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.
Highlights
The interaction between tumor cells and inflammatory cells has important role in cancer establishment and progression; this interaction has not been well defined
Expression of a2V and a2NTD in breast cancer cells a2V expression in breast cancer cell lines were investigated using immunofluorescence analysis. 2.5 × 104 cells were plated in 8 well chamber slides for overnight to allow the cells to attach to the slide
Images showed that a2V exhibited a distinctive surface accumulation on invasive breast cancer cell lines MDAMB-231 (MDA) and MCF-7 as compared to normal human mammary epithelial cell line (HMEC) as well as non-tumorigenic mammary epithelial cells; MCF-10a (Figure 1A). a2V surface expression was positively correlated with cancer cells reported invasiveness
Summary
The interaction between tumor cells and inflammatory cells has important role in cancer establishment and progression; this interaction has not been well defined. Tumor-associated macrophages (TAM) and tumor-associated neutrophils (TAN) exist in almost all solid neoplasms and can control cancer growth [1]. TAN represent a significant portion of the total mass of invasive breast carcinomas and are proposed to be an important component involved in breast cancer chemoresistance and metastasis [3,4,5]. Tumors secrete factors into the tumor microenvironment that induce a wound repair response from both TAM and TAN [2, 6, 7]. In an in vitro co-culture breast cancer model, GM-CSF released from breast cancer cells stimulates oncostatin-M secretion from neutrophils leading to an increase of their invasive capacity [3]; factors regulating TAN behavior in breast cancer remain unclear
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