Control of metastatic niche formation by targeting APBA3/Mint3 in inflammatory monocytes

Proceedings of the National Academy of Sciences of the United States of America
Toshiro HaraTakeharu Sakamoto

Abstract

Cancer metastasis is intricately orchestrated by both cancer and normal cells, such as endothelial cells and macrophages. Monocytes/macrophages, which are often co-opted by cancer cells and promote tumor malignancy, acquire more than half of their energy from glycolysis even during normoxic conditions. This glycolytic activity is maintained during normoxia by the functions of hypoxia inducible factor 1 (HIF-1) and its activator APBA3. The mechanism by which APBA3 inhibition partially suppresses macrophage function and affects cancer metastasis is of interest in view of avoidance of the adverse effects of complete suppression of macrophage function during therapy. Here, we report that APBA3-deficient mice show reduced metastasis, with no apparent effect on primary tumor growth. APBA3 deficiency in inflammatory monocytes, which strongly express the chemokine receptor CCR2 and are recruited toward chemokine CCL2 from metastatic sites, hampers glycolysis-dependent chemotaxis of cells toward metastatic sites and inhibits VEGFA expression, similar to the effects observed with HIF-1 deficiency. Host APBA3 induces VEGFA-mediated E-selectin expression in the endothelial cells of target organs, thereby promoting extravasation of cancer c...Continue Reading

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Citations

Jun 22, 2017·Biochemical and Biophysical Research Communications·Toshiro HaraTakeharu Sakamoto
Jul 30, 2017·Colorectal Disease : the Official Journal of the Association of Coloproctology of Great Britain and Ireland·M YahagiY Kitagawa
Oct 9, 2019·Proceedings of the National Academy of Sciences of the United States of America·Catharina HagerlingZena Werb
Sep 10, 2019·Frontiers in Immunology·Sheri A C McDowell, Daniela F Quail
Oct 9, 2021·Communications Biology·Takeharu SakamotoMotoharu Seiki

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