Background: Transforming growth factor-Beta (TGF-Beta) plays a key role in bone metastasis\nformation; we hypothesized the possible involvement of TGF-Beta in the induction of cancer stem cells\n(CSCs) in the bone microenvironment (micro-E), which may be responsible for chemo-resistance.\nMethods: Mouse mammary tumor cells were implanted under the dorsal skin flap over the calvaria\nand into a subcutaneous (subQ) lesions in female mice, generating tumors in the bone and subQ\nmicro-Es. After implantation of the tumor cells, mice were treated with a TGF-Beta R1 kinase inhibitor\n(R1-Ki). Results: Treatment with R1-Ki decreased tumor volume and cell proliferation in the bone\nmicro-E, but not in the subQ micro-E. R1-Ki treatment did not affect the induction of necrosis\nor apoptosis in either bone or subQ micro-E. The number of cells positive for the CSC markers,\nSOX2, and CD166 in the bone micro-E, were significantly higher than those in the subQ micro-E.\nR1-Ki treatment significantly decreased the number of CSC marker positive cells in the bone\nmicro-E but not in the subQ micro-E. TGF-Beta activation of the MAPK/ERK and AKT pathways was\nthe underlying mechanism of cell proliferation in the bone micro-E. BMP signaling did not play a role\nin cell proliferation in either micro-E. Conclusion: Our results indicated that the bone micro-E is a key\nniche for CSC generation, and TGF-Beta signaling has important roles in generating CSCs and tumor\ncell proliferation in the bone micro-E. Therefore, it is critically important to evaluate responses to\nchemotherapeutic agents on both cancer stem cells and proliferating tumor cells in different tumor\nmicroenvironments in vivo.
Loading....