Stimulation of invariant natural killer T cells by α‐Galactosylceramide activates the JAK‐STAT pathway in endothelial cells and reduces angiogenesis in the 5T33 multiple myeloma model |
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Authors: | Haneen Nur Luigia Rao Maria Antonia Frassanito Hendrik De Raeve Domenico Ribatti Josué Kunjom Mfopou Els Van Valckenborgh Elke De Bruyne Angelo Vacca Karin Vanderkerken Eline Menu |
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Affiliation: | 1. Department of Haematology and Immunology, Myeloma Centre Brussels, Vrije Universiteit Brussel (VUB), , Brussels, Belgium;2. Department of Biology, Faculty of Science and Technology, Hebron University, , Hebron, Palestine;3. Department of Biomedical Sciences and Human Oncology, University of Bari “AldoMoro” Medical School, , Bari, Italy;4. Department of Surgical Pathology, Universitair Ziekenhuis Brussel, , Brussels, Belgium;5. Department of Basic Medical Sciences, Neurosciences and Sensory Organs, University of Bari Medical School, , Bari, Italy;6. National Cancer Institute “Giovanni Paolo II”, , Bari, Italy;7. Cell Differentiation Unit, Diabetes Research Centre, Vrije Universiteit Brussel (VUB), , Brussels, Belgium |
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Abstract: | Tumour pathogenesis in multiple myeloma (MM) correlates with a high vascular index. Therefore, targeting angiogenesis is an important therapeutic tool to reduce MM progression. This study aimed to investigate the role of invariant natural killer T (iNKT) cells in angiogenesis and the mechanisms behind the stimulation by α‐Galactosylceramide (α‐GalCer). We have previously found that α‐GalCer could increase the survival of 5T33MM mice and here we demonstrate that α‐GalCer reduces the microvessel density. We performed both in vivo and in vitro angiogenic assays to confirm this observation. We found that conditioned medium of α‐GalCer stimulated iNKT cells reduced neovascularization in the chick chorioallantoic membrane and in matrigel plug assays. Moreover, we observed a reduction in proliferation, migration and network formation and an induction of apoptosis upon exposure of murine endothelial cell lines to this conditioned medium. We furthermore observed that the JAK‐STAT signaling pathway was highly activated in endothelial cells in response to stimulated iNKT cells, indicating the possible role of IFN‐γ in the anti‐angiogenic process. In conclusion, these results highlight the possibility of recruiting iNKT cells to target MM and angiogenesis. This gives a rationale for combining immunotherapy with conventional anti‐tumour treatments in view of increasing their therapeutic potential. |
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Keywords: | multiple myeloma invariant natural killer T cells α ‐Galactosylceramide MM‐induced angiogenesis JAK‐STAT pathway |
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