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Molecular and Cellular Biology, February 2004, p. 1540-1559, Vol. 24, No. 4
0270-7306/04/$08.00+0     DOI: 10.1128/MCB.24.4.1540-1559.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Invasion of Normal Human Fibroblasts Induced by v-Fos Is Independent of Proliferation, Immortalization, and the Tumor Suppressors p16INK4a and p53

Linda A. Scott, J. Keith Vass, E. Kenneth Parkinson, David A. F. Gillespie, Joseph N. Winnie, and Bradford W. Ozanne*

Beatson Institute for Cancer Research, Cancer Research UK Beatson Laboratories, Glasgow G61 1BD, United Kingdom

Received 25 July 2003/ Returned for modification 26 August 2003/ Accepted 3 November 2003

Invasion is generally perceived to be a late event during the progression of human cancer, but to date there are no consistent reports of alterations specifically associated with malignant conversion. We provide evidence that the v-Fos oncogene induces changes in gene expression that render noninvasive normal human diploid fibroblasts highly invasive, without inducing changes in growth factor requirements or anchorage dependence for proliferation. Furthermore, v-Fos-stimulated invasion is independent of the pRb/p16INK4a and p53 tumor suppressor pathways and telomerase. We have performed microarray analysis using Affymetrix GeneChips, and the gene expression profile of v-Fos transformed cells supports its role in the regulation of invasion, independent from proliferation. We also demonstrate that invasion, but not proliferation, is dependent on the activity of the up-regulated epidermal growth factor receptor. Taken together, these results indicate that AP-1-directed invasion could precede deregulated proliferation during tumorigenesis and that sustained activation of AP-1 could be the epigenetic event required for conversion of a benign tumor into a malignant one, thereby explaining why many malignant human tumors present without an obvious premalignant hyperproliferative dysplastic lesion.

* Corresponding author. Mailing address: Beatson Institute for Cancer Research, Garscube Estate, Switchback Rd., Glasgow G61 1BD, United Kingdom. Phone: 44 (0)141 330 3971. Fax: 44 (0)141 330 6426. E-mail: b.ozanne{at}beatson.gla.ac.uk.

Molecular and Cellular Biology, February 2004, p. 1540-1559, Vol. 24, No. 4
0022-538X/04/$08.00+0     DOI: 10.1128/MCB.24.4.1540-1559.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



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