Recruitment of a myeloid cell subset (CD11b/Gr1 mid) via CCL2/CCR2 promotes the development of colorectal cancer liver metastasis.

Abstract

UNLABELLED:

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/Gr1(mid) 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/Gr1(mid) recruitment and decreased tumor burden. Depletion of the CD11b/Gr1(mid) 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/Gr1(mid) 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/Gr1(mid) subset--in sustaining development of colorectal cancer liver metastasis and identify a potential target for antimetastatic therapy.

• Authors: 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
• Journal: Hepatology (Baltimore, Md.) (Hepatology) Vol. 57 Issue 2 Pg. 829-39 (Feb 2013) ISSN: 1527-3350 [Electronic] United States
• PMID: 23081697 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2012 American Association for the Study of Liver Diseases.

Chemical References

• CD11b Antigen
• Ccl2 protein, mouse
• Ccr2 protein, mouse
• Chemokine CCL2
• Receptors, CCR2

Topics

• Animals
• CD11b Antigen (immunology)
• Chemokine CCL2 (physiology)
• Colorectal Neoplasms (immunology, pathology)
• Humans
• Liver Neoplasms (immunology, pathology, secondary)
• Mice
• Models, Animal
• Myeloid Cells (immunology, pathology, transplantation)
• Neoplasm Transplantation
• Receptors, CCR2 (physiology)