Podoplanin-Expressing Macrophages Promote Lymphangiogenesis and Lymphoinvasion in Breast Cancer
Podoplanin-Expressing Macrophages Promote Lymphangiogenesis and Lymphoinvasion in Breast Cancer
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DOI：
10.1016/j.cmet.2019.07.015
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发表时间：
2019-11-05
期刊：
影响因子：
29
通讯作者：
Mazzone, Massimiliano
中科院分区：
文献类型：
--
作者：
Bieniasz-Krzywiec, Pawel;Martin-Perez, Rosa;Mazzone, Massimiliano
在乳腺肿瘤浸润性免疫细胞中，podoplanin （PDPN）在肿瘤相关巨噬细胞（tam）的一个亚群中表达最高。我们在此证明PDPN参与了TAM亚群与淋巴内皮细胞（LECs）的附着。从机制上讲，PDPN以糖基化依赖的方式与lece衍生的GAL8 （GAL8）结合，促进了促迁移整合素β 1的激活。当靠近淋巴管时，表达pdpn的巨噬细胞（PoEMs）刺激局部基质重塑，促进血管生长和淋巴浸润。抗整合素β 1阻断、巨噬细胞特异性Pdpn敲除或GAL8抑制可损害TAM与LECs的粘附，抑制淋巴管生成并减少淋巴癌扩散。在乳腺癌患者中，PoEMs与肿瘤淋巴管的关联与淋巴结和远端器官转移的发生率相关。
Among mammary tumor-infiltrating immune cells, the highest expression of podoplanin (PDPN) is found in a subset of tumor-associated macrophages (TAMs). We hereby demonstrate that PDPN is involved in the attachment of this TAM subset to lymphatic endothelial cells (LECs). Mechanistically, the binding of PDPN to LEC-derived galectin 8 (GAL8) in a glycosylation-dependent manner promotes the activation of pro-migratory integrin beta 1. When proximal to lymphatics, PDPN-expressing macrophages (PoEMs) stimulate local matrix remodeling and promote vessel growth and lymphoinvasion. Anti-integrin beta 1 blockade, macrophage-specific Pdpn knockout, or GAL8 inhibition impairs TAM adhesion to LECs, restraining lymphangiogenesis and reducing lymphatic cancer spread. In breast cancer patients, association of PoEMs with tumor lymphatic vessels correlates with incidences of lymph node and distant organ metastasis.