THE SIGNIFICANCE OF THE NUCLEAR AND CYTOPLASMIC LOCALIZATION OF METALLOTHIONEIN IN HUMAN LIVER AND TUMOR-CELLS

Metallothioneins ate a group oi low-molecular-weight intracellular proteins present in high levels in fetal mammalian livers, bound to zinc and cop per. They ate also present in two major isoforms in low basal levels in various organs of adults in several species. Although a number of functions have been proposed for metallothioneins, their major biological roles may be in the storage of zinc and copper during rapid growth and develop ment. and also in the detoxification oi certain toxic metals. In adult liver, metallothionein is mainly localized in the cytoplasm, ii is localized also in the hepatocyte nuclei in human fetal liver and fetal and neonatal rat liver, as determined by immunohistochemical staining with a specific metallothionein antibody. Because of its high expression in fetal development, the potential role of metallothioneins in human tumors was investigated. The cellular localization of metallothionein was demonstrated in various human tumors such as thyroid tumors, testicular germ cell carcinoma, bladder transitional cell carcinomas, and salivary gland tumors. in most of these tumor tissues, metallothioneins were found in high levels in nucleus and cytoplasm in both benign and malignant tumors, although the proliferating edge of the malignant tumors showed most intense metallothionein staining. The expression of metallothionein is not universal to all tumor growth, its presence may depend on various factors, such as the type of tumor, cellular origin, morphological heterogeneity, or stage of growth. Human testicular seminomas, which are well differentiated, showed little expression of metallothionein irrespective of the staging, as compared to less well-differentiated embryonal carcinomas. Preliminary studies with DNA flow cytometry on adenocarcinoma of breast acid colon, using a fluorescent antibody to metallothionein, showed that metallothionein was present in the nucleus of the epithelial cells only in the S-phase of the cell cycle. Thus the nuclear presence of metallothionein in tumor cells is indicative of their proliferative activity, and metallothionein staining may be used as a marker of the proliferation index of certain tumors.