Cyclooxygenase (COX) inhibitors lower the risk of colorectal cancer (CRC) and inhibit tumor growth in animal and cell culture models. However, their efficacy in treating existing CRC remains controversial. Previous research in our laboratory has demonstrated that stromal colonic myofibroblasts (CMFs), and not epithelial cells are the principal COX-2 expressing cells in human colonic adenomas and adenocarcinomas. Wnt/ catenin signaling is a crucial pathway for the development of CRC and over 90% of sporadic colorectal adenocarcinomas harbor activating mutations along this axis. Elevated PGE2 levels due to increased COX-2 activity augments 13-catenin stability. The chemoprophylactic effect of COX inhibitors in reducing adenomas in humans and in mouse models can be partly attributed to their ability to suppress Wnt signaling. We have isolated CMFs from normal human colonic tissue and colorectal adenocarcinomas and have identified distinct phenotypic differences between them. We hypothesize that CMF-derived PGE2 regulates Wnt/f3-catenin/TCF signaling within the malignant epit helium by regulating the stability, nuclear translocation and transcriptional activity of /3- catenin.
The overall goal of this project is to develop more effective therapeutic regimens for the treatment of colorectal cancer. These regimens will target not only malignant epithelial cells of the tumor, but also the cancer stem cells responsible for tumor recurrence and the stroma that nurtures tumor progression and the cancer stem cell niche.
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