Gastrointestinal stem cells in development and cancer.

An enormous body of knowledge about the biology of stem cells and their role in development, tissue homeostasis and cancer formation has been gained in the last 20 years. This review gives a comprehensive overview on knowledge about localization and regulation of normal gastrointestinal stem cells and links it to our understanding of gastrointestinal tumourigenesis and malignant progression in the light of the cancer stem cell concept. The focus is on intestinal stem cells and newly identified stem cell factors, such as the beta-catenin target gene Lgr5. The basis of intestinal stem cell regulation is a permanent crosstalk between epithelial and underlying mesenchymal cells in the intestinal stem cell niche. This crosstalk is mediated by crucial pathways, including the Wnt, Hedgehog (HH), Notch, PI3K and BMP pathways. Disturbances in this fine-regulated interaction can both initiate intestinal tumours and, in association with additional genetic alterations or environmental activation of embryonic processes such as epithelial-mesenchymal transition (EMT), lead to tumour invasion and metastasis.

Epithelial-mesenchymal and mesenchymal-epithelial transitions during cancer progression.

Invasion by colorectal carcinomas is characterized by an epithelial-mesenchymal transition (EMT)-like de-differentiation of the tumor cells. However a re-differentiation towards an epithelial phenotype, resembling a mesenchymal-epithelial transition (MET) is detectable in metastases. This indicates that malignant progression is based on dynamic processes, which can not be explained solely by irreversible genetic alterations, but must be additionally regulated by the tumor environment. The main oncoprotein in colorectal cancer is the Wnt-pathway effector beta-catenin, which is overexpressed due to mutations in the APC tumor suppressor in most cases. EMT of the tumor cells is associated with a nuclear accumulation of the transcriptional activator beta-catenin, which is reversed in metastases. Nuclear beta-catenin is involved in two fundamental processes in embryonic development: EMT and stem cell formation. Accumulating data demonstrate that aberrant nuclear expression of beta-catenin can confere these two abilites also to tumor cells. The unusual combination of EMT with stem cell competence might result in a migrating tumor stem cell, which drives tumor invasion and metastasis.