Centrosome‐centriole abnormalities are markers for abnormal cell divisions and cancer in the transgenic adenocarcinoma mouse prostate (TRAMP) model

Abstract

We utilized the transgenic adenocarcinoma mouse prostate (TRAMP) model to study the formation of abnormal mitosis in malignant tumors of the prostate. The results presented here are focused on centrosome and centriole abnormalities and the implications for abnormal cell divisions, genomic instability, and apoptosis. Centrosomes are microtubule organizing organelles which assemble bipolar spindles in normal cells but can organize mono-, tri-, and multipolar mitoses in tumor cells, as shown here with histology and electron microscopy in TRAMP neoplastic tissue. These abnormalities will cause unequal distribution of chromosomes and can initiate imbalanced cell cycles in which checkpoints for cell cycle control are lost. Neoplastic tissue of the TRAMP model is also characterized by numerous apoptotic cells. This may be the result of multipolar mitoses related to aberrant centrosome formations. Our results also reveal that centrosomes at the poles in mitotic cancer cells contain more than the regular perpendicular pair of centrioles which indicates abnormal distribution of centrioles during separation to the mitotic poles. Abnormalities in the centriole-centrosome complex are also seen during interphase where the complex is either closely associated with the nucleus or loosely dispersed in the cytoplasm. An increase in centriole numbers is observed during interphase, which may be the result of increased centriole duplication. Alternatively, these centrioles may be derived from basal bodies that have accumulated in the cell's cytoplasm, after the loss of cell borders. The supernumerary centrioles may participate in the formation of abnormal mitoses during cell division. These results demonstrate multiple abnormalities in the centrosome-centriole complex during prostate cancer that result in abnormal mitoses and may lead to increases in genomic instability and/or apoptosis.

Rad21 is required for centrosome integrity in human cells independently of its role in chromosome cohesion

“…It has been argued that centriole engagement not only prevents centrosome re-duplication, but also contributes to the integrity of the centrosome which is important for bipolar chromosome segregation. Mis-regulation of the centrosome cycle significantly impacts human health and is closely associated with tumorigenesis, [12][13][14] developmental problems 15 and aging. 16 Recent work demonstrated that the cohesin complex localizes to centrosomes and spindle poles.…”

Centrosome amplification and the development of cancer

“…Electron microscope images revealed supernumerary centrioles in centrosomes of humans and animal model tumors, including leiomyosarcoma, neuroblastoma, glioma and thymic carcinoid tumors (Friedlander, 1982;Kaneko et al, 1980;Seifert, 1978;Sharp et al, 1981Sharp et al, , 1982Ring, 1982). Subsequent systematic analyses of centrosomes in human breast carcinomas and a mouse model for prostate cancer revealed a range of abnormalities in centrosome structure including: excess number of centrioles, increased pericentriolar material, abnormal centriole orientation, and inverted polarity of centrosome location (i.e., with the centrosome located within the cell in a basal rather than an apical position relative to the nucleus) Schatten et al, 2000). These structural centrosome abnormalities have been implicated as a potential cause of loss of cell and tissue architecture seen in cancer (i.e.…”

“…Centrosome amplification and chromosomal instability can be induced by over-expression of the centrosomal protein pericentrin and by over-expression of the centrosome kinase BTAK/STK15, suggesting that alternative mechanisms may lead to centrosome defects and consequent genomic instability (Pihan et al, 2001;Zhou et al, 1998). In prostate cancer, centrosome amplification has been implicated in the development of abnormal mitoses and CIN facilitating progression to advanced stages of the disease (Ouyang et al, 2001;Pihan et al, 2001;Schatten et al, 2000). Strong support for a direct mechanistic link between centrosome amplification and CIN is suggested by the significant linear correlation between centrosome amplification and the rate of change in karyotype (CIN) seen in human breast tumors .…”

Krüppel-like factor 4 prevents centrosome amplification following γ-irradiation-induced DNA damage

“…The term 'centrosome amplification' is commonly used to describe centrosomes that appear significantly larger than normal (as defined by staining of structural centrosome components, such as g-tubulin, which exceeds that seen in the corresponding normal tissue or cell type), centrosomes that contain an abnormal number of centrioles, or the presence of more than two centrosomes in a single cell (Lingle and Salisbury, 1999;Schatten et al, 2000). Numerous studies have also implicated centrosome amplification as a potential origin of chromosomal instability in the development of a variety of human tumors (Pihan et al, 1998;Ghadimi et al, 2000;Pihan et al, 2001;Sato et al, 2001;Lingle et al, 2002;Weaver et al, 2002;Al-Romaih et al, 2003;Mayer et al, 2003;Pihan et al, 2003;Bennett et al, 2004).…”