Centrosome amplification, chromosomal instability and cancer: mechanistic, clinical and therapeutic issues

Cosenza, Marco Raffaele; Krämer, Alwin

doi:10.1007/s10577-015-9505-5

Cited by 65 publications

(70 citation statements)

References 196 publications

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“…This shows that centrosomal abnormality precedes chromosomal abnormality in B-ALL. Other researchers also observed the same results with many other types of neoplasia (37). This shows that centrosomal abnormality may have predictive value in ALL and it may be used as a diagnostic and prognostic marker in this disease.…”

Section: Discussionsupporting

confidence: 70%

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Centrosome Aberration Frequency and Disease Association in B-Acute Lymphoblastic Leukemia

Kerketta

Ghosh

Nadkarni

et al. 2017

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Abstract. Recent developments in genome-wide genetic analysis in B-acute lymphoblastic leukemia (B-ALL) have provided insight into disease pathogenesis and prognosis. B-Recurrent cytogenetic abnormalities such as hyperdiploidy and t(12;21), t(4;10), t(6;10), t(1;19), t(9;22), t(4;11), etc. are common in B-acute lymphoblastic leukemia (B-ALL) and are seen in around 60% of cases (1-3). Hyperdiploidy is the commonest cytogenetic abnormality seen in around 25-30% of childhood B-ALL and is associated with good prognosis. Mechanism of hyperdiploidy and aneuploidy in ALL remains conjectural with four possible mechanisms proposed: i) Initial near haploidy followed by doubling of the chromosomes; ii) Prior tetraploidization with subsequent loss of chromosomes; iii) Sequential gains of chromosomes in consecutive cell divisions; or iv) Simultaneous gain of all additional chromosomes in a single abnormal mitosis (4-6). However, what underlies the initial chromosomal instability is still uncertain.The centrosome is a primary microtubule-organizing center of the cell, and regulates most microtubule-related functions, including transport of macromolecular complexes, positioning of cell organelles, cell motility, cell shape, polarity, and segregation of chromosomes during cell division (7). Each centrosome has a core of two centrioles, cylindrical structures consisting of nine microtubule triplets, surrounded by proteinaceous scaffold of the pericentriolar material .The centrosomes duplicate once per cell cycle and function as spindle poles to mediate the strictly balanced bipolar separation of chromosomes during mitosis (8, 9). Here we studied centrosome proteins α-tubulin, γ-tubulin and pericentrin in patients with B-ALL in order to understand the centrosome aberration role in disease progression.Centrosomal abnormalities lead to chromosomal instability and have been implicated in aneuploidy seen in various malignancies. Centrosomal amplification is the most common abnormality and correlates with the degree of aneuploidy and malignant behavior of tumor (10, 11). Abnormalities of 215

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Section: Discussionsupporting

confidence: 70%

“…This may be due to the association of centrosomal abnormalities with karyotypic abnormalities in neoplasia as many authors have already described in their reports (37). In our study, five patients showed centrosomal abnormalities (p<0.05) with abnormal DNA ploidy (>1.2) but had normal cytogenetics.…”

Section: Discussionsupporting

confidence: 70%

Centrosome Aberration Frequency and Disease Association in B-Acute Lymphoblastic Leukemia

Kerketta

Ghosh

Nadkarni

et al. 2017

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“…Centrosomes are often abnormal in cancer, including ovarian cancer [15–20] and centriolar amplification was recently shown to promote carcinogenesis [21]. Hence, centrosome-regulating proteins have been proposed as targets for therapy [17, 22–27]. Here we report that an unbiased shRNA screen identified STIL as essential for ovarian cancer cell survival.…”

Section: Introductionmentioning

confidence: 80%

“…Centrosomes are often abnormal in cancer cells and centrosome amplification was shown to create chromosomal instability that promotes carcinogenesis and contributes to the aggressive behavior of ovarian cancer [18, 21]. Hence, centrosomal regulating proteins have been considered as targets for cancer therapy [22, 24, 25]. For example, we have previously shown that the centrosomal mitotic kinase SIK2 may be such a target [15].…”

Section: Discussionmentioning

confidence: 99%

Targeting the centriolar replication factor STIL synergizes with DNA damaging agents for treatment of ovarian cancer

Rabinowicz

Mangala²,

Brown

et al. 2017

Oncotarget

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Advanced ovarian cancer is an incurable disease. Thus, novel therapies are required. We wished to identify new therapeutic targets for ovarian cancer. ShRNA screen performed in 42 ovarian cancer cell lines identified the centriolar replication factor STIL as an essential gene for ovarian cancer cells. This was verified in-vivo in orthotopic human ovarian cancer mouse models. STIL depletion by administration of siRNA in neutral liposomes resulted in robust anti-tumor effect that was further enhanced in combination with cisplatin. Consistent with this finding, STIL depletion enhanced the extent of DNA double strand breaks caused by DNA damaging agents. This was associated with centrosomal depletion, ongoing genomic instability and enhanced formation of micronuclei. Interestingly, the ongoing DNA damage was not associated with reduced DNA repair. Indeed, we observed that depletion of STIL enhanced canonical homologous recombination repair and increased BRCA1 and RAD51 foci in response to DNA double strand breaks. Thus, inhibition of STIL significantly enhances the efficacy of DNA damaging chemotherapeutic drugs in treatment of ovarian cancer.

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“…These plausible bipolar spindles function incorrectly, since lagging chromosomes are observed frequently during anaphase [48]. For bipolar spindles with an excess number of centrosomes, merotelic kinetochore-microtubule attachment errors occur easily, resulting in lagging chromosomes [48,66,67,68]. Thus, dysregulation of the number of centrosomes results in chromosome instability.…”

Section: V-src Can Induce Chromosome Instability Generating Genetmentioning

confidence: 99%

Cytokinesis Failure Leading to Chromosome Instability in v-Src-Induced Oncogenesis

Nakayama

Soeda

Ikeuchi

et al. 2017

IJMS

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v-Src, an oncogene found in Rous sarcoma virus, is a constitutively active variant of c-Src. Activation of Src is observed frequently in colorectal and breast cancers, and is critical in tumor progression through multiple processes. However, in some experimental conditions, v-Src causes growth suppression and apoptosis. In this review, we highlight recent progress in our understanding of cytokinesis failure and the attenuation of the tetraploidy checkpoint in v-Src-expressing cells. v-Src induces cell cycle changes—such as the accumulation of the 4N cell population—and increases the number of binucleated cells, which is accompanied by an excess number of centrosomes. Time-lapse analysis of v-Src-expressing cells showed that cytokinesis failure is caused by cleavage furrow regression. Microscopic analysis revealed that v-Src induces delocalization of cytokinesis regulators including Aurora B and Mklp1. Tetraploid cell formation is one of the causes of chromosome instability; however, tetraploid cells can be eliminated at the tetraploidy checkpoint. Interestingly, v-Src weakens the tetraploidy checkpoint by inhibiting the nuclear exclusion of the transcription coactivator YAP, which is downstream of the Hippo pathway and its nuclear exclusion is critical in the tetraploidy checkpoint. We also discuss the relationship between v-Src-induced chromosome instability and growth suppression in v-Src-induced oncogenesis.

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Centrosome amplification, chromosomal instability and cancer: mechanistic, clinical and therapeutic issues

Cited by 65 publications

References 196 publications

Centrosome Aberration Frequency and Disease Association in B-Acute Lymphoblastic Leukemia

Centrosome Aberration Frequency and Disease Association in B-Acute Lymphoblastic Leukemia

Targeting the centriolar replication factor STIL synergizes with DNA damaging agents for treatment of ovarian cancer

Cytokinesis Failure Leading to Chromosome Instability in v-Src-Induced Oncogenesis

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