Centrosome defects and genetic instability in malignant tumors

Abstract

Genetic instability is a common feature of many human cancers. This condition is frequently characterized by an abnormal number of chromosomes, although little is known about the mechanism that generates this altered genetic state. One possibility is that chromosomes are missegregated during mitosis due to the assembly of dysfunctional mitotic spindles. Because centrosomes are involved in spindle assembly, they could contribute to chromosome missegregation through the organization of aberrant spindles. As an initial test of this idea, we examined malignant tumors for centrosome abnormalities using antibodies to the centrosome protein pericentrin. We found that centrosomes in nearly all tumors and tumor-derived cell lines were atypical in shape, size, and composition and were often present in multiple copies. In addition, virtually all pericentrin-staining structures in tumor cells nucleated microtubules, and they participated in formation of disorganized mitotic spindles, 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 centrosome defects are a common feature of malignant tumors and suggest that they may contribute to genetic instability in cancer.