Mini-reviewCentrosome amplification in tumorigenesis
Section snippets
The centrosome
Centrosomes are organelles which function as microtubule-organizing centers of most animal cells. Besides controlling microtubule-associated processes like cell shape and intracellular transport, they are of crucial importance for the assembly of the mitotic spindle and subsequent cell division. Centrosomes consist of two orthogonally arranged, barrel-shaped centrioles which are embedded in the so called pericentriolar material (PCM; Fig. 1). Centrioles themselves are composed of a central
The centrosome duplication cycle
Cells in G1-phase of the cell cycle harbor a single centrosome with loosely connected centrioles. New centrioles are formed at the proximal part of each of the two pre-existing centrioles upon transition from G1- to S-phase. These newly formed centrioles elongate and mature during S- until late G2-phase, giving rise to two pairs of centrioles – centrosomes – per cell before these enter mitosis. In early mitosis the two centrosomes are separated in order to build up a bipolar mitotic spindle
Mechanisms leading to centrosome amplification
Although the centrosome number is tightly regulated, it is well documented that solid as well as hematologic malignancies often harbor incorrect centrosome numbers [34]. Various mechanisms leading to centrosome amplification have been described (Fig. 2).
One proposed mechanism leading to supernumerary centrosomes is overduplication of centrioles during interphase which may arise by elevated levels of proteins which are involved in the centrosome duplication process. In vitro it has been shown
Supernumerary centrosomes and aneuploidy
Impressively, as early as 1890 David von Hansemann described that aneuploidy is a common feature of cancer cells [57]. This observation was extended at the beginning of the last century by Theodor Boveri, who observed the presence of supernumerary centrosomes and abnormal mitotic figures in sea urchin embryos. His, then proposed, theory that centrosomal defects might cause aneuploidy and cancer is still prevailing [58].
Aneuploidy defines a state of cells with abnormal numbers of chromosomes as
Consequences of supernumerary centrosomes
Since cancer cells are often aneuploid and display elevated centrosome numbers, MT-kinetochore attachment is error-prone in such cells. Besides, supernumerary centrosomes can lead to the formation of multipolar mitotic spindles, an abnormal mitotic arrangement which is believed to result in chromosome missegregation and aneuploidy [34]. Interestingly, in mouse hepatocytes it was shown recently that multipolar cell divisions per se are not necessarily detrimental [67]. A characteristic hallmark
Centrosome amplification and tumorigenesis in Drosophila melanogaster
At first sight it does not seem promising to investigate a condition such as cancer that mainly occurs in higher mammals in an insect model system. On the other hand, since the beginning of the last century numerous scientists have helped to establish flies as one of the genetically most unraveled model systems available. Although the genome of Drosophila melanogaster (Dm) is comprised of only ∼13.600 genes [81], an overall analysis of human disease-associated genes revealed that 62% of these
Centrosome amplification and tumorigenesis in mice
As indicated above, consecutive causal interplays in tumorigenesis are difficult to establish. Despite more than 100 years of intensive efforts, our understanding of tumor initiation and progression is still incomplete, although many deregulated key players have meanwhile been identified. Importantly, mouse knockout or overexpression models provide us with the chance of gaining insights in a defined genetic setting and causal relationships can sometimes be derived.
If the assumption that
Acknowledgment
We apologize to all authors whose work is not cited due to space limitations. This work was supported by the Deutsche Krebshilfe (Grants 108560 and 107739), the Deutsche José Carreras Leukämie-Stiftung (DJCLS R 06/04) and the DKFZ-MOST (Israel) Cooperation in Cancer Research.
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