Oncotarget

Research Papers:

Breast cancer associated a2 isoform vacuolar ATPase immunomodulates neutrophils: potential role in tumor progression

Safaa A. Ibrahim _, Gajendra K. Katara, Arpita Kulshrestha, Mukesh K. Jaiswal, Magdy A. Amin and Kenneth D. Beaman

PDF  |  HTML  |  Supplementary Files  |  How to cite  |  Order a Reprint

Oncotarget. 2015; 6:33033-33045. https://doi.org/10.18632/oncotarget.5439

Metrics: PDF 1201 views  |   HTML 1628 views  |   ?  


Abstract

Safaa A. Ibrahim1,2, Gajendra K. Katara1, Arpita Kulshrestha1, Mukesh K. Jaiswal1, Magdy A. Amin2, Kenneth D. Beaman1

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

2Department of Microbiology and Immunology, Faculty of Pharmacy, Cairo University, Giza, Egypt

Correspondence to:

Kenneth D. Beaman, e-mail: kenneth.beaman@rosalindfranklin.edu

Keywords: breast cancer, a2 vacuolar ATPase, tumor associated neutrophils, angiogenesis, invasion

Received: June 15, 2015     Accepted: September 29, 2015     Published: October 09, 2015

ABSTRACT

In invasive breast cancer, tumor associated neutrophils (TAN) represent a significant portion of the tumor mass and are associated with increased angiogenesis and metastasis. Identifying the regulatory factors that control TAN behavior will help in developing ideal immunotherapies. Vacuolar ATPases (V-ATPases), multi-subunit proton pumps, are highly expressed in metastatic breast cancer cells. A cleaved peptide from a2 isoform V-ATPase (a2NTD) has immunomodulatory role in tumor microenvironment. Here, we report for the first time the role of V-ATPase in neutrophils modulation. In invasive breast cancer cells, a2NTD was detected and a2V was highly expressed on the surface. Immunohistochemical analysis of invasive breast cancer tissues revealed that increased neutrophil recruitment and blood vessel density correlated with increased a2NTD levels. In order to determine the direct regulatory role of a2NTD on neutrophils, recombinant a2NTD was used for the treatment of neutrophils isolated from the peripheral blood of healthy volunteers. Neutrophils treated with a2NTD (a2Neuɸ) showed increased secretion of IL-1RA, IL-10, CCL-2 and IL-6 that are important mediators in cancer related inflammation. Moreover, a2Neuɸ exhibited an increased production of protumorigenic factors including IL-8, matrix metaloprotinase-9 and vascular endothelial growth factor. Further, functional characterization of a2Neuɸ revealed that a2Neuɸ derived products induce in vitro angiogenesis as well as increase the invasiveness of breast cancer cells. This study establishes the modulatory effect of breast cancer associated a2V on neutrophils, by the action of a2NTD, which has a positive impact on tumor progression, supporting that a2V can be a potential selective target for breast cancer therapy.


Creative Commons License All site content, except where otherwise noted, is licensed under a Creative Commons Attribution 3.0 License.
PII: 5439