapeutics
Vascular Endothelial Growth Factor A
Notch1 Receptor
Monoclonal Gammopathy of Undetermined Significance
Amyloid Precursor Protein Secretases
Aptitude
Chemotaxis
Conditioned Culture Medium
Microvessels
Blood Vessels
Cultured Cells
Cytokines
Ligands
Phenotype
3-(4-((4-chlorophenyl)sulfonyl)-4-(2,5-difluorophenyl)cyclohexyl)propanoic acid
Genes
In Vitro Techniques

ASJC Scopus subject areas

  • Cancer Research

Cite this

Homotypic and Heterotypic Activation of the Notch Pathway in Multiple Myeloma–Enhanced Angiogenesis : A Novel Therapeutic Target? / Saltarella, Ilaria; Frassanito, Maria Antonia; Lamanuzzi, Aurelia; Brevi, Arianna; Leone, Patrizia; Desantis, Vanessa; Di Marzo, Lucia; Bellone, Matteo; Derudas, Daniele; Ribatti, Domenico; Chiaramonte, Raffaella; Palano, Maria Teresa; Neri, Antonino; Mariggiò, Maria Addolorata; Fumarulo, Ruggiero; Dammacco, Franco; Racanelli, Vito; Vacca, Angelo; Ria, Roberto.

In: Neoplasia (United States), Vol. 21, No. 1, 01.01.2019, p. 93-105.

Research output: Contribution to journalArticle

Saltarella, I, Frassanito, MA, Lamanuzzi, A, Brevi, A, Leone, P, Desantis, V, Di Marzo, L, Bellone, M, Derudas, D, Ribatti, D, Chiaramonte, R, Palano, MT, Neri, A, Mariggiò, MA, Fumarulo, R, Dammacco, F, Racanelli, V, Vacca, A & Ria, R 2019, 'Homotypic and Heterotypic Activation of the Notch Pathway in Multiple Myeloma–Enhanced Angiogenesis: A Novel Therapeutic Target?', Neoplasia (United States), vol. 21, no. 1, pp. 93-105. https://doi.org/10.1016/j.neo.2018.10.011
Saltarella, Ilaria ; Frassanito, Maria Antonia ; Lamanuzzi, Aurelia ; Brevi, Arianna ; Leone, Patrizia ; Desantis, Vanessa ; Di Marzo, Lucia ; Bellone, Matteo ; Derudas, Daniele ; Ribatti, Domenico ; Chiaramonte, Raffaella ; Palano, Maria Teresa ; Neri, Antonino ; Mariggiò, Maria Addolorata ; Fumarulo, Ruggiero ; Dammacco, Franco ; Racanelli, Vito ; Vacca, Angelo ; Ria, Roberto. / Homotypic and Heterotypic Activation of the Notch Pathway in Multiple Myeloma–Enhanced Angiogenesis : A Novel Therapeutic Target?. In: Neoplasia (United States). 2019 ; Vol. 21, No. 1. pp. 93-105.
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AU - Brevi, Arianna

AU - Leone, Patrizia

AU - Desantis, Vanessa

AU - Di Marzo, Lucia

AU - Bellone, Matteo

AU - Derudas, Daniele

AU - Ribatti, Domenico

AU - Chiaramonte, Raffaella

AU - Palano, Maria Teresa

AU - Neri, Antonino

AU - Mariggiò, Maria Addolorata

AU - Fumarulo, Ruggiero

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