研究领域

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CEA is a member of a family of cell surface glyocoproteins that are over-expressed in a wide variety of human cancers, including colon, breast and lung cancer. This feature represents the basis for its wide clinical use as a tumor marker. We have cloned genes coding for most of the family members in order to discern their normal functions and to determine the significance of their overexpression for cancer. We discovered that they function as intercellular adhesion molecules and suggested that, when inappropriately expressed at high levels in cells still capable of proliferation, they interfere with other cell surface interactions, leading to a distortion of tissue architecture and a to a block in terminal cellular differentiation. In agreement with this hypothesis, we have shown that CEA expression can block the myogenic differentiation of rodent myoblasts and that this block can be released by peptides representing the adhesive domains of CEA. The cells are left in a quiescent state with continuous proliferation potential, and are particularly susceptible to the acquisition of further oncogenic lesions. It appears, therefore, that CEA-CEA interactions trigger a cellular response which contributes to malignancy. We have shown recently that other types of differentiation are also inhibited by CEA expression, including adipogenic, neuronal and, most importantly, human colonocyte differentiation. In the latter case, human colon cells transfected to overexpress CEA show a loss of cellular polarization and differentiation and a distortion of tissue architecture. In addition, a tissue architecture quality control mechanism known as anoikis, that kills cells not properly attached to their basement membranes by apoptosis, is inhibited. The molecular mechanism for these effects appears to involve a perturbation of integrin-substrate molecule interactions induced by CEA expression. This mechanism is currently under investigation.