Hematopoietic stem cell specific V-ATPase controls breast cancer progression and metastasis via cytotoxic T cells.

Citation:
Sahoo, M., G. K. Katara, M. Y. Bilal, S. A. Ibrahim, A. Kulshrestha, S. Fleetwood, K. Suzue, and K. D. Beaman, "Hematopoietic stem cell specific V-ATPase controls breast cancer progression and metastasis via cytotoxic T cells.", Oncotarget, vol. 9, issue 69, pp. 33215-33231, 2018 Sep 04.

Abstract:

The interaction of recruited immune effector cells and cancer cells within tumor microenvironment (TME) shapes the fate of cancer progression and metastasis. Many cancers including breast cancer, express a specific vacuolar ATPase (a2V) on their cell surface which acidifies the extracellular milieu helping cancer cell proliferation and metastasis. To understand the role of immune cell-associated-a2V during breast tumor pathogenesis, we knocked-out a2V (KO) from the hematopoietic stem cells (HSC) and generated breast tumors in mice. The a2V-KO mice developed faster growing, larger, and metastatic breast tumors compared to control mice. Further investigation of the TME revealed a significant reduction in the presence of CD4 and CD8 T cells in the a2V-KO tumors. Targeted RNA-Seq of the cells of the TME demonstrated that pro-inflammatory cytokines, death receptors, death receptor ligands, and cytotoxic effectors were significantly down-regulated within the a2V-KO TME. Interestingly, analysis of immune cells in the blood, spleen, and thymus of the non-tumor bearing a2V-KO mice revealed a significant decrease in CD4 and CD8 T cell populations. For the first time, this study demonstrates that inhibition of V-ATPase expression in HSC leads to a decrease in CD4 and CD8 T cell populations and thus promotes breast tumor growth and metastasis.

Notes:

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