肿瘤相关中性粒细胞在乳腺癌发生、发展中的作用研究进展

Advances in the role of tumor-associated neutrophils in the development of breast cancer

中性粒细胞起源于骨髓,由骨髓干细胞增殖分化形成,是血液循环中最常见的多形核白细胞,约占成人外周血白细胞总数的70%。中性粒细胞也是人体内寿命较短的细胞之一,正常成人外周血中性粒细胞半衰期仅数小时,依赖骨髓的不断补充维持中性粒细胞的数量稳定。作为固有免疫系统的短效效应细胞,中性粒细胞参与多种炎症和免疫过程,并构建抵抗感染的第一道防线,在激活和调节先天性及适应性免疫反应中发挥着至关重要的作用。虽然过去人们普遍认为中性粒细胞主要与急、慢性炎症和抗感染过程相关,而由于其寿命较短和不可增殖的特性,一度忽视了其在癌症中的作用。如今越来越多的研究表明,中性粒细胞在癌症中的作用远超以往的认知。乳腺癌是女性常见的恶性肿瘤之一,其发病率和死亡率均位居女性恶性肿瘤的前列。全球范围内乳腺癌的发病率逐年升高,严重威胁全世界女性的身心健康。最近有研究证实,肿瘤相关中性粒细胞(tumor-associated neutrophils,TANs)已成为肿瘤微环境(tumor microenvironment,TME)的重要组成部分,在乳腺癌的发生、发展和转移过程中均发挥重要作用。TANs是由多种肿瘤源性细胞因子相互作用,刺激诱导中性粒细胞募集至TME中积累形成的。中性粒细胞的强可塑性和多样性赋予TANs促进和抑制肿瘤的双重潜能。TANs可通过促进肿瘤生长和转移、推动肿瘤新生血管生成、免疫抑制和生成中性粒细胞胞外诱捕网(neutrophil extracellular traps,NET)来促进乳腺癌进展。反之,TANs也可通过直接杀伤肿瘤细胞和参与形成抗肿瘤的免疫网络间接介导抗肿瘤反应。TANs相关的乳腺癌治疗已逐步成为研究热点,尤其是在三阴性乳腺癌(triple-negative breast cancer,TNBC)中。本综述回顾乳腺癌中TANs起源、形成、分型和功能机制方面的研究进展,并详细阐述TANs与乳腺癌的临床相关性,进一步结合近期乳腺癌中TANs的相关临床研究,系统总结针对乳腺癌患者靶向TANs的治疗策略,以期为乳腺癌中TANs作用机制研究和乳腺癌治疗提供新思路。

Neutrophils originate from the bone marrow,differentiating from hematopoietic stem cells,and are the most prevalent polymorphonuclear leukocytes in the blood,accounting for approximately 70%of the total white blood cells in adult peripheral blood.Neutrophils are recognized as one of the relatively short-lived cells in the body,with a normal half-life of just a few hours in the peripheral blood,which rely on continuous replenishment from the bone marrow to maintain the number.As short-lived effectors of the innate immune system,neutrophils participate in various inflammatory and immune processes,and constitute the first line of defense against infection,playing a crucial role in the activation and regulation of both innate and adaptive immunity.Neutrophils were once considered as key effectors of inflammation and infection.Because of their short lifespan and non-proliferative nature,the role of neutrophils in cancer was overlooked.Their role in cancer has been increasingly recognized in recent years.However,more and more studies demonstrate that neutrophils play a much more significant role in cancer than previously thought.Breast cancer is one of the common malignant tumors in women,and its morbidity and mortality are in the forefront of female malignant tumors.The incidence of breast cancer is rising globally,posing a severe threat to the physical and mental health of women worldwide.Recent studies confirm that tumor-associated neutrophils(TANs)have become a critical component of the tumor microenvironment(TME)and play a significant role in the development,progression and metastasis of breast cancer.TANs are formed via the interaction of various tumor-derived cytokines which stimulate and recruit neutrophils to accumulate in the TME.The strong plasticity and diversity of neutrophils endow TANs with dual potential to both promote and inhibit tumors.TANs advance breast cancer progression by promoting tumor growth and metastasis,supporting tumor angiogenesis,immune suppression,and generating neutrophil extracellular traps(NETs).Conversely,TANs mediate antitumor responses through direct tumor cell killing and contributing to the formation of antitumor immune network.Research on TANs-related breast cancer therapies,particularly in triple-negative breast cancer(TNBC),has become a research hotspot.This review summarized recent advances in the origin,formation,classification and function of TANs in breast cancer,as well as a detailed discussion of their clinical relevance.We further combined recent clinical studies to systematically summarize the treatment strategies targeting TANs in breast cancer,with the aim of providing new insights into the functional mechanisms of TANs and the treatment of breast cancer.