Correlation between centrosome abnormalities and chromosomal instability in human pancreatic cancer cells

Chromosomal instability, characterized by abnormal numbers or structures of chromosomes, is a common feature of human cancers, but the mechanisms behi nd these changes are still unclear. Since centrosomes play a pivotal role i n balanced chromosomal segregation during mitosis, we attempted to investig ate the association between centrosorne abnormalities and chromosomal insta bility in a large number of human pancreatic cancer cell lines. Immunofluor escence microscopy revealed centrosomes that were highly atypical with resp ect to their size, shape, and number in most cell lines. These abnormal cen trosomes contributed to the assembly of multipolar spindles, resulting in d efective mitosis and chromosome mis-segregation. Interestingly, a high freq uency of centrosome defects inversely correlated with the growth rate of ce lls in culture. Fluorescence in situ hybridization revealed a dramatic vari ation of chromosome numbers in cell lines with the defective centrosome phe notype. Furthermore, a significant positive correlation existed between the level of centrosome defects and the level of chromosomal imbalances. These results indicate that centrosome abnormalities can lead to spindle disorga nization and chromosome segregation errors, which may drive the accumulatio n of chromosomal alterations. Thus. defects in centrosome function ma!: be an underlying cause of genetic instability in human pancreatic cancers. (C) 2001 Elsevier Science Inc. All rights reserved.