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

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 cells and micrometastasis formation. Administration of E-selectin-neutralizing antibody also abolished host APBA3-mediated metastatic formation. Thus, targeting APBA3 is useful for controlling metastatic niche formation by inflammatory monocytes.

• Authors: Toshiro Hara, Hiroki J Nakaoka, Tetsuro Hayashi, Kouhei Mimura, Daisuke Hoshino, Masahiro Inoue, Fumitaka Nagamura, Yoshinori Murakami, Motoharu Seiki, Takeharu Sakamoto
• Journal: Proceedings of the National Academy of Sciences of the United States of America (Proc Natl Acad Sci U S A) Vol. 114 Issue 22 Pg. E4416-E4424 (05 30 2017) ISSN: 1091-6490 [Electronic] United States
• PMID: 28507122 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Adaptor Proteins, Signal Transducing
• Apba3 protein, mouse
• E-Selectin
• Vascular Endothelial Growth Factor A
• vascular endothelial growth factor A, mouse

Topics

• Adaptor Proteins, Signal Transducing (deficiency, genetics, metabolism)
• Animals
• Cell Line, Tumor
• Chemotaxis
• E-Selectin (antagonists & inhibitors, metabolism)
• Glycolysis
• Lung Neoplasms (genetics, metabolism, secondary)
• Melanoma, Experimental (genetics, metabolism, secondary)
• Mice
• Mice, Knockout
• Models, Biological
• Monocytes (metabolism, pathology)
• Neoplasm Metastasis (genetics, physiopathology, prevention & control)
• Tumor Microenvironment (genetics, physiology)
• Vascular Endothelial Growth Factor A (metabolism)