Recruitment of a myeloid cell subset (CD11b/Gr1(mid)) via CCL2/CCR2 promotes the development of Colorectal Cancer Liver Metastasis

Lei Zhao, Su Yin Lim, Alex N. Gordon-Weeks, Thomas T. Tapmeier, Jae Hong Im, Yunhong Cao, John Beech, Danny Allen, Sean Smart, Ruth J. Muschel*

*Corresponding author for this work

Research output: Contribution to journalArticle

130 Citations (Scopus)

Abstract

Liver metastasis from colorectal cancer is a leading cause of cancer mortality. Myeloid cells play pivotal roles in the metastatic process, but their prometastatic functions in liver metastasis remain incompletely understood. To investigate their role, we simulated liver metastasis in C57BL/6 mice through intrasplenic inoculation of MC38 colon carcinoma cells. Among the heterogeneous myeloid infiltrate, we identified a distinct population of CD11b/Gr1mid cells different from other myeloid populations previously associated with liver metastasis. These cells increased in number dramatically during establishment of liver metastases and were recruited from bone marrow by tumor-derived CCL2. Liver metastasis of Lewis lung carcinoma cells followed this pattern but this mechanism is not universal as liver colonization by B16F1 melanoma cells did not recruit similar subsets. Inhibition of CCL2 signaling and absence of its cognate receptor CCR2 reduced CD11b/Gr1mid recruitment and decreased tumor burden. Depletion of the CD11b/Gr1mid subset in a transgenic CD11b-diphtheria toxin receptor mouse model markedly reduced tumor cell proliferation. There was no evidence for involvement of an adaptive immune response in the prometastatic effects of CD11b/Gr1mid cells. Additionally, an analogous myeloid subset was found in liver metastases of some colorectal cancer patients. Conclusion: Collectively, our findings highlight the importance of myeloid cells-in this case a selective CD11b/Gr1mid subset-in sustaining development of colorectal cancer liver metastasis and identify a potential target for antimetastatic therapy.

Original languageEnglish
Pages (from-to)829-839
Number of pages11
JournalHepatology
Volume57
Issue number2
DOIs
Publication statusPublished - Feb 2013
Externally publishedYes

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