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Science Signaling  10 Nov 2009:
Vol. 2, Issue 96, pp. ec358
DOI: 10.1126/scisignal.296ec358

To visualize tumor cell mobility in vivo, Giampieri et al. (see also Matise et al.) induced tumor formation in mice by injecting MTLn3E mammary carcinoma cell lines expressing various fluorescent fusion proteins into mammary fat pads. Intravital imaging revealed that a subset of tumor cells that were closely packed and had cell-cell junctions moved as groups, a type of movement referred to as cohesive or collective. In contrast, tumor cells with “amoeboid,” amorphous morphology tended to move singly and more rapidly than did cells showing cohesive movement. Signaling through the transforming growth factor–β (TGF-β) pathway can promote cancer cell motility and metastasis through the activation and nuclear translocation of the Smad family of transcription factors. The activation status of the TGF-β signaling pathway was determined in vivo with two tumor cell lines in which nuclear accumulation of Smad2 or the fluorescence produced by a reporter for Smad3 transcriptional activity could be assessed. Tumor cells that moved singly showed nuclear localization of Smad2 and transcriptional activity, whereas those moving collectively showed cytoplasmic localization of Smad2 and no transcriptional activity. To inhibit or activate the TGF-β pathway in vivo, tumors were created from cell lines expressing a dominant-negative, green fluorescent protein (GPF)–tagged TGF-β type II receptor (TGFβRDN-GFP) or overexpressing TGF-β1, respectively. Tumor cells expressing TGFβRDN-GFP preferentially moved collectively and metastasized by spreading to lymph nodes. In contrast, tumor cells overexpressing TGF-β1 showed increased single cell motility and metastasized by entering the blood. Thus, TGF-β signaling causes breast cancer cells to switch from collective to single cell movement and promotes metastasis by hematogenous rather than lymphatic spread.

S. Giampieri, C. Manning, S. Hooper, L. Jones, C. S. Hill, E. Sahai, Localized and reversible TGFβ signalling switches breast cancer cells from cohesive to single cell motility. Nat. Cell Biol. 11, 1287–1296 (2009). [PubMed]

L. A. Matise, M. W. Pickup, H. L. Moses, TGFβ helps cells fly solo. Nat. Cell Biol. 11, 1281–1284 (2009). [PubMed]

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