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.