Abstract
Background: Transforming growth factor-β (TGF-β) plays a key role in bone metastasis formation; we hypothesized the possible involvement of TGF-β in the induction of cancer stem cells (CSCs) in the bone microenvironment (micro-E), which may be responsible for chemo-resistance. Methods: Mouse mammary tumor cells were implanted under the dorsal skin flap over the calvaria and into a subcutaneous (subQ) lesions in female mice, generating tumors in the bone and subQ micro-Es. After implantation of the tumor cells, mice were treated with a TGF-β R1 kinase inhibitor (R1-Ki). Results: Treatment with R1-Ki decreased tumor volume and cell proliferation in the bone micro-E, but not in the subQ micro-E. R1-Ki treatment did not affect the induction of necrosis or apoptosis in either bone or subQ micro-E. The number of cells positive for the CSC markers, SOX2, and CD166 in the bone micro-E, were significantly higher than those in the subQ micro-E. R1-Ki treatment significantly decreased the number of CSC marker positive cells in the bone micro-E but not in the subQ micro-E. TGF-β activation of the MAPK/ERK and AKT pathways was the underlying mechanism of cell proliferation in the bone micro-E. BMP signaling did not play a role in cell proliferation in either micro-E. Conclusion: Our results indicated that the bone micro-E is a key niche for CSC generation, and TGF-β signaling has important roles in generating CSCs and tumor cell proliferation in the bone micro-E. Therefore, it is critically important to evaluate responses to chemotherapeutic agents on both cancer stem cells and proliferating tumor cells in different tumor microenvironments in vivo.
Funder
Japan Society for Promotion of Science
Subject
Inorganic Chemistry,Organic Chemistry,Physical and Theoretical Chemistry,Computer Science Applications,Spectroscopy,Molecular Biology,General Medicine,Catalysis
Cited by
24 articles.
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