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Activation of invariant natural killer T cells reduces angiogenesis in the 5T33 multiple myeloma model

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Activation of invariant natural killer T cells reduces angiogenesis in the 5T33 multiple myeloma model

Nur H1,2, Rao L3, Vacca A3, , Elewaut D4, Van Valckenborgh E1, De Bruyne E1, Vanderkerken K1 and Menu E1

1 Department of Hematology and Immunology, Myeloma Center Brussels, Vrije Universiteit Brussel, Brussels, Belgium.
2 Department of Biology, Hebron University, Hebron, Palestine.
3 Department of Biomedical Sciences and Human Oncology, University of Bari "Aldo Moro" Medical School, Bari, Italy.
4 Laboratory for Molecular Immunology and Inflammation, Department of Rheumatology, Ghent University, Ghent, Belgium.

Angiogenesis refers to the generation of new vasculature from pre-existing blood vessels. In cancer, it is required for tumor growth. We used the immunocompetent 5T33MM model to investigate the anti-angiogenic effect of iNKTs. iNKTs respond to glycolipids such as ?-Galactosylceramide (?-GalCer). We first examined whether ?-GalCer-activated iNKTs have an effect on tumor angiogenesis by treating 5T33MM mice with ?-GalCer. A significant decrease of the microvessel density (MVD) was observed in the treated group (23.7%) compared to untreated group (33.3%). This was independent of the reduction in tumor load indicating that the secretory products of iNKTs such as IFN-? can reduce angiogenesis. To proceed further, conditioned media (CM) were prepared by coculturing DC with iNKT in presence (CM+) or absence (CM-) of ?-GalCer. Chorioallantoic membrane (CAM) and matrigel plug (MP) assays were performed by injecting CM into fertilized chicken eggs and NOD-SCID mice, respectively. Results showed a reduction in both blood vessel count in CAM (from 26 in CM- to 13 in CM+) and CD31+ cell count in MP (from 112 in CM- to 25 in CM+). To see whether this inhibition is mediated by IFN-?, endothelial cells (ECs) were cultured in vitro in CM, IFN-? and CM+ ?-IFN-? antibody. Cell Titer-Glo assays showed a significant reduction in the viability of ECs in CM+ and IFN-?. This reduction was partially blocked when CM+ was blocked by ?-IFN-?. To determine if the cells' low viability is related to anti-proliferative and/or apoptotic mechanisms, proliferation and TUNEL assays were performed. We found a reduction in ECs proliferation in CM+. This defect was confirmed using matrigel capillarogenesis assay which was then used for TUNEL stainings. A high number of apoptotic cells was observed in CM+ (18%) compared to CM- (7%) and control (8%). Therefore, we can conclude that anti-angiogenesis can be achieved by both pathways, and IFN-? is involved as an angiostatic factor. Taken together, these preclinical data indicate the possibility of harnessing the anti-angiogenic activity of iNKTs in MM.
Tijdschrift: Belgian Journal of Hematology
ISSN: 2033-3749
Issue: 2014
Pagina's: 24-25
Aantal pagina's: 2
Jaar van publicatie:2014
Trefwoorden:Multiple myeloma, invariant NKT, angiogenesis