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 language | English |
|---|---|
| Pages (from-to) | 93-105 |
| Number of pages | 13 |
| Journal | Neoplasia (United States) |
| Volume | 21 |
| Issue number | 1 |
| DOIs | |
| Publication status | Published - Jan 1 2019 |
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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 journal › Article
}
TY - JOUR
T1 - Homotypic and Heterotypic Activation of the Notch Pathway in Multiple Myeloma–Enhanced Angiogenesis
T2 - A Novel Therapeutic Target?
AU - Saltarella, Ilaria
AU - Frassanito, Maria Antonia
AU - Lamanuzzi, Aurelia
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
AU - Dammacco, Franco
AU - Racanelli, Vito
AU - Vacca, Angelo
AU - Ria, Roberto
PY - 2019/1/1
Y1 - 2019/1/1
N2 - 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.
AB - 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.
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UR - http://www.scopus.com/inward/citedby.url?scp=85057840204&partnerID=8YFLogxK
U2 - 10.1016/j.neo.2018.10.011
DO - 10.1016/j.neo.2018.10.011
M3 - Article
C2 - 30529074
AN - SCOPUS:85057840204
VL - 21
SP - 93
EP - 105
JO - Neoplasia
JF - Neoplasia
SN - 1522-8002
IS - 1
ER -