Tumors and neutrophils undergo an unexpected interaction, in which products released by tumor cells interact to support neutrophils that in turn support cancer growth, angiogenesis, and metastasis. A key protein that is highly expressed by cancer cells in tumors is the a2 isoform V-ATPase (a2V). A peptide from a2V (a2NTD) is secreted specifically by cancer cells, but not normal cells, into the tumor microenvironment. This peptide reprograms neutrophils to promote angiogenesis, cancer cell invasiveness, and neutrophil recruitment. Here, we provide evidence that cancer-associated a2V regulates the life span of protumorigenic neutrophils by influencing the intrinsic pathway of apoptosis. Immunohistochemical analysis of human cancer tissue sections collected from four different organs shows that levels of a2NTD and neutrophil counts are increased in cancer compared with normal tissues. Significant increases in neutrophil counts were present in both poorly and moderately differentiated tumors. In addition, there is a positive correlation between the number of neutrophils and a2NTD expression. Human neutrophils treated with recombinant a2NTD show significantly delayed apoptosis, and such prolonged survival was dependent on NF-κB activation and ROS generation. Induction of antiapoptotic protein expression (Bcl-xL and Bcl-2A1) and decreased expression of proapoptotic proteins (Bax, Apaf-1, caspase-3, caspase-6, and caspase-7) were a hallmark of these treated neutrophils. Autocrine secretion of prosurvival cytokines of TNF-α and IL-8 by treated neutrophils prolongs their survival. Our findings highlight the important role of cancer-associated a2V in regulating protumorigenic innate immunity, identifying a2V as a potential important target for cancer therapy.

中文翻译：

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癌症相关的V-ATPase诱导致瘤性中性粒细胞延迟凋亡。

肿瘤和嗜中性粒细胞经历意想不到的相互作用，其中肿瘤细胞释放的产物相互作用以支持嗜中性粒细胞，而嗜中性粒细胞又支持癌症的生长，血管生成和转移。癌细胞在肿瘤中高表达的关键蛋白是a2亚型V-ATPase（a2V）。来自a2V的肽（a2NTD）被癌细胞（而非正常细胞）特异性分泌到肿瘤微环境中。该肽重编程中性粒细胞以促进血管生成，癌细胞侵袭和中性粒细胞募集。在这里，我们提供的证据表明，癌症相关的a2V通过影响细胞凋亡的内在途径来调节原发性中性粒细胞的寿命。从四个不同器官收集的人类癌症组织切片的免疫组织化学分析显示，与正常组织相比，癌症中a2NTD和嗜中性粒细胞计数水平增加。在分化较差和中等分化的肿瘤中嗜中性粒细胞计数均显着增加。另外，中性粒细胞的数目与a2NTD表达之间存在正相关。用重组a2NTD处理的人中性粒细胞显示出明显的细胞凋亡延迟，并且这种延长的存活取决于NF-κB的活化和ROS的产生。抗凋亡蛋白表达（Bcl-xL和Bcl-2A1）的诱导和凋亡蛋白（Bax，Apaf-1，caspase-3，caspase-6和caspase-7）表达的降低是这些中性粒细胞的标志。处理过的中性粒细胞自分泌分泌TNF-α和IL-8的生存细胞因子可延长其生存期。我们的研究结果突显了与癌症相关的a2V在调节致瘤性先天性免疫中的重要作用，并将a2V鉴定为癌症治疗的潜在重要靶标。