The long term goal is to elucidate the processes by which mitogenic signals are relayed intracellularly, and to apply this information to understanding how normal growth control is deregulated enabling the progression of lung cancer. Among the differences between normal and tumor lung cells is that the tumor cells secrete increased concentrations of growth factors, which in some instances drive the increased growth rate of the tumors. Thus one of the mechanisms by which normal lung tissue becomes tumorigenic involves increased concentrations of growth factors. However, increased concentrations of growth factors alone are probably not enough to cause lung tumors, since chronic stimulation of tissue culture cells with high levels of growth factors does not usually lead to transformation. More often, cells become transformed when they overexpress and/or harbor mutations within their growth factor receptors. The short-term goal, to be addressed in this research proposal, is to test whether progression of normal lung cells to the malignant state involves both the increased production of growth factors and the mutation and/or overexpression of growth factor receptors. The first specific aim will define the incidence of overexpression and mutation of known growth factor receptors, while the second specific aim will focus on identifying novel lung-specific receptor tyrosine kinases. In the third specific aim, the biological significance of the first two specific aims will be tested. The mutant and novel receptors will be expressed in normal lung tissue to test whether they act as oncogenes. The effect of growth factor stimulation on the ability to transform will also be determined. Finally, we will test the contribution of the identified growth factor receptors to the progression of lung cells from the premalignant to the tumorigenic state. The direct benefit of understanding the role of growth factors and their receptors in the progression of lung tumors will significantly contribute to both prognosis of the stage of a lung tumor, as well as the treatment and management of lung tumors.
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