期刊
CANCER CELL
卷 19, 期 2, 页码 192-205出版社
CELL PRESS
DOI: 10.1016/j.ccr.2010.12.022
关键词
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资金
- Brewster Foundation
- Department of Defense [8C051647]
- New Jersey Commission on Cancer Research (NJCCR)
- National Institutes of Health [R01CA134519]
- American Cancer Society
- Merck
Despite evidence supporting an oncogenic role in breast cancer, the Notch pathway's contribution to metastasis remains unknown. Here, we report that the Notch ligand Jagged1 is a clinically and functionally important mediator of bone metastasis by activating the Notch pathway in bone cells. Jagged1 promotes tumor growth by stimulating IL-6 release from osteoblasts and directly activates osteoclast differentiation. Furthermore, Jagged1 is a potent downstream mediator of the bone metastasis cytokine TGF beta that is released during bone destruction. Importantly, gamma-secretase inhibitor treatment reduces Jagged1-mediated bone metastasis by disrupting the Notch pathway in stromal bone cells. These findings elucidate a stroma-dependent mechanism for Notch signaling in breast cancer and provide rationale for using gamma-secretase inhibitors for the treatment of bone metastasis.
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