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Neutrophil Extracellular Traps (NETs) in Cancer Metastasis

癌癥轉移中的中性粒細胞胞外陷阱 (NETs)

Neutrophil Extracellular Traps (NETs) are formed following the activation of neutrophils and play an important role in the development of cancer, especially metastatic disease. In this review, we will portray the role of Neutrophils/NETs in the tumor microenvironment and circulation. We will furthermore discuss the role of neutrophil reverse migration, NET-mediated pre-metastatic niche formation, and possible treatment strategies to decrease metastatic cascade.

中性粒細胞胞外陷阱 (NETs) 是在中性粒細胞激活后形成的，在癌癥，尤其是轉移性疾病的發(fā)展中發(fā)揮重要作用。在這篇綜述中，我們將描述中性粒細胞/NETs 在腫瘤微環(huán)境和循環(huán)中的作用。我們將進一步討論中性粒細胞反向遷移的作用、NET 介導的轉移前生態(tài)位形成以及減少轉移級聯(lián)的可能治療策略。

細胞工廠

Metastasis is the leading cause of cancer related morbidity and mortality. The metastatic process involves several identifiable biological stages, including tumor cell dissemination, intravasation, and the extravasation of circulating cancer cells to facilitate colonization at a distant site. Immune cell infiltration and inflammation within the tumor microenvironment coincide with tumor progression and metastatic spread and are thought to be the key mediators of this complex process. Amongst many infiltrating cells, neutrophils have recently emerged as an important player in fueling tumor progression, both in animal models and cancer patients. The production of Neutrophil Extracellular Traps (NETs) is particularly important in the pathogenesis of the metastatic cascade. NETs are composed of web-like DNA structures with entangled proteins that are released in response to inflammatory cues in the environment. NETs play an important role in driving tumor progression both in experimental and clinical models. In this review, we aim to summarize the current advances in understanding the role of NETs in cancer, with a specific focus on their role in promoting premetastatic niche formation, interaction with circulating cancer cells, and in epithelial to mesenchymal transition during cancer metastasis. We will furthermore discuss the possible role and different treatment options for targeting NETs to prevent tumor progression.

轉移是癌癥相關發(fā)病率和死亡率的主要原因。轉移過程涉及幾個可識別的生物學階段，包括腫瘤細胞擴散、內滲和循環(huán)癌細胞外滲以促進遠處定植。腫瘤微環(huán)境內的免疫細胞浸潤和炎癥與腫瘤進展和轉移擴散相吻合，被認為是這一復雜過程的關鍵介質。在許多浸潤細胞中，中性粒細胞最近已成為促進腫瘤進展的重要參與者，無論是在動物模型中還是在癌癥患者中。中性粒細胞胞外陷阱 (NET) 的產(chǎn)生在轉移級聯(lián)的發(fā)病機制中尤為重要。NET 由網(wǎng)狀 DNA 結構組成，其中包含糾纏蛋白，這些蛋白響應環(huán)境中的炎癥信號而釋放。NET 在實驗和臨床模型中都在推動腫瘤進展方面發(fā)揮著重要作用。在這篇綜述中，我們旨在總結目前在了解 NET 在癌癥中的作用方面取得的進展，特別關注它們在促進轉移前生態(tài)位形成、與循環(huán)癌細胞的相互作用以及癌癥轉移過程中上皮向間充質轉化中的作用。我們將進一步討論靶向 NET 以防止腫瘤進展的可能作用和不同的治療方案。我們旨在總結目前在了解 NET 在癌癥中的作用方面取得的進展，特別關注它們在促進轉移前生態(tài)位形成、與循環(huán)癌細胞的相互作用以及癌癥轉移過程中上皮到間充質轉化中的作用。我們將進一步討論靶向 NET 以防止腫瘤進展的可能作用和不同的治療方案。我們旨在總結目前在了解 NET 在癌癥中的作用方面取得的進展，特別關注它們在促進轉移前生態(tài)位形成、與循環(huán)癌細胞的相互作用以及癌癥轉移過程中上皮到間充質轉化中的作用。我們將進一步討論靶向 NET 以防止腫瘤進展的可能作用和不同的治療方案。

細胞培養(yǎng)瓶

In recent years, significant advances have been made to understand the effect and mechanism of neutrophils and NETs in aiding tumor growth, progression, and metastasis. Neutrophils display a large amount of plasticity within the TME and pose a major challenge in the therapeutic targeting of cancer and metastasis. Different types of tumors and disease stages generate various cancer-derived factors that can promote the phenotypic shift of neutrophils towards a pro- or antitumor type. The identification of specific markers and the better characterization of these two populations could improve the specific targeting of pro-tumor neutrophils. In addition, understanding the biology of how these different neutrophil populations predispose NETs along with the type of traits can better elucidate the downstream effects of NETs in tumor growth and progression. On the other hand, NETs are frequently found within the TME and can promote pro-tumorigenic effects such as increased cancer metabolism, invasion, and growth; however, they can also directly interact with infiltrating immune cells to protect the tumor. Targeting NETs, specifically those that are formed from the protumor neutrophil subgroup, could play a promising role in anticancer therapy; however, due to the complexity and multifaced roles of neutrophils within the TME, further investigation is needed.

細胞搖瓶

近年來，在了解中性粒細胞和 NET 在幫助腫瘤生長、進展和轉移方面的作用和機制方面取得了重大進展。中性粒細胞在 TME 中表現(xiàn)出大量的可塑性，并對癌癥和轉移的治療靶向提出了重大挑戰(zhàn)。不同類型的腫瘤和疾病階段會產(chǎn)生各種癌癥衍生因子，這些因子可以促進中性粒細胞向促腫瘤或抗腫瘤類型的表型轉變。特異性標志物的鑒定和這兩個群體的更好表征可以提高促腫瘤中性粒細胞的特異性靶向。此外，了解這些不同中性粒細胞群體如何使 NETs 易感的生物學以及特征類型可以更好地闡明 NETs 在腫瘤生長和進展中的下游影響。另一方面，NETs 經(jīng)常出現(xiàn)在 TME 中，可以促進促腫瘤發(fā)生作用，例如增加癌癥代謝、侵襲和生長；然而，它們也可以直接與浸潤的免疫細胞相互作用以保護腫瘤。靶向 NET，特別是那些由原中性粒細胞亞群形成的 NET，可以在抗癌治療中發(fā)揮有希望的作用；然而，由于中性粒細胞在 TME 中的復雜性和多方面作用，需要進一步研究。入侵和增長；然而，它們也可以直接與浸潤的免疫細胞相互作用以保護腫瘤。靶向 NET，特別是那些由原中性粒細胞亞群形成的 NET，可以在抗癌治療中發(fā)揮有希望的作用；然而，由于中性粒細胞在 TME 中的復雜性和多方面作用，需要進一步研究。入侵和增長；然而，它們也可以直接與浸潤的免疫細胞相互作用以保護腫瘤。靶向 NET，特別是那些由原中性粒細胞亞群形成的 NET，可以在抗癌治療中發(fā)揮有希望的作用；然而，由于中性粒細胞在 TME 中的復雜性和多方面作用，需要進一步研究。

關鍵詞：中性粒細胞可塑性,中性粒細胞胞外陷阱,腫瘤微環(huán)境,轉移,neutrophil plasticity; neutrophil extracellular traps, tumor microenvironment,metastasis

來源：MDPI https://www.mdpi.com/2072-6694/13/23/6131/htm