Tracking of intertissue migration reveals the origins of tumor-infiltrating monocytes.
Myeloid cells such as monocytes and monocyte-derived macrophages promote tumor progression. Recent reports suggest that extramedullary hematopoiesis sustains a sizable reservoir of tumor-infiltrating monocytes in the spleen. However, the influence of the spleen on tumor development and the extent to which spleen monocytes populate the tumor relative to bone marrow (BM) monocytes remain controversial. Here, we used mice expressing the photoconvertible protein Kikume Green-Red to track the redistribution of monocytes from the BM and spleen, and mice expressing fluorescent ubiquitination-based cell-cycle indicator proteins to monitor active hematopoiesis in these tissues. In mice bearing late-stage tumors, the BM, besides being the major site of monocyte production, supplied the expansion of the spleen reservoir, replacing 9% of spleen monocytes every hour. Deployment of monocytes was equally rapid from the BM and the spleen. However, BM monocytes were younger than those in the spleen and were 2.7 times more likely to migrate into the tumor from the circulation. Partly as a result of this intrinsic difference in migration potential, spleen monocytes made only a minor contribution to the tumor-infiltrating monocyte population. At least 27% of tumor monocytes had traveled from the BM in the last 24 h, compared with only 2% from the spleen. These observations highlight the importance of the BM as the primary hematopoietic tissue and monocyte reservoir in tumor-bearing mice, despite the changes that occur in the spleen monocyte reservoir during tumor development.
Department of Molecular Preventive Medicine, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan;Department of Pharmacology and Therapeutics, The University of Melbourne, Parkville, Victoria 3010, Australia;
Francis H W
http://orcid.org/0000-0002-4222-6564
FH
Shand
Department of Molecular Preventive Medicine, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan;
Satoshi
S
Ueha
Department of Molecular Preventive Medicine, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan;
Mikiya
M
Otsuji
Department of Pharmacology and Therapeutics, The University of Melbourne, Parkville, Victoria 3010, Australia;St. Vincent's Institute of Medical Research, Fitzroy, Victoria 3065, Australia;
Suang Suang
SS
Koid
Department of Molecular Preventive Medicine, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan;
Shigeyuki
S
Shichino
Department of Molecular Preventive Medicine, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan;
Tatsuya
T
Tsukui
Department of Molecular Preventive Medicine, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan;Department of Hematology, Hokkaido University Graduate School of Medicine, Kita-15 Nishi-7, Kita-ku, Sapporo, Hokkaido 060-8638, Japan; and.
Mizuha
M
Kosugi-Kanaya
Department of Molecular Preventive Medicine, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan;
Jun
J
Abe
Center for Innovation in Immunoregulative Technology and Therapeutics, Graduate School of Medicine, Kyoto University, Yoshidakonoe-cho, Sakyo-ku, Kyoto 606-8501, Japan.
Michio
M
Tomura
Department of Pharmacology and Therapeutics, The University of Melbourne, Parkville, Victoria 3010, Australia;
James
J
Ziogas
Department of Molecular Preventive Medicine, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan; koujim@m.u-tokyo.ac.jp.
Kouji
K
Matsushima
D000704:Analysis of Variance; D000818:Animals; D001854:Bone Marrow Cells / Q000276:immunology*; D063646:Carcinogenesis / Q000276:immunology*; D002465:Cell Movement / Q000276:immunology*; D005453:Fluorescence; D006410:Hematopoiesis / Q000502:physiology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009000:Monocytes / Q000276:immunology*; D013154:Spleen / Q000166:cytology* / Q000276:immunology
Fucci; KikGR; cancer immunity; monocytopoiesis; tumor-associated macrophage