A Clinical Overview of Centrosome Amplification in Human Cancers

Abstract

The turn of the 21st century had witnessed a surge of interest in the centrosome and its causal relation to human cancer development - a postulate that has existed for almost a century. Centrosome amplification (CA) is frequently detected in a growing list of human cancers, both solid and haematological, and is a candidate "hallmark" of cancer cells. Several lines of evidence support the progressive involvement of CA in the transition from early to advanced stages of carcinogenesis, being also found in pre-neoplastic lesions and even in histopathologically-normal tissue. CA constitutes the major mechanism leading to chromosomal instability and aneuploidy, via the formation of multipolar spindles and chromosomal missegregation. Clinically, CA may translate to a greater risk for initiation of malignant transformation, tumour progression, chemoresistance and ultimately, poor patient prognosis. As mechanisms underlying CA are progressively being unravelled, the centrosome has emerged as a novel candidate target for cancer treatment. This Review summarizes mainly the clinical studies performed to date focusing on the mechanisms underlying CA in human neoplasia, and highlights the potential utility of centrosomes in the diagnosis, prognosis and treatment of human cancers.

Novel Piperazine-based Compounds Inhibit Microtubule Dynamics and Sensitize Colon Cancer Cells to Tumor Necrosis Factor-induced Apoptosis

“…The formation of the multipolar spindles was accompanied by appearance of multiple ␥-tubulin and Aurora kinase A staining loci, which is consistent with disruption of centrosome regulation and bipolar spindle formation. Most cancer cells have over-replicated centrosomes (35,36), which are clustered at the poles during mitosis (37); disruption of centrosome clustering by disruption of microtubule spindles by AK301 may prevent the concerted segregation of supernumerary centrosomes and lead to spindle multipolarity (38). These complex, multipolar structures are apparently difficult to resolve because cell division is significantly inhibited even after the removal of AK301.…”

A novel role for the deubiquitinase USP1 in the control of centrosome duplication

“…[4][5][6][7] In fact, centrosome abnormalities, usually increased numbers, are common in human cancers and these changes have been observed at various stages of human cancers. [6][7][8][9] Therefore, the elucidation of the regulatory mechanisms that control centrosome homeostasis is important for understanding a causal relationship between centrosome amplification and human cancers and may lead to more effective anticancer therapies. 10 The USP1 gene encodes a member of the ubiquitin-specific proteases that is a deubiquitinating enzyme (DUB) with His and Cys domains.…”

SAPK pathways and p53 cooperatively regulate PLK4 activity and centrosome integrity under stress

“…Because chromosome missegregation results in both numerical (aneuploidy) and structural (translocations) abnormalities of chromosomes 6 , ablation of the numeral integrity of centrosomes induces chromosomal instability, and thus is considered to be a major cause of carcinogenesis and malignant progression. Indeed, centrosome amplification and the resulting chromosomal instability are common features of human cancers, and correlate with poor clinical outcomes 7,8 . Interestingly, centrosome number is often increased in cancer cells after various stress stimuli including DNA damage, oxidative stress and heat shock [9][10][11] , although the mechanism by which centrosome amplification arises after stress in cancer cells remains obscure.…”