Dynamic differentiation of F4/80+tumor-associated macrophage and its role in tumor vascularization in a syngeneic mouse model of colorectal liver metastasis

Qiao, Ting1; Yang, Wanli2,3; He, Xiangchuan2,4,5; Song, Ping2,6; Chen, Xiao1; Liu, Ruijie2; Xiao, Jian7,8; Yang, Xiaoli1; Li, Mingqi9; Gao, Yudan1; Chen, Guoan1; Lu, Yi1,10; Zhang, Jian1,10; Leng, Jing7,8; Ren, Huan1

2023-02-13

10.1038/s41419-023-05626-1

Cell Death & Disease   Impact Factor & Quartile

2041-4889

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(-) CD11b(int) 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.

SCI

English

First ; Corresponding

Natural Science Foundation of China["NSFC-81472367","NSFC-81871993","NSFC-81972766","NSFC-82173336","NSFC-81972420","NSFC-81773146"] ; Shenzhen Science and Technology Innovation Commission[JCYJ20190809161811237]

Cell Biology

Cell Biology

WOS:000944246400005

SPRINGERNATURE

Web of Science

1.Southern Univ Sci & Technol, Sch Med, Shenzhen 518055, Peoples R China
2.Harbin Med Univ, Dept Immunol, Harbin, Peoples R China
3.Shanghai Univ Med & Hlth Sci, Chongming Hosp, Shanghai, Peoples R China
4.Fudan Univ, Zhongshan Hosp, Clin Ctr BioTherapy, Shanghai, Peoples R China
5.Fudan Univ, Zhongshan Hosp, Inst Biomed Sci, Shanghai, Peoples R China
6.Jiarun Hosp Harbin, Dept Ophthalmol, Harbin, Peoples R China
7.Guangxi Chinese Med Univ, Dept Microbiol & Immunol, Nanning, Peoples R China
8.Guangxi Key Lab Translat Med Treating High Inciden, Nanning, Peoples R China
9.Harbin Med Univ, Dept Colorectal Surg, Hosp 3, Harbin, Peoples R China
10.Guangdong Prov Key Lab Cell Microenvironm & Dis Re, Shenzhen, Guangdong, Peoples R China

Qiao, Ting,Yang, Wanli,He, Xiangchuan,et al. Dynamic differentiation of F4/80+tumor-associated macrophage and its role in tumor vascularization in a syngeneic mouse model of colorectal liver metastasis[J]. Cell Death & Disease,2023,14(2).

Qiao, Ting.,Yang, Wanli.,He, Xiangchuan.,Song, Ping.,Chen, Xiao.,...&Ren, Huan.(2023).Dynamic differentiation of F4/80+tumor-associated macrophage and its role in tumor vascularization in a syngeneic mouse model of colorectal liver metastasis.Cell Death & Disease,14(2).

Qiao, Ting,et al."Dynamic differentiation of F4/80+tumor-associated macrophage and its role in tumor vascularization in a syngeneic mouse model of colorectal liver metastasis".Cell Death & Disease 14.2(2023).