Grant: Operating Grant

The protein CEACAM1 is a unique member of a large protein family. A number of functions have been defined for this protein, based on biochemistry and cell biology techniques. We have used genetic techniques to completely eliminate the expression of CEACAM1 from the mouse. The mouse exhibits a number of problems associated with its important functions. One of these is the development of colon cancer once an appropriate triggering event has been initiated. We have recently shown that CEACAM1 plays an important role in the metastatic process; indeed, a specific type of immune progenitor cell that normally expresses CEACAM1 significantly contributes to survival and implantation of the colorectal tumor cells in the liver. We have also observed that expression of a particular form of CEACAM1, CEACAM1-L, in the tumor cells themselves is sufficient to decrease its metastatic abilities. To understand how this works, we will first examine which functions are affected by the dissemination of the tumor cells and which motifs within the CEACAM1-L cytoplasmic domain might be conveying these functions. Then we will examine how CEACAM1-L is involved in the production of an important chemokine mediator responsible for recruitment of immune cells to the site of metastasis. This will be followed by examination of clinical primary colon cancer samples and metastasis samples from patients for CEACAM1-L expression to gauge whether it is a good indicator of disease progression. Finally, we will examine in the wild-type mice and the experimental Cc1-/- mice which types of cells normally expressing CEACAM1 are responsible for responses to the invading metastatic cells. We expect that some of our results could lead to a new treatment option or become a biomarker for the prevention of colon cancer progression in humans.