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Metastasis is driven by sequential elevation of H-ras and Smad2 levels

Nature Cell Biology volume 4, pages 487–494 (2002)Cite this article

Abstract

Metastasis is a multistep process that involves local tumour invasion followed by dissemination to, and re-establishment at, distant sites. Here we show that during multistage tumorigenesis, discrete expression thresholds of activated Smad2 and H-ras are sequentially surpassed, driving tumour progression through distinct phases from a differentiated squamous carcinoma to a motile invasive stage, followed by an overt change from epithelial to mesenchymal cell type, finally culminating in metastatic tumour spread. Smad2 activation alone induces migration of tumour cells. Elevated H-ras levels, however, are required for nuclear accumulation of Smad2, both of which are essential for the epithelial–mesenchymal transition (EMT). Having undergone EMT, fibroblastoid carcinoma cells with elevated levels of activated Smad2, gain the capability to spread to a wide variety of tissues by a further increase in Smad2 expression. These findings have far-reaching implications for the prevention of tumour growth, invasion and metastasis.

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Figure 1: Smad2 activation is elevated in invasive tumour cells.
Figure 2: Co-expression of H-ras and Smad2 is sufficient to induce EMT of squamous carcinoma cells.
Figure 3: Smad2 and/or Smad3 cooperate with H-ras to induce EMT of squamous carcinoma cells.
Figure 4: Smad2 inhibits proliferation but is necessary for the EMT and for tumour cells to become invasive.
Figure 5: Expression of Smad2dom.act augments metastasizing capability of spindle tumour cells.
Figure 6: Spindle, but not squamous, carcinoma cells show nuclear localization of phosphorylated Smad2 in vivo.

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Acknowledgements

This work was supported by grant K01 CA84244 from the NCI.

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Author notes

  1. Martin Oft

    Present address: Department of Oncology, DNAX Research Institute, 901 California Avenue, Palo Alto, California, 94304, USA

Authors and Affiliations

  1. University of California at San Francisco Comprehensive Cancer Center, Box 0875, San Francisco, 94143-0875, California, USA

    Martin Oft, Rosemary J. Akhurst & Allan Balmain

  2. Onyx Pharmaceuticals, 3031 Research Drive, Building A, Richmond, California, USA

    Martin Oft, Rosemary J. Akhurst & Allan Balmain

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Correspondence to Allan Balmain.

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Oft, M., Akhurst, R. & Balmain, A. Metastasis is driven by sequential elevation of H-ras and Smad2 levels. Nat Cell Biol 4, 487–494 (2002). https://doi.org/10.1038/ncb807

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