[Growth factors and intestinal cancers]

This review focuses on the growth factors (primarily IGFs, TGF-alpha and TGB-beta) that control both proliferation and differentiation of the normal intestinal epithelial cells and their involvement in intestinal tumorigenesis. Integrity of the digestive tissue is dependent on continuous coordination between cell growth and maturation along the crypt- villus axis. Beyond an intricate network of various regulatory molecules, such a regulation is essentially in close connection with the opposite biological effects delivered on a same target cell by TGF-alpha and TGF-beta. Growth factors act via regulatory autocrine/paracrine loops that are physiological means to deliver biological signals throughout the normal gut tissue. During tumorigenesis, cell progressively lose their sensitivity towards such extracellular regulatory loops. TGF-alpha insensitivity is linked to constitutive activation of intracellular pathways that induce uncontrolled cell growth. The incapacity to respond to TGF-beta that is due to an alteration of its intracellular pathway does not allow the negative regulation of cell proliferation or the induction of cell differentiation. Concurrently, the disappearance of an IGF-II extracellular autocrine loop appears to be correlated with cells maintained in an undifferentiated state. These alterations lead to a break between the metabolic pathways involved in the delicate control of the proliferation/differentiation balance. This leads to an unscheduled increase of positive proliferative signals which are responsible for an uncoordinated epithelial cell growth that favour tumor cell clone outgrowth. From these experimental data, essentially obtained in vitro, we propose a tentative colorectal tumorigenesis model that links both growth factor pathways and genetic (oncogenes and tumor suppressor genes) alterations. However, such a model only represents a part of the multiple cell and molecular interactions that are set in action in vivo. It remains to decipher their consistency in order to improve new therapeutic strategies.