Freshly isolated bone marrow cells induce death of various carcinoma cell lines.
In some carcinomas such as digestive tract carcinomas, bone marrow infiltration by tumor cells is a frequent event but usually remains a micrometastatic disease and rarely induces overt bone lesions. The mechanisms responsible for the control of these metastases in the bone marrow remain poorly known. We show that freshly isolated bone marrow cells from human, murine and rat origin rapidly kill a wide range of syngeneic or xenogeneic carcinoma cell lines in culture. Further analysis of this cytotoxic process in the rat indicated that neither resident bone marrow macrophages nor NK cells were responsible for this cytotoxic effect that was restricted to a subpopulation of bone marrow cells expressing CD90 (Thy-1), a marker of hemopoietic precursors. The tumoricidal activity of these cells did not require long-term culture nor addition of exogenous cytokines or growth factors. A subset of CD90+ cells that rapidly differentiates into CD163(ED2)-expressing macrophages was observed to be responsible for tumor cell killing. These macrophages induced a non-apoptotic death of tumor cells, a process that required both a direct interaction with the tumor cell and nitric oxide (NO) production through the activation of inducible nitric oxide-synthase (iNOS). This ability of pluripotent hemopoietic stem cells to rapidly differentiate into macrophages capable of killing invasive tumor cells may account for the limited expansion of micrometastases of some carcinomas in the bone marrow.
Larmonier
Nicolas
N
INSERM U517, IFR 100, Faculty of Medicine, Dijon, France.
Ghiringhelli
François
F
Larmonier
Claire B
CB
Moutet
Monique
M
Fromentin
Annie
A
Baulot
Emmanuel
E
Solary
Eric
E
Bonnotte
Bernard
B
Martin
François
F
D000818:Animals; D001854:Bone Marrow Cells / Q000166:cytology* / Q000502:physiology*; D016923:Cell Death / Q000502:physiology*; D002469:Cell Separation / Q000379:methods; D002470:Cell Survival / Q000502:physiology*; D003110:Colonic Neoplasms; D006801:Humans; D019169:Jurkat Cells; D051379:Mice; D008807:Mice, Inbred BALB C; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II; D051381:Rats; D011919:Rats, Inbred Strains; D011946:Receptors, Antigen / Q000032:analysis; D014407:Tumor Cells, Cultured; D019323:omega-N-Methylarginine / Q000494:pharmacology
D011946:Receptors, Antigen; D019323:omega-N-Methylarginine; C496319:NOS2 protein, human; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse; C496318:Nos2 protein, rat