Breast cancer associated a2 isoform vacuolar ATPase immunomodulates neutrophils: potential role in tumor progression.
Breast cancer associated a2 isoform vacuolar ATPase immunomodulates neutrophils: potential role in tumor progression.
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DOI：
10.18632/oncotarget.5439
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发表时间：
2015-10-20
期刊：
影响因子：
--
通讯作者：
Beaman KD
中科院分区：
文献类型：
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作者：
Ibrahim SA;Katara GK;Kulshrestha A;Jaiswal MK;Amin MA;Beaman KD
在浸润性乳腺癌中，肿瘤相关中性粒细胞（TAN）占肿瘤肿块的很大一部分，并与血管生成和转移增加有关。确定控制TAN行为的调节因子将有助于开发理想的免疫疗法。液泡atp酶（v - atp酶）是一种多亚单位质子泵，在转移性乳腺癌细胞中高度表达。a2亚型V-ATPase （a2NTD）的裂解肽在肿瘤微环境中具有免疫调节作用。在这里，我们首次报道了v - atp酶在中性粒细胞调节中的作用。在浸润性乳腺癌细胞中检测到a2NTD， a2V在细胞表面高表达。浸润性乳腺癌组织的免疫组化分析显示，中性粒细胞募集和血管密度增加与a2NTD水平升高相关。为了确定a2NTD对中性粒细胞的直接调节作用，我们用重组a2NTD治疗健康志愿者外周血分离的中性粒细胞。用a2NTD （a2Neu）处理的中性粒细胞显示IL-1RA、IL-10、CCL-2和IL-6的分泌增加，这些是癌症相关炎症的重要介质。此外，a2Neu还显示出IL-8、基质金属蛋白酶-9和血管内皮生长因子等致瘤因子的增加。此外，a2Neu的功能表征表明，a2Neu衍生产物诱导体外血管生成，并增加乳腺癌细胞的侵袭性。本研究通过a2NTD的作用，确立了乳腺癌相关a2V对中性粒细胞的调节作用，对肿瘤进展有积极影响，支持a2V可能是乳腺癌治疗的潜在选择性靶点。
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.