Reversal of chemotherapy-induced leukopenia using granulocyte macrophage colony-stimulating factor promotes bone metastasis that can be blocked with osteoclast inhibitors.
Hematopoietic growth factors are used to reverse chemotherapy-induced leukopenia. However, some factors such as granulocyte macrophage colony-stimulating factor (GM-CSF) induce osteoclast-mediated bone resorption that can promote cancer growth in the bone. Accordingly, we evaluated the ability of GM-CSF to promote bone metastases of breast cancer or prostate cancer in a mouse model of chemotherapy-induced leukopenia. In this model, GM-CSF reversed cyclophosphamide-induced leukopenia but also promoted breast cancer and prostate cancer growth in the bone but not in soft tissue sites. Bone growth was associated with the induction of osteoclastogenesis, yet in the absence of tumor GM-CSF, it did not affect osteoclastogenesis. Two osteoclast inhibitors, the bisphosphonate zoledronic acid and the RANKL inhibitor osteoprotegerin, each blocked GM-CSF-induced tumor growth in the bone but did not reverse the ability of GM-CSF to reverse chemotherapy-induced leukopenia. Our findings indicate that it is possible to dissociate the bone-resorptive effects of GM-CSF, to reduce metastatic risk, from the benefits of this growth factor in reversing leukopenia caused by treatment with chemotherapy.
Dai
Jinlu
J
Department of Urology, University of Michigan, Ann Arbor, Michigan 48109-8940, USA.
Lu
Yi
Y
Yu
Chunyan
C
Keller
Jill M
JM
Mizokami
Atsushi
A
Zhang
Jian
J
Keller
Evan T
ET
D000818:Animals; D018906:Antineoplastic Agents, Alkylating / Q000009:adverse effects; D050071:Bone Density Conservation Agents / Q000627:therapeutic use*; D001859:Bone Neoplasms / Q000556:secondary*; D001943:Breast Neoplasms / Q000556:secondary*; D003520:Cyclophosphamide / Q000009:adverse effects; D004164:Diphosphonates / Q000627:therapeutic use; D005260:Female; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000037:antagonists & inhibitors / Q000627:therapeutic use*; D006801:Humans; D007093:Imidazoles / Q000627:therapeutic use; D007970:Leukopenia / Q000139:chemically induced / Q000188:drug therapy*; D008297:Male; D051379:Mice; D008819:Mice, Nude; D010010:Osteoclasts / Q000187:drug effects*; D053244:Osteoprotegerin / Q000627:therapeutic use; D011471:Prostatic Neoplasms / Q000556:secondary*; D053245:RANK Ligand / Q000378:metabolism; D000077211:Zoledronic Acid
D018906:Antineoplastic Agents, Alkylating; D050071:Bone Density Conservation Agents; D004164:Diphosphonates; D007093:Imidazoles; D053244:Osteoprotegerin; D053245:RANK Ligand; D000077211:Zoledronic Acid; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D003520:Cyclophosphamide