Minichromosome maintenance proteins as biological markers of dysplasia and malignancy

Dysplasia, an intermediate stage in the progression from normal tissue to neoplasia, is defined morphologically by a loss of normal orientation between epithelial cells, with changes in cellular and nuclear shape and size. However, little is known about the functional properties of dysplastic cells, including their replicative state, largely due to a lack of available biological markers. We have used novel antibodies against minichromosome maintenance (MCM) proteins to examine the proliferative status of a range of histological lesions and to characterize dysplastic cells in functional terms. Immunoperoxidase staining was used to localize the MCM proteins, components of the prereplicative complex that is essential for initiating eukaryotic DNA replication. These proteins are down-regulated in cells undergoing differentiation or quiescence and, thus, serve as specific markers for proliferating cells. In normal and some reactive tissues, MCM expression was present only in restricted proliferative compartments, consistent with our published findings in the uterine cervix. In dysplastic and malignant tissues, in contrast, MCM proteins were expressed in the majority of cells, extending to surface layers of dysplastic stratified epithelia. In carcinomas, the frequency of expression of MCM proteins showed an inverse correlation with the degree of tumor differentiation. Thus, we suggest that dysplastic cells may be characterized in functional terms as remaining in cell cycle, due to deregulation of normal controls over cell proliferation. Antibodies against MCM proteins have potential clinical applications, for example, in the assessment of tumor prognosis in histological sections and the identification of proliferating cells in clinical samples using biochemical or cytological assays.