期刊
BRITISH JOURNAL OF HAEMATOLOGY
卷 167, 期 5, 页码 651-663出版社
WILEY
DOI: 10.1111/bjh.13092
关键词
multiple myeloma; invariant natural killer T cells; alpha-Galactosylceramide; MM-induced angiogenesis; JAK-STAT pathway
类别
资金
- Vlaams Liga tegen Kanker (VLK)
- FWO-Vl
- European Commission Framework of the Erasmus Mundus External Cooperation Window [2009-1642/001-001-ECW]
- Associazione Italiana per la Ricerca sul Cancro (AIRC, Milan) [14095]
- 5 per thousand Molecular Clinical Oncology Special Program [9965]
- European Union [278570]
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 alpha-Galactosylceramide (alpha-GalCer). We have previously found that alpha-GalCer could increase the survival of 5T33MM mice and here we demonstrate that alpha-GalCer reduces the micro-vessel density. We performed both in vivo and in vitro angiogenic assays to confirm this observation. We found that conditioned medium of alpha-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-gamma 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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