Gut Stem Cells Multipotent, Clonogenic and the Origin of Gastrointestinal Cancer

Tissue stem cells are multipotent and maybe clonogenic. These characters are similar to those of the earliest progenitor cells of carcinomas. In the gastrointestinal tract, epithelial stem cells exist in the region of the isthmus/neck in the stomach, in the small intestine in the crypt base, just superior to the Paneth cells, and towards the bottom of the crypt in the colon, giving rise to all epithelial cell lineages in all these tissues. Recent reports have revealed that many supposed alterations found in cancer cells are also present in morphologically-normal stem cells. In this context, carcinomas can perhaps be explained as stem cell diseases. To understand the clonal expansion of a single, normal or mutated stem cell brings new insights for not only into the biology of the gastrointestinal tract but also in tumorigenesis in the intestine. In this review, the authors will describe; (1) general aspects of gastrointestinal tract biology, (2) the development of the gastrointestinal tract and molecular factors regulating gut embryogenesis, (3) the proposal that stem cells yield all of the gastrointestinal epithelial cell lineages; the 'Unitarian Theory', and (4) the way in which stem cells, or cancer cells, clonally expand, especially focusing on the two basic models; the 'top-down' theory and the 'bottom-up' concepts. In addition (5) the authors will assess the mechanisms which maintain the crypt stem cell populations, (6) putative stem cell markers, (7) the stem cell niche, thought to be provided by subepithelial myofibroblasts, (8) the plasticity of the adult bone marrow stem cells in relation to gastrointestinal epithelial cells and subepithelial myofibroblasts, and finally (9) molecular mechanisms regulating epithelial proliferation and differentiation.