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 surrounding stromal cells that secrete factors favorable for tumor development. We have found that the stromal myofibroblasts are the source of prostaglandin E2, the target of chemopreventative non-steroidal antiinflammatory drugs (NSAIDs). Colorectal cancer cells are also dependent upon the Wnt signal transduction pathway for survival. We will test the hypothesis that NSAIDs, combined with inhibitors of Wnt signaling will be an effective treatment for colorectal cancer using rodent models.
| Pinchuk, Irina V; Beswick, Ellen J; Saada, Jamal I et al. (2011) Human colonic myofibroblasts promote expansion of CD4+ CD25high Foxp3+ regulatory T cells. Gastroenterology 140:2019-30 |
| Powell, D W; Pinchuk, I V; Saada, J I et al. (2011) Mesenchymal cells of the intestinal lamina propria. Annu Rev Physiol 73:213-37 |
| Mifflin, R C; Pinchuk, I V; Saada, J I et al. (2011) Intestinal myofibroblasts: targets for stem cell therapy. Am J Physiol Gastrointest Liver Physiol 300:G684-96 |
| Pinchuk, I V; Mifflin, R C; Saada, J I et al. (2010) Intestinal mesenchymal cells. Curr Gastroenterol Rep 12:310-8 |
| Kosinski, Cynthia; Stange, Daniel E; Xu, Chuanrui et al. (2010) Indian hedgehog regulates intestinal stem cell fate through epithelial-mesenchymal interactions during development. Gastroenterology 139:893-903 |
