Does TGF-b modulate Metastasis of Small Cell Lung Carcinoma
Initial Award Abstract
Tobacco smoking contributes considerably to the development of lung cancers, among which small lung cell carcinoma is a predominant type. It is not the formation of the primary tumor but the dissemination of the tumor due to metastasis is responsible for the severity and the high mortality of many cancers. Tumor cells frequently synthesize high levels of a particular growth factor called transforming growth factor-beta (TGF- ), suggesting that TGF- may provide an advantage to tumor cell behavior. TGF- has a strong ability to regulate the expression of genes that are important in inter-actions of the cells with the surrounding extracellular matrix. In this project, we are studying the influence of the endogenous TGF- expression level on invasiveness and spontaneous metastasis of a small cell lung carcinoma cell line. This type of tumor is a very aggressive and common tumor caused by tobacco smoking. We have now used specific TGF- expression vectors to over express TGF- or abolish its expression (by over expressing dominant negative TGF- mutants) to generate transfected cell lines, all derived from the same parental small cell lung carcinoma line, that either over express high levels of active TGF- , or have a major decrease of endogenous TGF- expression. These cell lines are now ready for evaluation for several parameters in vitro and in vivo that are important for or indicative of invasiveness and metastasis.
This study should allow an evaluation of the effects of alterations of endogenous TGF- expression and the resulting effects on the invasiveness and metastasis of small cell lung carcinoma cells. Insight in the role of autocrine/paracrine effects of endogenous TGF- synthesis in invasiveness and metastasis is not only important for our understanding of metastasis of the many tobacco-related or unrelated cancers, but could also open up TGF- based therapeutic modalities to interfere with metastasis. |