Ga. Pihan et al., Centrosome defects can account for cellular and genetic changes that characterize prostate cancer progression, CANCER RES, 61(5), 2001, pp. 2212-2219
Factors that determine the biological and clinical behavior of prostate can
cer are largely unknown. Prostate tumor progression is characterized by cha
nges in cellular architecture, glandular organization, and genomic composit
ion. These features are reflected in the Gleason grade of the tumor and in
the development of aneuploidy, Cellular architecture and genomic stability
are controlled in part by centrosomes, organelles that organize microtubule
arrays including mitotic spindles. Here we demonstrate that centrosomes ar
e structurally and numerically abnormal in the majority of prostate carcino
mas. Centrosome abnormalities increase with increasing Gleason grade and wi
th increasing levels of genomic instability. Selective induction of centros
ome abnormalities by elevating levels of the centrosome protein pericentrin
in prostate epithelial cell lines reproduces many of the phenotypic charac
teristics of high-grade prostate carcinoma. Cells that transiently or perma
nently express pericentrin exhibit severe centrosome and spindle defects, c
ellular disorganization, genomic instability, and enhanced growth in soft a
gar, On the basis of these observations, we propose a model in which centro
some dysfunction contributes to the progressive loss of cellular and glandu
lar architecture and increasing genomic instability that accompany prostate
cancer progression, dissemination, and lethality.