EIF-4E and Metastasis in Lung Cancer

The expression of high levels of the eukaryotic initiatipn factor eIF-4E Is associated with cancer development and has been shown In a number of systemsl to playa causal role In the biology of cancer cells. Examination of two widely studied lung cancer cell Unes indicates that this is true for these cell lines and may Indeed be important for their biological behaviqr. This proposal seeks to study the effect of high 4E levels on the metastatic capacity of these celllln~.lndeed the cell lines will be extensively examined for altered metastatic capacity under condlt'lons of high or low levels of 4E expression using antisense technology. Likewise, the cells willal$o be examined when the 4E binding protein (4EBP)expression has been restored in these cells. Both ,pproaches result In lowered 4E functional activity which can have a major Influence on the expre~slon of mRNAsthat are sensitive to 4E levels.Manyof these genes are oncogenes, growth regulatory ~enes, or angiogenesis factors.Thus many of the mediators of malignancy can be affected at the level of translation. These aspects will be investigated in terms of invasion and metastasis. Once a suitable 'model system has been developed a search for genes which are altered in their expression in met+ ver.us met. cells will be done using cDNAarrays. Anovel aspect of this search is that the expression pf genes sensitive to changes in 4E levels will also be examined using polysome gradients. Th;s appr~ach directly examines mRNAsthat exhibit altered translation efficiencies when eIF-4Efunctionalleve:ls are affected. This search will Identify both known and unknown genes that could playa specific role in lung cancer metastasis. Finally, a scheme to selectivly target tumor cells expressing high ,evels of 4E is described. The approach Is designed to utilize the high expression of 4E in tumo~cells as a means of controlling the expression of a tumor suicide gene ( the herpesvirus thymidine kirasel Ganciclovir system). The suicide gene would be engineered to be efficiently expressed only in cell~ expressing high 4E ( I.e. the tumor cells). Another approach using a 4E sensitive promoter is also de$cribed.