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Cancer Res. 2006 Jun 15;66(12):6327-35.

Bone sialoprotein mediates the tumor cell-targeted prometastatic activity of transforming growth factor beta in a mouse model of breast cancer.

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  • 1Laboratory of Cell Regulation and Carcinogenesis, National Cancer Institute, MD 20892-5055, USA.

Abstract

Transforming growth factor betas (TGF-beta) play a dual role in carcinogenesis, functioning as tumor suppressors early in the process, and then switching to act as prometastatic factors in late-stage disease. We have previously shown that high molecular weight TGF-beta antagonists can suppress metastasis without the predicted toxicities. To address the underlying mechanisms, we have used the 4T1 syngeneic mouse model of metastatic breast cancer. Treatment of mice with a monoclonal anti-TGF-beta antibody (1D11) significantly suppressed metastasis of 4T1 cells to the lungs. When metastatic 4T1 cells were recovered from lungs of 1D11-treated and control mice, the most differentially expressed gene was found to be bone sialoprotein (Bsp). Immunostaining confirmed the loss of Bsp protein in 1D11-treated lung metastases, and TGF-beta was shown to regulate and correlate with Bsp expression in vitro. Functionally, knockdown of Bsp in 4T1 cells reduced the ability of TGF-beta to induce local collagen degradation and invasion in vitro, and treatment with recombinant Bsp protected 4T1 cells from complement-mediated lysis. Finally, suppression of Bsp in 4T1 cells reduced metastasis in vivo. We conclude that Bsp is a plausible mediator of at least some of the tumor cell-targeted prometastatic activity of TGF-beta in this model and that Bsp expression in metastases can be successfully suppressed by systemic treatment with anti-TGF-beta antibodies.

PMID:
16778210
[PubMed - indexed for MEDLINE]
PMCID:
PMC1528715
Free PMC Article

Images from this publication.See all images (7)Free text

Figure 1. 1D11 decreases 4T1 metastasis to the lung following orthotopic implantation.
Figure 2. Metastatic cells recovered from 1D11-treated lungs show persistent morphological changes in culture and elevated Bsp expression  in vitro  and  in vivo .
Figure 3. TGF-β regulates and is correlated with Bsp expression in 4T1-related cell lines  in vitro .
Figure 4. Bsp knockdown suppresses basal and TGF-β-induced invasion through Matrigel.
Figure 5. Bsp knockdown does not affect induction of MMPs by TGF-β, but does reduce local activation of matrix degrading enzymes.
Figure 6. Bsp protects 4T1 cells from complement-mediated cell lysis.
Figure 7. Knockdown of Bsp suppresses metastasis of 4T1 cells to the lung.
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