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IDENTIFYING INHIBITORS OF PROX1 IN COLORECTAL CANCER

Final Report Summary - PROX1 (IDENTIFYING INHIBITORS OF PROX1 IN COLORECTAL CANCER)

At least 50% of the Western population develops a colorectal tumor by the age of 70, and in about 1 in 10 of these individuals, progression to malignancy ensues (1). The lifetime risk of developing colorectal cancer (CRC) is thus estimated at approximately 5-6%. As a result, CRC is the second leading cause of cancer related morbidity and mortality in Europe (2). Based on the high incidence rate and malignancy of CRC, there is a high need to identify molecules involved in its pathogenesis that can serve as potential novel therapeutic targets.

Activation of the APC/-catenin/Tcf pathway is an initiating event in the majority of human CRCs and the ß-catenin protein is one of the key determinants in the pathogenesis of colon cancer (1). Levels of free ß-catenin are usually strictly controlled in the cell through a multiprotein complex that comprises for example the adenomatous polyposis coli (APC) and the kinases GSK-3 and CKIα. These enzymes are capable of phosphorylating ß-catenin, thus inducing its degradation. Not surprisingly, in about 80% of individuals suffering from the sporadic version of CRC, both APC alleles are mutated and thus inactivated (1). Unfortunately, although activation of the APC/-catenin/Tcf pathway is crucially involved in the vast majority of human CRCs, this signal transduction system is also responsible for the normal proliferation of intestinal crypt cells and thus, its inhibition leads to serious consequences. Alternative targets for therapy must therefore be sought for new treatments of colorectal cancer.

The homeobox transcription factor PROX1 is critical for the establishment of the lymphatic endothelial cell phenotype, retinal progenitor cell differentiation, and pancreas and liver development (3). Importantly, our laboratory previously discovered that PROX1 is overexpressed in approximately 70% of human CRCs as well as in mouse models of intestinal cancer with abnormal ß-catenin/Tcf signaling (4). PROX1 expression is associated with the transition from benign to malignant tumor phenotype, and it is only present in cells with high nuclear ß-catenin content, while in normal colonic and small intestinal epithelium PROX1 is expressed in a rare subpopulation of enteroendocrine cells. We have also found that PROX1 expression is associated with a more malignant phenotype among various human colon adenocarcinoma cell lines, and have shown that suppression of PROX1 inhibits the growth of tumor xenografts, whereas PROX1 overexpression strongly enhances the growth and malignant potential of tumors in a transgenic mouse model of colon cancer (4). Importantly, deleting PROX1 specifically from the gut has no detectable phenotypic consequences, thus showing that this transcription factor serves an ideal target for new therapies.

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