Invasion of normal human fibroblasts induced by v-Fos is independent of proliferation, immortalization, and the tumor suppressors p16INK4a and p53.
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/p16(INK4a) 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.
Scott
Linda A
LA
Beatson Institute for Cancer Research, Cancer Research UK Beatson Laboratories, Glasgow G61 1BD, United Kingdom.
Vass
J Keith
JK
Parkinson
E Kenneth
EK
Gillespie
David A F
DA
Winnie
Joseph N
JN
Ozanne
Bradford W
BW
D000818:Animals; D002455:Cell Division; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000473:pathology*; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000378:metabolism*; D004249:DNA Damage; D066246:ErbB Receptors / Q000235:genetics / Q000378:metabolism; D005347:Fibroblasts / Q000378:metabolism* / Q000473:pathology*; D020869:Gene Expression Profiling; D006801:Humans; D007621:Karyotyping; D051379:Mice; D009361:Neoplasm Invasiveness / Q000235:genetics / Q000473:pathology*; D016761:Oncogene Proteins v-fos / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D019098:Telomerase / Q000235:genetics / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*; D015854:Up-Regulation; D014945:Wound Healing
D019941:Cyclin-Dependent Kinase Inhibitor p16; D016761:Oncogene Proteins v-fos; D016159:Tumor Suppressor Protein p53; D066246:ErbB Receptors; D019098:Telomerase