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The Effects of TGF-? Signaling on Cancer Cells and Cancer Stem Cells in the Bone Microenvironment.


ABSTRACT: BACKGROUND:Transforming growth factor-? (TGF-?) plays a key role in bone metastasis formation; we hypothesized the possible involvement of TGF-? 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-? 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-? 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-? 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.

SUBMITTER: Futakuchi M 

PROVIDER: S-EPMC6829436 | biostudies-literature | 2019 Oct

REPOSITORIES: biostudies-literature

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The Effects of TGF-β Signaling on Cancer Cells and Cancer Stem Cells in the Bone Microenvironment.

Futakuchi Mitsuru M   Lami Kris K   Tachibana Yuri Y   Yamamoto Yukari Y   Furukawa Masahiro M   Fukuoka Junya J  

International journal of molecular sciences 20191015 20


<h4>Background</h4>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.<h4>Methods</h4>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 impl  ...[more]

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