Expression of the T24ras oncogene induces malignancy (tumor growth, invasion and metastasis) in cloned rat embryo fibroblasts (CREF T24). In CREF T24, the rate of phosphorylation of eukaryotic translation initiation factor 4E (elF-4E) is increased, resulting in increased protein synthesis rates. We have recently shown that reducing the protein levels of elF-4E in CREF T24 (AME line) markedly decreases soft-agar colonization, increases tumor latency periods and increases tumor doubling times without significantly altering monolayer growth. In this study, cells with reduced elF-4E had delayed and reduced invasiveness and decreased experimental metastasis. Furthermore, reduced elF-4E levels correlated with decreased expression of the metastasis-associated 92-kDa collagenase type-IV and exon-6 variants of the CD44 adhesion molecule [CD44(6v)]. Reduced elF-4E levels correlated inversely with increased levels of the putative metastasis-suppressor protein nm23. Cell lines established from AWE tumors and lung metastases exhibited increased levels of elF-4E protein and protein synthesis rates compared to the AWE line. Tumor-derived AS4E had the shortened tumor latency periods of CREF T24 but displayed the slow tumor-growth rates of AWE.Tumor-derived AS4E exhibited the metastatic capacity of CREF T24 controls. Furthermore, tumor-and lung-nodule-derived AS4E expressed levels of CD44 (6v) and the 92-kDa collagenase type IV comparable to CREF 124 and displayed reduced levels of nm23 relative to AWE. These results demonstrate that elF-4E is an important effector molecule involved in oncogenic p2 I '%nduced malignant transformation.

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