CENTROSOME DEFECTS AND GENETIC INSTABILITY IN MALIGNANT-TUMORS

Genetic instability is a common feature of many human cancers, This co ndition is frequently characterized by an abnormal number of chromosom es, although little is known about the mechanism that generates this a ltered genetic state, One possibility is that chromosomes are missegre gated during mitosis due to the assembly of dysfunctional mitotic spin dles. Because centrosomes are involved in spindle assembly, they could contribute to chromosome missegregation through the organization of a berrant spindles, As an initial test of this idea, we examined maligna nt tumors for centrosome abnormalities using antibodies to the centros ome protein pericentrin. We found that centrosomes in nearly all tumor s and tumor-derived cell lines were atypical in shape, size, and compo sition and were often present in multiple copies. In addition, virtual ly all pericentrin-staining structures in tumor cells nucleated microt ubules, and they participated in formation of disorganized mitotic spi ndles, upon which chromosomes were missegregated. All tumor cell lines had both centrosome defects and abnormal chromosome numbers, whereas neither was observed in nontumor cells. These results indicate that ce ntrosome defects are a common feature of malignant tumors and suggest that they may contribute to genetic instability in cancer.