In the murine small intestine, the epithelium renews every five days. This vigorous self- renewing process is controlled by several secreted Wnt factors at the base of the crypt-villus axis. Lgr5/Gpr49 gene is a Wnt target gene that displays a complex expression pattern during embryogenesis, yet expression in most tissues subsides around birth. In adult mice, Lgr5 expression is restricted to rare, scattered cells in multiple tissues including the hair follicles, mammary glands and the intestinal epithelium. In the intestinal epithelium, Lgr5 is expressed throughout the proliferative crypt compartment and has been recently identified as a marker of adult stem cells in small intestine and colon. The cancer stem cell hypothesis postulates that a small reservoir of self-sustaining cells is exclusively able to self-renew and generate the heterogeneous cell population that constitutes the bulk of the tumour. Importantly, Cancer Stem Cells (CSC) not only fuel tumour growth but also tumor metastases. In 2002, Lgr5 was identified as a gene expressed in colon cancer. Therefore, the main goal of this project is to identify colon Cancer Stem Cells by using Lgr5 as a marker and compare the expression profile of this CSC cells with normal adult intestinal Stem Cells. First, I propose to analyse the Lgr5 expression pattern in tumours deriving from the intestinal tract, and compare it with the appropriate non-tumor controls. Following, Lgr5 positive cells will be isolated from fresh tumour suspensions, by antibody-based FACS sorting, and tested for Cancer Stem cell potential. Finally, the expression profile of Lgr5 positive colon Cancer Stem Cells will be compared with the genetic profile of Lgr5 normal intestinal Stem cells, to identify the genes implicated in Stem Cell malignant transformation. The results obtained from these studies would allow identifying potential target cells and target genes for the diagnosis and treatment of colon cancer.
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