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Local Radiotherapy Induces Homing of Hematopoietic Stem Cells to the Irradiated Bone Marrow

Departments of ¹ Medical Biophysics, ² Medicine, and ³ Radiation Oncology, University of Toronto; Divisions of ⁴ Applied Molecular Oncology and ⁵ Stem Cell and Developmental Biology, Ontario Cancer Institute and ⁶ Division of Medical Oncology and ⁷ Department of Radiation Oncology, Princess Margaret Hospital, University Health Network; and ⁸ Sunnybrook Health Sciences Centre, Toronto, Ontario, Canada

Requests for reprints: Fei-Fei Liu, Department of Radiation Oncology, Princess Margaret Hospital/Ontario Cancer Institute, 610 University Avenue, Room 10-203, Toronto, Ontario, Canada, M5G 2M9. Phone: 416-946-2123; Fax: 416-946-4586; E-mail: Fei-Fei.Liu{at}rmp.uhn.on.ca.

Local breast radiation therapy (RT) is associated with a 3-fold increased risk of secondary acute myeloid leukemia. As a first step in determining the mechanism(s) underlying this observation, we investigated the role of RT in mediating the active recruitment of hematopoietic stem cells (HSC) to the site of RT. Our results show in a mouse model that local RT delivered to the left leg causes preferential accumulation of bone marrow mononuclear cells to the irradiated site, with maximum signal intensity observed at 7 days post-RT. This is associated with a 4-fold higher number of donor-derived HSC present in the left leg, demonstrating recruitment of HSC to the site of RT. SDF-1, matrix metalloproteinase 2 (MMP-2), and MMP-9 expression is significantly increased in the irradiated bone marrow, and their inhibition significantly reduced HSC recruitment to the irradiated bone marrow. Our data show that local RT has significant systemic effects by recruiting HSC to the irradiated bone marrow site, a process mediated by SDF-1, MMP-2, and MMP-9. These results raise the possibility that the exposure of increased numbers of HSC at a local site to fractionated irradiation may increase the risk of leukemogenesis. Our data also suggest some opportunities for leukemia prevention in breast cancer patients undergoing RT. [Cancer Res 2007;67(21):10112–6]