Dynamic differentiation of F4/80+ tumor-associated macrophage and its role in tumor vascularization in a syngeneic mouse model of colorectal liver metastasis.
Dynamic differentiation of F4/80+ tumor-associated macrophage and its role in tumor vascularization in a syngeneic mouse model of colorectal liver metastasis.
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DOI：
10.1038/s41419-023-05626-1
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发表时间：
2023-02-13
影响因子：
9
通讯作者：
Ren, Huan
中科院分区：
文献类型：
--
作者：
Qiao, Ting;Yang, Wanli;He, Xiangchuan;Song, Ping;Chen, Xiao;Liu, Ruijie;Xiao, Jian;Yang, Xiaoli;Li, Mingqi;Gao, Yudan;Chen, Guoan;Lu, Yi;Zhang, Jian;Leng, Jing;Ren, Huan
肿瘤相关巨噬细胞（TAM）是高度异质性的，在肿瘤进展中起着重要作用。本研究采用门静脉注射Mc 38结直肠癌细胞模拟晚期结直肠癌肝转移（CRLM）的C57 BL/6小鼠模型。通过CRLM活检的连续切片，我们将注射后7-9天定义为肿瘤新血管形成的关键时期，其通过血管共选择从先天性肝血管开始，并通过血管拟态及其CD 34+细胞的生长而延长。在肝转移灶大小增加的样本中，浸润的Ly 6C + CD 11b + F4/80−单核细胞在转化为Ly 6C − CD 11bint F4/80+细胞之前稳定地获得了F4/80（库普弗细胞标志物）的表达，Ly 6C − CD 11b − F4/80+细胞也适应了相同的表型。F4/80+ TAMs在体内显示出与新生血管和肿瘤血管的接近性，具有血管生成功能;在体外极大地促进了内皮细胞中一些关键的血管生成标志物如VEGFA、Ki 67等的活化。在新生血管形成过程中，巨噬细胞的消耗或巨噬细胞极化的转移阻碍了肿瘤生长和血管形成，并导致F4/80+ TAM大大减少，但由于TAM分化的抑制而导致CD 11b+细胞增加。总之，我们的研究结果显示了肿瘤微环境中的动态和时空F4/80+ TAM转化，并加强了其在CRLM中作为血管周围和血管生成TAM的作用。
Tumor-associated macrophages (TAMs) are highly heterogeneous and play vital roles in tumor progression. Here we adopted a C57BL/6 mouse model imitating the late-stage colorectal liver metastasis (CRLM) by Mc38 colorectal cancer cell injection via the portal vein. With serial sections of CRLM biopsies, we defined 7–9 days post-injection as the critical period for tumor neovascularization, which was initiated from the innate liver vessels via vessel cooption and extended by vascular mimicry and thereof growth of CD34+cells. In samples with increasing-sized liver metastases, the infiltrated Ly6C+ CD11b+ F4/80− monocytes steadily gained the expression of F4/80, a Kupffer cell marker, before transformed into Ly6C− CD11bint F4/80+ cells, which, the same phenotype was also adapted by Ly6C− CD11b− F4/80+ Kupffer cells. F4/80+ TAMs showed proximity to neovascularization and tumor vessels, functionally angiogenic in vivo; and greatly promoted the activation of a few key angiogenic markers such as VEGFA, Ki67, etc. in endothelial cells in vitro. Depletion of macrophages or diversion of macrophage polarization during neovascularization impeded tumor growth and vascularization and resulted in greatly reduced F4/80+ TAMs, yet increased CD11b+ cells due to inhibition of TAM differentiation. In summary, our results showed dynamic and spatial–temporal F4/80+ TAM transformation within the tumor microenvironment and strengthened its role as perivascular and angiogenic TAMs in CRLM.
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影响因子：
5.8
作者：
Dixon LJ;Barnes M;Tang H;Pritchard MT;Nagy LE
通讯作者：
Nagy LE
影响因子：
50.3
作者：
Lewis CE;Harney AS;Pollard JW
通讯作者：
Pollard JW
影响因子：
64.8
作者：
Guerriero JL;Sotayo A;Ponichtera HE;Castrillon JA;Pourzia AL;Schad S;Johnson SF;Carrasco RD;Lazo S;Bronson RT;Davis SP;Lobera M;Nolan MA;Letai A
通讯作者：
Letai A
影响因子：
5.2
作者：
Sidney, Laura E.;Branch, Matthew J.;Dunphy, Siobhan E.;Dua, Harminder S.;Hopkinson, Andrew
通讯作者：
Hopkinson, Andrew
seq-ImmuCC：组织转录组的以细胞为中心的视图，从小鼠 RNA-Seq 数据测量免疫微环境的细胞组成
影响因子：
7.3
作者：
Chen Z;Quan L;Huang A;Zhao Q;Yuan Y;Yuan X;Shen Q;Shang J;Ben Y;Qin FX;Wu A
通讯作者：
Wu A