Zentrosomendefekte korrelieren mit Aneuploidie und implizieren einen eigenen Karzinogenesemechanismus beim kolorektalen Karzinom

Abstract

Measurement of the nuclear DNA content allows classification of human cancers as either diploid or aneuploid. To gain further insight into mechanisms of aneuploidy, we compared the cytogenetic profile of mismatch-repair deficient diploid versus mismatch-repair proficient aneuploid colorectal carcinoma cell lines using comparative genomic hybridization (CGH) and spectral karyotyping (SKY). Aneuploid carcinomas, most of which had p53 tumor suppressor gene mutations, revealed an average of 19 chromosomal imbalances per cell line. Such numerical aberrations were exceedingly scarce in the diploid tumors. This pattern of chromosomal aberrations is consistent with a mechanism involving the impairment of chromosome segregation fidelity during mitotic cell division. In support of this idea, we demonstrate the exclusive occurrence of centrosome amplification and instability in all of the aneuploid tumor cell lines analyzed. Of note, all diploid tumors contained centrosomes that were functionally and structurally indistinguishable from those in normal human fibroblasts. Due to the observed differences in centrosomes between these two classes of tumors, we performed toxicity assays using the microtubule-depolymerizing drugs nocodazole and griseofulvin. Our results revealed that the aneuploid tumor lines had an increased sensitivity to these reagents compared with diploid tumors and normal controls. Our observations support the notion that the integrity of the centrosome plays a central role in the development of aneuploidy and defines this particular pathway of carcinogenesis.