ABSTRACT
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.
Molecular pathways executing the “trophic sentinel” response in HPV-16 E7-expressing normal human diploid fibroblasts upon growth factor deprivation
