Abstract
CD47 is highly expressed on various hematopoietic malignancies, and enables cancer cells to avoid immunosurveillance. Its ligand, thromobospondin-1 (TSP-1) is a multifunctional protein, and CD47/TSP-1 interactions promote tumor progression in various malignancies. In this study, we investigated roles of TSP-1 and CD47 in cutaneous T-cell lymphoma (CTCL). Flow cytometric analysis and immunohistochemistry showed that CTCL tumor cells and CTCL cell lines (Hut78, HH, and MyLa cells) overexpressed CD47 compared with normal CD4+ T cells. Overexpression of CD47 was partially induced by high c-Myc expression in CTCL tumor cells. TSP-1 mRNA expression levels in CTCL lesional skin were higher than those in normal skin and correlated with increased risk of disease-related death. Moreover, TSP-1 was expressed on CTCL tumor cells by immunohistochemistry. Serum soluble TSP-1 levels in patients with Sézary syndrome were significantly elevated. TSP-1 promotes proliferation and survival of CTCL tumor cells, which is inhibited by anti-CD47 neutralizing antibody or CD47 knockdown. Stimulation with TSP-1 also induces cell migration and in vivo growth. These effects were mediated by phosphorylation of ERK1/2 and AKT and expression of survivin. Collectively, our findings prompt a novel therapeutic approach to CTCL based on discovery that CD47/TSP-1 interactions play important roles in progression of CTCL.
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Acknowledgements
The authors thank Dr Kazuyasu Fujii (Department of Dermatology, Kagoshima University, Kagoshima, Japan) for providing Hut78, HH, and MyLa cells. The authors thank Tamami Kaga for technical assistance. This work was supported in part by grants from the Ministry of Education, Culture, Sports, Science and Technology in Japan (16K19709).
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Kamijo, H., Miyagaki, T., Takahashi-Shishido, N. et al. Thrombospondin-1 promotes tumor progression in cutaneous T-cell lymphoma via CD47. Leukemia 34, 845–856 (2020). https://doi.org/10.1038/s41375-019-0622-6
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DOI: https://doi.org/10.1038/s41375-019-0622-6
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