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Role of PTEN in the Tumor Microenvironment

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Final rept. 15 May 2007-14 May 2010

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Recent scientific advances have revealed that a malignant tumor can be viewed as an organ consisting of different types of interacting cells. Different tumor cell types play different roles in the growth and development of the tumor and thus in the end, all cells within the tumor may help pave the way for further tumor growth in a patient with cancer. Current work in the field indicates that fibroblasts surrounding breast cancers are particularly important for cancer progression, but no one knows why. Our experimental approach to this problem is a direct one we targeted the mutation of genes in stromal fibroblasts surrounding the tumor in order to learn whether these genes are important for cancer progression. Using this approach, we have shown that the PTEN gene in fibroblasts is a major gene involved in suppressing epithelial breast cancers. In order to understand how PTEN works in fibroblasts, we measured the immediate and long-term consequences of PTEN mutation on the biology of all the cells surrounding the tumor, including the tumor cells themselves, as well as the matrix that holds these cells together. Because the entire system is so complex, we studied how the PTEN gene behaves as a tumor suppressor by developing extremely detailed three dimensional images of tumors where each image is annotated with detailed cancer related molecular information. From this work we were able to quantify major and minor changes in the extracellular matrix and cells in the microenvironment. We showed that Pten function in stromal fibroblasts is involved in reprogramming the entire tumor microenvironment to suppress mammary epithelial tumors. We anticipate that this work will lead to the design of novel therapeutic strategies that target fibroblasts and that could be used in combination with current therapies that target epithelial cells to stop tumor growth and prevent reoccurrence of metastasis.

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  • Medicine and Medical Research

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