Genetic Analysis Of Specialized Tumor Associated Macrophages And Tumor Associated Fibroblast

Download or read book Genetic Analysis of Specialized Tumor Associated Macrophages and Tumor Associated Fibroblast written by Jeff Anderson and published by . This book was released on 2008 with total page 34 pages. Available in PDF, EPUB and Kindle. Book excerpt: Abstract: Tumor associated macrophages (TAMs) perform various task that are essential for tumor growth, angiogenesis, metastasis, and tumor invasion. Growth factors, chemokines, cytokines and the extra cellular matrix in the tumor microenvironments signal the TAMs to perform these tasks. The tumor microenvironment is not homogeneous and can be classified into several distinct regions such as sites of tumor invasion, perivascular, hypoxic and stromal regions. Each of these sites likely has different cytokines and signaling molecules in their microenvironment that might signal and direct the function of TAMs. The purpose of this project is to isolate and analyze TAMs from distinct tumor regions to gain a better understanding of the mechanism behind the specialized role of these TAMs. As a first step towards this goal, micro array analysis was conducted on flow sorted TAMs and developmental macrophages expressing yellow fluorescence protein (YFP). Micro array data from age matched developmental macrophages was compared to TAMS from early, premalignant stage of breast cancer, and late stage metastatic breast cancer to find the genes which were upregulated in TAMs versus developmental macrophages, and in late stage TAMs versus TAMs from the earlier premalignant stage of breast cancer. From this list of genes upregulated in TAMs, candidate cell surface macrophage markers that could be used to classify TAMs based on there association with one of the distinct tumor microenvironments was selected. These candidate markers will be used to visualize macrophages associated with different regions within the tumor microenvironment using immuno-staining of tumor sections. In preliminary work, CD16 was selected as one potential candidate gene that was upregulated late in tumor development compared to earlier stages. Immunostaining indicated CD16 was expressed on a set of macrophages near blood vessels near the tumors, but not in macrophages located within tumors. Further evaluation of these markers would facilitate isolation of different subsets of macrophages within tumor and understanding the function of these macrophages in tumor microenvironment. Another major cell group involved in all the changes in the tumor microenvironment discussed is the fibroblast. Originally the fibroblast inhibits the growth of the tumor. However through natural selection tumors evolve to change the microenvironment and like wise the function the fibroblast are performing to aid in tumor progression rather than suppress tumor progression. These fibroblast reprogrammed by the tumor cells are called tumor associated fibroblast TAFs. TAFs aid in tumor progression by angiogenesis, immune suppression, and matrix remodeling, providing growth and anti apoptotic factors and aid in metastasis by recruiting TAMs. A key gene involved with this is IKK. It is our hypothesis that ablating IKK in the fibroblast will lead to a reduction of tumor growth.