PROTEINS OF THE INTERMEDIATE FILAMENT CYTOSKELETON AS MARKERS FOR ASTROCYTES AND HUMAN ASTROCYTOMAS

There is a pressing need for a more accurate system of classifying human astrocytomas, one that is based on morphologic characteristics and that could also make use of distinctive biochemical markers. However, little is known about the phenotypic characteristics of astrocytomas. Recent studies have shown that the expression of proteins comprising the intermediate filament (IF) cytoskeleton of astrocytic cells is developmentally regulated. It is our hypothesis that this changing protein profile can be used as the basis of a system for clearly and objectively classifying astrocytomas. A spectrum of human astrocytomas has been examined by immunofluorescence microscopy employing antibodies to several IF structural subunit proteins (GFAP, vimentin, and keratins) and an IF-associated protein, IFAP-300kDa. These proteins occupy unique temporal niches in the cytogenesis of the astrocytic cells: keratins in cells of the neuroectoderm; vimentin and IFAP300-kDa in radial glia and immature glia; GFAP in mature astrocytes; and vimentin in some mature astrocytes. In agreement with previous reports, our immunofluorescence studies have revealed both GFAP and vimentin in all astrocytoma specimens. Two new observations, however, are of particular interest: IFAP-300kDa is detectable in all astrocytic tumors, and the proportion of keratin-containing cells present in the astrocytomas is in direct relationship to the degree of the malignancy. Because IFAP-300kDa is not present in either normal mature or reactive astrocytes, this protein appears to represent a specific marker of transformed (malignant) astrocytes. If it is presumed that higher malignancy grades represent the most dedifferentiated cellular state of the astrocytes, the presence of keratin-containing cells is not totally unexpected, given the ectodermal (epithelial) origin of the CNS. Specific developmentally regulated proteins of the IF cytoskeleton thus appear to hold great potential as diagnostic markers of astrocytomas and as tools for investigating the biology of these tumors.