MICROENVIRONMENT INFLUENCE ON STEM CELLS: PRE-CARCINOGENESIS FEATURES IN THE LIVER OF TRANSGENIC MMTV-NEU (erbB-2) MICE BEARING MAMMARY TUMOR.

Attention is called to a non-negligible risk in the Regenerative Medicine setting using bone marrow-derived stem cells of inducing a tumor in the organ to be repaired or else in a different organ. Premises for this concern came from a recent research of ours on a transgenic animal model of human mammary carcinoma (MMTV-neu (erbB-2 transgenic mice). In these animals several lobular-zone dependent features of initial liver carcinogenesis were detected. In portal and sub-capsular regions CD34+ cells were seen followed, in time, by extramedullary hemopoiesis. In portal tracts liver oval cells were identified followed by ductular reaction, while portal hepatocytes expressed CK19, AFP and GGT (markers of hepatocytes in the embryo). In the mid-zone and centrolobular regions Large cell Dysplasia was seen. The fetal portal microenvironment might be better suited than that of the adult to the activation of liver cell progenitors. By contrast, dysplasia suggests polyploidy and terminal differentiation. Taken together, these observations might be induced by sustained metabolic stress induced by the tumor on the liver. It is speculated that hemopoietic precursors, recruited by the tumor for angiogenic purposes, find in the liver a permissive environment for their arrest and differentiation. Attention is called for the fact that the final fate of stem/progenitor cells depends on their microenvironment and that currently Cancer is considered as a stem-cell pathology. The conclusion is drawn that the final consequence of the activation of such an ancestral and non-specific system of repair might be diversified according to the final destination of the activated precursors.