Crucial role for the inactivation of positioning gene in epithelial transformation

Abstract

1795

A consistent hallmark of malignancy is tissue disorganization: carcinoma cells undergo uncontrolled, disordered cell growth and overcome the constraint of epithelial structure. Likely, alterations of the genes and pathways controlling epithelial cell organization and surface positioning are necessary for morphological transformation in cancer. We use the formation of the first epithelium in mammalian embryos, the primitive endoderm, as a model system to study genes and pathways that are critical for the surface positioning and organization of epithelial cells. In embryoid bodies formed from mouse embryonic carcinoma (F9) and stem (ES) cells, we found that differentiated endoderm cells were able to sort to the surface when they are mixed with undifferentiated cells, indicating that surface positioning is an intrinsic property of epithelial cells. Disabled-2 (Dab2) is involved in endoderm development and a candidate tumor suppressor of ovarian cancer. When Dab2 expression was eliminated, the differentiated endoderm epithelial cells were no longer located on surface, rather were but distributed throughout the interior of the embryoid bodies, indicating Dab2 directs the surface positioning of the epithelial cells. Similarly, loss of Dab2 is common (more than 80%) in ovarian epithelial cancer and correlates closely with morphological transformation of ovarian surface epithelia. We conclude that inactivation of gene(s) controlling epithelial surface positioning and organization, such as DAB2, is a critical component in carcinogenesis.