Colorectal cancer (CRC) is the second leading cause of cancer deaths in the western world. Identification of genetic factors that influence CRC risk can be used to characterize the molecular mechanisms underlying CRC development, and to predict an individual's CRC risk. Signaling between the epithelial and stromal compartments of the mammalian intestine is essential for maintenance of gut homeostasis and the prevention of diseases such as inflammation and cancer. Our previous studies have focused on the secretory phospholipase A2 gene Pla2g2a, which has been identified as a susceptibility gene for intestinal cancer. Importantly, Pla2g2a is not a `classical'oncogene or tumor suppressor gene that functions in a cell-autonomous manner, but rather affects epithelial - stroma interactions, probably through modulation of inflammatory responses. We have demonstrated that Pla2g2a confers resistance to inflammation-induced colon cancer using various mouse models (Muc2-deficiency, IL-10-deficiency), in addition to its tumor suppressive effects in ApcMin/+ mice and in an AOM carcinogen-induced model of colon tumor development. Characterization of the effects of Pla2g2a by comparison of genome-wide expression profiles from healthy (non-neoplastic) colon of Pla2g2a- `knockout'and Pla2g2a-transgenic mice confirmed its effects on inflammation, and revealed Runx1 as its major target. As Runx1 plays a key role in differentiation of hematopoietic cells, such as Foxp3-positive regulatory T cells (TR), these data imply that genetic predisposition to colon cancer is influenced by factors that mediate gut immune homeostasis. The central hypothesis of this application is that Runx1 is a suppressor of intestinal cancer whose activity is regulated by Pla2g2a, and that expression of Runx1 underlies the tumor resistance of Pla2g2a in mouse models. Our general, long-term objectives are to reduce CRC mortality rates by characterizing the mechanisms through which epithelial - stroma interactions mediate gut immune homeostasis and modulate colon tumor development. The goal of the specific research proposed here is the pathologic characterization of colon tumor development, initiated by genetic modification of epithelial or stromal immune cells that determine gut homeostasis, in particular by making use of Pla2g2a-transgenic and Runx1-conditional-knockout mice.
We hope to reduce mortality rates for colorectal cancer by secondary prevention by characterizing the mechanisms through which epithelial - stroma interactions mediate gut immune homeostasis and modulate colon tumor development. In this project we will use genetically engineered mouse models of GI immune cell cancer susceptibility to identify biomarkers that can be used in the early detection and prevention of colorectal cancer.
| Fijneman, Remond J A; Anderson, Rebecca A; Richards, Ethan et al. (2012) Runx1 is a tumor suppressor gene in the mouse gastrointestinal tract. Cancer Sci 103:593-9 |
