Neutrophil-Derived Proteases in the Microenvironment of Pancreatic Cancer -Active Players in Tumor Progression.
Neutrophil-Derived Proteases in the Microenvironment of Pancreatic Cancer -Active Players in Tumor Progression.
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DOI：
10.7150/ijbs.14996
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发表时间：
2016
影响因子：
9.2
通讯作者：
Gaida MM
中科院分区：
文献类型：
--
作者：
Felix K;Gaida MM
胰腺导管腺癌（PDAC）的一个特征是纤维炎症微环境，由活化的胰腺星状细胞、细胞外基质蛋白和各种炎症细胞（如T细胞、巨噬细胞或中性粒细胞）组成。肿瘤浸润性免疫细胞存在于包括PDAC在内的几乎所有癌症中，通常不能消除肿瘤，但相反，它可以通过改变肿瘤微环境来促进肿瘤的进展。胰腺癌细胞能够通过肿瘤分泌的趋化因子吸引多形核中性粒细胞（PMN），在人PDAC中，PMN浸润可在肿瘤细胞附近和肿瘤间质中观察到，这与肿瘤未分化生长和预后不良有关。肿瘤浸润中性粒细胞在肿瘤微环境中的行为尚未在机制水平上得到理解。已有研究表明，PMN具有直接或通过抗体依赖细胞介导的细胞毒性杀死肿瘤细胞的潜力，但另一方面，PMN的各种不良反应，如促进侵袭性肿瘤生长，实现上皮细胞向间质细胞的转化和增加转移潜力，已被描述。最近的PDAC治疗方法不仅关注肿瘤细胞本身，而且关注肿瘤微环境的要素。因此，PMN及其衍生产品（如细胞因子，蛋白酶）作为治疗靶点的新静脉的作用应在此背景下进行严格评估。本文综述了目前对肿瘤浸润性中性粒细胞蛋白酶与胰腺肿瘤细胞和促结缔组织间质成分之间相互作用的认识。
A hallmark of pancreatic ductal adenocarcinoma (PDAC) is the fibro-inflammatory microenvironment, consisting of activated pancreatic stellate cells, extracellular matrix proteins, and a variety of inflammatory cells, such as T cells, macrophages, or neutrophils. Tumor-infiltrating immune cells, which are found in nearly all cancers, including PDAC, often fail to eliminate the tumor, but conversely can promote its progression by altering the tumor microenvironment. Pancreatic cancer cells are able to attract polymorphonuclear neutrophils (PMN) via tumor secreted chemokines and in human PDAC, PMN infiltrates can be observed in the vicinity of tumor cells and in the desmoplastic tumor stroma, which correlate with undifferentiated tumor growth and poor prognosis. The behavior of tumor-infiltrating neutrophils in the tumor micromilieu is not yet understood at a mechanistic level. It has been shown that PMN have the potential to kill tumor cells, either directly or by antibody-dependent cell-mediated cytotoxicity, but on the other side various adverse effects of PMN, such as promotion of aggressive tumor growth with epithelial-to-mesenchymal transition and increased metastatic potential, have been described. Recent therapeutic approaches for PDAC focus not only the tumor cell itself, but also elements of the tumor microenvironment. Therefore, the role of PMN and their derived products (e.g. cytokines, proteases) as a new vein for a therapeutic target should be critically evaluated in this context. This review summarizes the current understanding of the interplay between proteases of tumor-infiltrating neutrophils and pancreatic tumor cells and elements of the desmoplastic stroma.