肿瘤相关巨噬细胞与结肠肿瘤微环境关系的研究进展

摘 要：肿瘤微环境（tumor microenvironment,TME）是肿瘤细胞与人体免疫系统相互作用的首要场所,包含肿瘤细胞、免疫细胞、间质细胞及其分泌的活性因子等,深深地影响着肿瘤的产生、发展和转移。巨噬细胞是非常可塑的细胞,TME中的巨噬细胞被称为肿瘤相关巨噬细胞（tumor-associated macrophages,TAMs）,在结肠癌发生发展的不同阶段,对TME的刺激能表达不同的功能。近年来TAMs在TME中的作用也得到了更多的关注。因此了解TAMs与结肠癌TME的关系,对深入研究TAMs在结肠肿瘤中的作用具有重要意义。全文对TAMs与结肠癌TME的关系进行综述,以期为深入探究TAMs在结肠癌中的作用提供新的线索。     

肿瘤相关巨噬细胞在结直肠癌中的作用及潜在的治疗价值

结直肠癌(CRC)是消化系统常见的恶性肿瘤,其发生、发展不仅与肿瘤细胞本身的特性有关,也与肿瘤微环境(TME)密切相关。作为TME的重要组成部分,肿瘤相关巨噬细胞(TAMs)调节CRC中多种关键致癌过程,通过分泌细胞因子和趋化因子,并与炎症机制协调,促进肿瘤的发生、增殖和转移。基于TAMs对肿瘤进展的影响,目前靶向肿瘤巨噬细胞的相关治疗策略主要集中在将TAMs作为免疫治疗的靶点、抑制巨噬细胞募集、重新诱导TAMs的表型极化、将TAMs靶向治疗与常规治疗相结合等方面。不仅如此,有研究指出将针对TAMs的靶向疗法互相结合,可能未来会成为治疗CRC联合疗法的重大突破,为临床CRC治疗提供更多选择。因此,对TAMs的功能和调节机制的日益了解将更有效探索它们在CRC中的临床应用。本文将对TAMs在CRC中发生、发展中的作用及相关机制进行综述,并总结了与TAMs相关的CRC潜在治疗策略,为CRC的诊治提供了新兴的思路和方法,具有参考价值。     

肿瘤相关巨噬细胞在胃癌微环境中的作用

肿瘤微环境（TME）是肿瘤细胞及其周围的非肿瘤细胞和基质成分构成的复杂生态系统,包括免疫细胞、成纤维细胞和细胞外基质等多种成分。其中,肿瘤相关巨噬细胞（TAMs）是TME中的重要成分。TAMs是在TME中浸润并且聚集在恶性肿瘤细胞周围的巨噬细胞,是TME中最为重要的组成细胞之一,在肿瘤发生发展中发挥重要作用。TAMs可通过分泌细胞因子和外泌体等与TME中的其他细胞相互作用,导致免疫抑制型TME,促进肿瘤细胞增殖转移。文章重点讨论TAMs在胃癌TME中的生物学特征、在胃癌侵袭和转移中的作用、免疫耐药机制以及与其他细胞间的相互作用,以期为实现针对TAMs的胃癌靶向治疗提供思路。     

肿瘤相关巨噬细胞糖代谢重编程及靶向治疗

肿瘤相关巨噬细胞（tumor-associated macrophages,TAMs）作为肿瘤微环境（tumor microenvironment,TME）中重要的免疫细胞,具有高度异质性及可塑性,在肿瘤细胞分泌的细胞因子刺激下,可发生表型、代谢及功能变化。TAMs代谢改变以糖代谢重编程为主,M1型TAMs有氧糖酵解、磷酸戊糖途径增强,三羧酸循环减弱,具有抗肿瘤功能;M2型TAMs具有完整的三羧酸循环,可促进肿瘤进展。而在TME作用下TAMs具有多种表现形式,其糖代谢重编程可影响肿瘤迁移、侵袭及血管生成,而具体作用机制尚不明确。本文旨在探讨TAMs糖代谢重编程作用机制及其与肿瘤免疫相关性,提示TME中TAMs糖代谢重编程对肿瘤发展和靶向治疗有重要意义,可为肿瘤治疗提供新思路。     

TAMs为靶点的抗肿瘤治疗研究进展

肿瘤微环境与肿瘤细胞通过分子和细胞间的相互作用,在肿瘤的发生发展和转移扩散中具有重要意义。肿瘤相关巨噬细胞（TAMs）作为肿瘤微环境中数量最多的炎症细胞群之一,在肿瘤进展中起到重要作用。肿瘤细胞通过释放多种趋化因子、细胞因子和生长因子招募巨噬细胞,并使其向M2型巨噬细胞类似的特性发展。同时,巨噬细胞释放多种因子,促进肿瘤细胞的生长、血管新生、迁移、侵袭、侵入血管并最终形成远处转移。TAMs在肿瘤组织中的密度与肿瘤患者治疗失败和不良预后密切相关,以TAMs为靶点的抗肿瘤治疗相关研究近年来取得重大进展。在肿瘤发生发展中根据TAMs的作用机制,以TAMs为靶点的抗肿瘤治疗策略是抑制肿瘤微环境中巨噬细胞招募、TAMs生存能力、TAMs表型即由M2型转化为M1型的重塑。本文就TAMs为靶点的抗肿瘤治疗最新进展进行综述。      

lncRNA通过肿瘤相关巨噬细胞极化影响肿瘤生长的机制研究进展

肿瘤的生长转移不仅取决于自身特性，还与其所处的肿瘤微环境（tumor microenvironment，TME）密切相关。肿瘤相关巨噬细胞（tumor-associated macrophages，TAMs)是存在于肿瘤微环境中的一类重要免疫细胞，多数为免疫抑制的极化M2型，少数为免疫激活的极化M1型，在肿瘤发生发展过程中发挥着重要作用，但其极化过程的调控机制仍不十分清楚。长链非编码RNA（long non-coding RNA，lncRNA）作为重要的非编码RNA，可直接影响肿瘤细胞的生长，近年来越来越多研究发现TAMs中或TAMs外的lncRNA可对TAMs极化产生影响，间接调控肿瘤的生长、血管形成、转移和代谢等。因此，针对lncRNA调控TAMs极化过程进行靶向干预，逆转M2极化，有望成为肿瘤治疗的新靶点，TAMs中lncRNA的表达谱也可成为肿瘤诊断或预后判定的重要生物学指标。     

肿瘤相关巨噬细胞对恶性肿瘤临床预后和治疗的影响

肿瘤相关巨噬细胞(tumor-associated macrophages,TAMs)作为肿瘤微环境中(tumor microenvi-ronment,TME)的核心调控者在肿瘤的发生发展中具有重要作用.活化的肿瘤相关巨噬细胞可分化出具有不同活化状态和功能的M1型和M2型,M1型肿瘤相关巨噬细胞主要介导抗肿瘤免疫效应,...     

靶向肿瘤相关巨噬细胞治疗卵巢癌的研究进展

摘 要：肿瘤微环境对卵巢癌的进展具有重要的调控作用。肿瘤相关巨噬细胞（tumor-associated macrophages,TAMs）是肿瘤微环境重要的组成部分。众所周知,TAMs通过调节肿瘤微环境在肿瘤进展中发挥重要作用。目前关于TAMs与肿瘤相互作用的模式包括消耗TAMs,减少TAMs募集、削弱TAMs吞噬能力、诱导M2 TAMs凋亡和向M1样表型转化、抑制M2 TAMs的极化、调节TAMs极化等。靶向肿瘤相关巨噬细胞是改善免疫抑制性肿瘤微环境和提高肿瘤免疫治疗的一种有前景的策略。     

肿瘤相关巨噬细胞在鼻咽癌中的研究进展

肿瘤相关巨噬细胞(tumor-associated?macrophages,?TAMs)是肿瘤微环境中重要的免疫细胞,主要分为两种类型,即经典活化的M1型巨噬细胞和替代性活化的M2型巨噬细胞.TAMs在许多肿瘤组织中发挥M2型作用,即促进肿瘤的增殖、血管生成,诱导肿瘤细胞侵袭和转移,目前有关肿瘤相关巨噬细胞与肿瘤细胞之...     

肿瘤微环境中肿瘤相关巨噬细胞极化的影响因素及其意义

肿瘤相关巨噬细胞（tumor-associated macrophages, TAMs）具有极高的可塑性，是肿瘤微环境（tumor microenvironment, TME）中含量最丰富的免疫细胞。各种TME成分（如细胞因子、趋化因子以及外泌体等）将TAMs招募到肿瘤区域内。随后，这些环境因子把TAMs诱导为抗肿瘤状态（M1样）或促肿瘤状态（M2样）之间的某一极化状态。另外，TAMs的极化过程是连续的，并且会随着肿瘤恶性进展而逐渐地朝向M2样状态，构成了一个有利于肿瘤生长和转移的正反馈环。因此，深入研究影响TAMs极化的各种因素和机制，有助于研发一种新的且可以与其他免疫治疗相结合的肺癌治疗策略。在既往的研究中已发现了许多可以促进TAMs的M2极化的分子和通路。然而，肿瘤细胞、间质细胞和TAMs之间这种复杂的串扰的潜在机制仍然难以研究清楚。在这篇综述中我们总结了促进TAMs向M2表型极化的各种因素，并进一步探讨了相关的分子机制。     

Role of tumor-associated macrophages in common digestive system malignant tumors

Many digestive system malignant tumors are characterized by high incidence and mortality rate. Increasing evidence has revealed that the tumor microenvironment(TME) is involved in cancer initiation and tumor progression. Tumor-associated macrophages(TAMs) are a predominant constituent of the TME, and participate in the regulation of various biological behaviors and influence the prognosis of digestive system cancer. TAMs can be mainly classified into the antitumor M1 phenotype and protumor M2 ph...     

Depletion of tumor-associated macrophages inhibits lung cancer growth and enhances the antitumor effect of cisplatin

In lung cancer, tumor-associated macrophages (TAMs), especially M2-like TAMs, represent the main tumor progression components in the tumor microenvironment (TME). Therefore, M2-like TAMs may serve as a therapeutic target. The purpose of this study was to investigate the effect of M2-like TAM depletion in the TME on tumor growth and chemotherapy response in lung cancer. The levels of secreted monocyte chemoattractant protein (MCP-1) and prostaglandin E2 (PGE2) in the supernatants of lung cancer cell lines A549 and LLC were evaluated via ELISA. Cell migration assays were performed to assess the recruitment ability of macrophage cell lines THP-1 and J774-1 cells. Differentiation of macrophages was assessed via flow cytometry. Immunohistochemical staining was performed to visualize M2-like TAMs in transplanted lung cancer in mouse. We used the COX-2 inhibitor nimesulide to inhibit the secretion of MCP-1 and PGE2, which promotes macrophage migration and M2-like differentiation. Nimesulide treatment decreased the secretion of MCP-1 and PGE2 from lung cancer cells. Nimesulide treatment suppressed the migration of macrophages by blocking MCP-1. Lung cancer supernatant induced the differentiation of macrophages toward the M2-like phenotype, and nimesulide treatment inhibited M2-like differentiation by blocking MCP-1 and PGE2. In the lung cancer mouse model, treatment with nimesulide depleted M2-like TAMs in the TME and enhanced the tumor inhibitory effect of cisplatin. Our results indicated that blocking the secretion of MCP-1 and PGE2 from tumor cells depleted M2-like TAMs in the TME and the combination therapy with cisplatin considerably suppressed tumor growth in the LLC mouse model.     

Engulfment and cell motility protein 1 fosters reprogramming of tumor-associated macrophages in colorectal cancer

Functional reprogramming of tumor-associated macrophages (TAMs) is crucial to their potent tumor-supportive capacity. However, the molecular mechanism behind the reprogramming process remains poorly understood. Here, we identify engulfment and cell motility protein 1 (ELMO1) as a crucial player for TAM reprogramming in colorectal cancer (CRC). The expression of ELMO1 in stromal but not epithelial tumor cells was positively associated with advanced clinical stage and poor disease-free survival in CRC. An increase in ELMO1 expression was specifically found in TAMs, but not in other multiple nonmalignant stromal cells. Gain- and loss-of-function assays indicated ELMO1 reprogrammed macrophages to a TAM-like phenotype through Rac1 activation. In turn, ELMO1-reprogrammed macrophages were shown to not only facilitate the malignant behaviors of CRC cells but exhibited potent phagocytosis of tumor cells. Taken together, our work underscores the importance of ELMO1 in determining functional reprogramming of TAMs and could provide new insights on potential therapeutic strategies against CRC.     

Intratumoral macrophage counts correlate with tumor progression in colorectal cancer

Background

The role of intratumoral tumor‐associated macrophages (TAMs) in colorectal cancer (CRC) is not clear. We aim to examine the relationships of TAMs and the clinicopathologic features of CRC and the expression of matrix metalloproteinases (MMP)‐2 and MMP‐9.

Methods

Immunohistochemical staining of CD68, MMP‐2, and MMP‐9 was determined in tissue samples from CRC patients. To test the biological effect of macrophages on tumor cells, cancer cells were cocultured with macrophages and function change of cancer cells were examined.

Results

Intratumoral TAM count correlated with depth of invasion (P = 0.048), lymph node metastasis (P < 0.0001), and staging (P < 0.0001) of CRC. MMP‐2 and MMP‐9 expression was significantly associated with lymph node metastasis and staging. A significant association between intratumoral TAM counts and MMP‐2 (P < 0.0001) and MMP‐9 (P < 0.0001) expression was noted. When cocultured with macrophages, cancer cells increased their invasiveness and migration and elevated MMP‐2 and MMP‐9 secretion.

Conclusions

Intratumoral TAMs cause cancer cells to have a more aggressive behavior, and this may be due to an upregulation of tumor cell‐derived MMP‐2 and MMP‐9. Examination of intratumoral TAMs can serve as a progressive marker for CRC patients. J. Surg. Oncol. 2010;102:242–248. © 2010 Wiley‐Liss, Inc.     

Clinical significance of macrophage heterogeneity in human malignant tumors

The fact that various immune cells, including macrophages, can be found in tumor tissue has long been known. With the recent introduction of the novel concept of macrophage differentiation into a classically activated phenotype (M1) and an alternatively activated phenotype (M2), the role of tumor‐associated macrophages (TAMs) is gradually beginning to be elucidated. Specifically, in human malignant tumors, TAMs that have differentiated into M2 macrophages act as “protumoral macrophages” and contribute to the progression of disease. Based on recent basic and preclinical research, TAMs that have differentiated into protumoral or M2 macrophages are believed to be intimately involved in the angiogenesis, immunosuppression, and activation of tumor cells. In this paper, we specifically discuss both the role of TAMs in human malignant tumors and the cell–cell interactions between TAMs and tumor cells.