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Imaging transforming growth factor-Β signaling dynamics and therapeutic response in breast cancer bone metastasis

Department of Molecular Biology, Princeton University, Princeton, New Jersey, USA.
Nature medicine (Impact Factor: 28.05). 09/2009; 15(8):960-6. DOI: 10.1038/nm.1943
Source: PubMed

ABSTRACT Although the transforming growth factor-beta (TGF-beta) pathway has been implicated in breast cancer metastasis, its in vivo dynamics and temporal-spatial involvement in organ-specific metastasis have not been investigated. Here we engineered a xenograft model system with a conditional control of the TGF-beta-SMAD signaling pathway and a dual-luciferase reporter system for tracing both metastatic burden and TGF-beta signaling activity in vivo. Strong TGF-beta signaling in osteolytic bone lesions is suppressed directly by genetic and pharmacological disruption of the TGF-beta-SMAD pathway and indirectly by inhibition of osteoclast function with bisphosphonates. Notably, disruption of TGF-beta signaling early in metastasis can substantially reduce metastasis burden but becomes less effective when bone lesions are well established. Our in vivo system for real-time manipulation and detection of TGF-beta signaling provides a proof of principle for using similar strategies to analyze the in vivo dynamics of other metastasis-associated signaling pathways and will expedite the development and characterization of therapeutic agents.

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    • "Following osteoclast maturation, the " vicious cycle " of lytic bone metastasis takes place whereby degradation of the bone matrix by osteoclasts releases various growth factors such as IGFs, TGFβ, EGFs and FGFs, spurring tumor cell growth and further promoting osteoclast activation (Hauschka et al., 1986; Mundy, 2002). Dynamic in vivo imaging coupled with genetic and pharmacological inhibition of the TGFβ pathway showed that TGFβ signaling is most important in the early establishment of breast cancer metastatic lesions (Korpal et al., 2009), and a milestone study by Yin and colleagues demonstrated that blockade of TGFβ signaling in tumor cells inhibits PTHrP secretion and reduces osteolysis (Yin et al., 1999). In addition to inducing RANKL production from osteoblasts to increase osteoclastogenesis , the pro-metastatic function of PTHrP has been attributed to other important functions. "
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