Department of Obstetrics & Gynaecology, LKS Faculty of Medicine, University of Hong Kong, Hong Kong, China.
Int J Mol Sci. 2021 Jun 18;22(12):6560. doi: 10.3390/ijms22126560.
Rather than primary solid tumors, metastasis is one of the hallmarks of most cancer deaths. Metastasis is a multistage event in which cancer cells escape from the primary tumor survive in the circulation and disseminate to distant sites. According to Stephen Paget's "Seed and Soil" hypothesis, metastatic capacity is determined not only by the internal oncogenic driving force but also by the external environment of tumor cells. Throughout the body, macrophages are required for maintaining tissue homeostasis, even in the tumor milieu. To fulfill these multiple functions, macrophages are polarized from the inflammation status (M1-like) to anti-inflammation status (M2-like) to maintain the balance between inflammation and regeneration. However, tumor cell-enforced tumor-associated macrophages (TAMs) (a high M2/M1 ratio status) are associated with poor prognosis for most solid tumors, such as ovarian cancer. In fact, clinical evidence has verified that TAMs, representing up to 50% of the tumor mass, exert both protumor and immunosuppressive effects in promoting tumor metastasis through secretion of interleukin 10 (IL10), transforming growth factor β (TGFβ), and VEGF, expression of PD-1 and consumption of arginine to inhibit T cell anti-tumor function. However, the underlying molecular mechanisms by which the tumor microenvironment favors reprogramming of macrophages to TAMs to establish a premetastatic niche remain controversial. In this review, we examine the latest investigations of TAMs during tumor development, the microenvironmental factors involved in macrophage polarization, and the mechanisms of TAM-mediated tumor metastasis. We hope to dissect the critical roles of TAMs in tumor metastasis, and the potential applications of TAM-targeted therapeutic strategies in cancer treatment are discussed.
相较于原发性实体肿瘤，转移是大多数癌症死亡的标志之一。转移是一个多步骤的过程，在此过程中，癌细胞从原发性肿瘤中逃脱，在循环中存活并扩散到远处部位。根据 Stephen Paget 的“种子与土壤”假说，转移性能力不仅取决于内部致癌驱动因素，还取决于肿瘤细胞的外部环境。在全身范围内，巨噬细胞对于维持组织稳态是必需的，即使在肿瘤微环境中也是如此。为了履行这些多种功能，巨噬细胞从炎症状态（M1 样）极化到抗炎状态（M2 样），以维持炎症和再生之间的平衡。然而，肿瘤细胞强制的肿瘤相关巨噬细胞（TAM）（高 M2/M1 比值状态）与大多数实体瘤（如卵巢癌）的预后不良相关。事实上，临床证据已经证实，TAMs 占肿瘤质量的 50%，通过分泌白细胞介素 10（IL10）、转化生长因子 β（TGFβ）和血管内皮生长因子（VEGF）、表达 PD-1 和消耗精氨酸来抑制 T 细胞抗肿瘤功能，在促进肿瘤转移方面发挥着促肿瘤和免疫抑制作用。然而，肿瘤微环境有利于巨噬细胞重编程为 TAM 以建立前转移龛的潜在分子机制仍存在争议。在这篇综述中，我们检查了 TAMs 在肿瘤发展过程中的最新研究、参与巨噬细胞极化的微环境因素以及 TAM 介导的肿瘤转移的机制。我们希望剖析 TAMs 在肿瘤转移中的关键作用，并讨论 TAM 靶向治疗策略在癌症治疗中的潜在应用。
