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Tumor-associated vacuolar ATPase subunit promotes tumorigenic characteristics in macrophages

Oncogene volume 33, pages 5649–5654 (2014)Cite this article

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Abstract

Macrophage polarization contributes to distinct human pathologies. In tumors, a polarized M2 phenotype called tumor-associated macrophages (TAMs) are associated with promotion of invasion and angiogenesis. In cancer cells, vacuolar ATPase (V-ATPase), a multi-subunit enzyme, is expressed on the plasma/vesicular membranes and critically influences the metastatic behavior. In addition, the soluble, cleaved N-terminal domain of a2 isoform of V-ATPase (a2NTD) is associated with in vitro induction of pro-tumorigenic properties in monocytes. This activity of a2 isoform of V-ATPase (a2V) caused us to investigate its role in cancer progression through the evaluation of the immunomodulatory properties of a2NTD. Here, we present direct evidence that surface expression of V-ATPase is associated with macrophage polarization in tumor tissue. Macrophages from BALB/c mice (peritoneal/bone marrow derived) were stimulated with recombinant a2NTD in both ex vivo and in vivo systems and evaluated for TAM characteristics. a2V was highly expressed in tumor tissues (breast and skin) as well as on the surface of tumor cell lines. The a2NTD-stimulated macrophages (a2MΦ) acquired TAM phenotype, which was characterized by elevated expression of mannose receptor-1, Arginase-1, interleukin-10 and transforming growth factor-β. a2MΦ also exhibited increased production of other tumorigenic factors including matrix metalloproteinase-9 and vascular endothelial growth factor. Further, a2MΦ were cocultured with mouse B-16F0 melanoma cells for their functional characterization. The coculture of these a2MΦ subsequently increased the invasion and angiogenesis of less invasive B-16F0 cells. When cocultured with naive T cells, a2MΦ significantly inhibited T-cell activation. The present data establish the role of V-ATPase in modulating a macrophage phenotype towards TAMs through the action of a2NTD, suggesting it to be a potential therapeutic target in cancer.

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Acknowledgements

We thank Robert Dickinson for technical assistance and the Rosalind Franklin University of Medicine and Science Flow Cytometry Core Facility. This work was supported by grants from the Clinical Immunology Laboratory, Rosalind Franklin University of Medicine and Science, North Chicago, IL, USA.

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  1. Department of Microbiology and Immunology, Rosalind Franklin University of Medicine and Science, North Chicago, IL, USA

    G K Katara, M K Jaiswal, A Kulshrestha, B Kolli, A Gilman-Sachs & K D Beaman

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  1. G K Katara
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  2. M K Jaiswal
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  3. A Kulshrestha
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  4. B Kolli
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  5. A Gilman-Sachs
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Correspondence to K D Beaman.

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Katara, G., Jaiswal, M., Kulshrestha, A. et al. Tumor-associated vacuolar ATPase subunit promotes tumorigenic characteristics in macrophages. Oncogene 33, 5649–5654 (2014). https://doi.org/10.1038/onc.2013.532

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