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.

Keywords: Boveri hypothesis; aneuploidy; aurora kinase; centrosome; chromosomal instability; p53.

Figure 1

Model supporting centrosome amplification as a cause of carcinogenesis. Centrosome amplification has been detected in broad range of tumours, both solid and haematological, and has been implicated in the generation of multipolar mitoses, chromosomal instability (CIN), and aneuploidy. Centrosome amplification also contributes to loss of tissue architecture, and possibly angiogenesis in human cancers. Defective centrosomes are capable of abnormal microtubule nucleation and formation of disorganized mitotic spindles, leading to chromosomal missegregation and aneuploidy. However, the presence of extra centrosomes does not necessarily lead to major cell division errors as extra centrosomes may undergo clustering, thereby preserving bipolarity of the mitotic spindle. Ultimately, the "mutator phenotype" generated as a result raises the possibility of producing cells with the rare genomic complement that may confer survival advantage through a Darwinian selection process, thereby promoting cancer development and progression.