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


CONCLUSIONS
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.
Gray Institute for Radiation Oncology and Biology, University of Oxford, Oxford, OX3 7LJ, United Kingdom.
Lei
L
Zhao
Su Yin
SY
Lim
Alex N
AN
Gordon-Weeks
Thomas T
TT
Tapmeier
Jae Hong
JH
Im
Yunhong
Y
Cao
John
J
Beech
Danny
D
Allen
Sean
S
Smart
Ruth J
RJ
Muschel
D000818:Animals; D039481:CD11b Antigen / Q000276:immunology; D018932:Chemokine CCL2 / Q000502:physiology*; D015179:Colorectal Neoplasms / Q000276:immunology / Q000473:pathology*; D006801:Humans; D008113:Liver Neoplasms / Q000276:immunology / Q000473:pathology / Q000556:secondary*; D051379:Mice; D023421:Models, Animal; D022423:Myeloid Cells / Q000276:immunology* / Q000473:pathology / Q000637:transplantation; D009368:Neoplasm Transplantation; D054390:Receptors, CCR2 / Q000502:physiology*
D039481:CD11b Antigen; C491768:Ccl2 protein, mouse; C515335:Ccr2 protein, mouse; D018932:Chemokine CCL2; D054390:Receptors, CCR2