Phenotypic transitions within the category of human cell lung cancer (SCLC) and, potentially, between SCLC and forms of non- SCLC lung cancer, may play a vital role in tumor progression events in patients with these tumors. These cellular events also provide clues to the histogenic link between SCLC and non-SCLC lung tumors. Specifically, loss of neuroendocrine properties in SCLC cells and/or acquisition of features of large cell undifferentiated lung cancer correlates with emergence of some characteristics of treatment resistance. SCLC cells with such transitions (""""""""variant"""""""" SCLC cells) often have amplified and highly expressed myc family genes. The current proposal is based on initial data that insertion of the v-Ha-ras gene into """"""""variant"""""""" SCLC cells pushes the phenotype towards large cell carcinoma while other SCLC phenotypes either have no changes or differentiate more towards endocrine cells. The work will explore: (a) the role of complementation between myc and ras oncogenes in the progression of """"""""variant"""""""" SCLC to non-SCLC phenotypes by co-introduction of myc and ras genes into SCLC cells and by use of antisense RNA to the c-myc gene; (b) what gene expression events, such as those for known growth factors, may be induced by ras genes to change SCLC towards the non- SCLC phenotype; (c) how ras gene mutations map with respect to the different cell phenotypes constituting human lung carcinomaas; and (d) what signal transduction events are activated by ras genes in SCLC cells and how they differ among lung carcinoma cell types with different phenotypic responses. The results should help clarify molecular events underlying tumor progression and histogenesis events in lung cancer and increase understanding of the role of ras genes in normal and neoplastic cells.
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