Centrosome amplification arises before neoplasia and increases upon p53 loss in tumorigenesis

Abstract

Lopes et al. examine centrosomes in human samples progressing from premalignant to metastatic lesions from patients with Barrett’s esophagus. They find that centrosome amplification can occur before transformation during human tumorigenesis, being repressed by p53, suggesting that centrosome amplification contributes to tumor initiation before p53 mutation.

Patterns of selection against centrosome amplification in human cell lines

“…Numeric aberrations of the centrosome and their putative link to cancer formation have long been described (3), although accurate quantifications of centriole numbers in tumor biopsies and cancer-derived cell lines have emerged only recently (9)(10)(11)(12) . To this day, the contribution of centrosomal anomalies to cancer development remain controversial, with some studies showing that higher numbers, via Plk4 overexpression, can initiate or aggravate tumorigenesis (28,29), and others showing that it is not sufficient and may even slow down progression (30,31).…”

“…In stark contrast with most proliferating cells, centriole numbers are often de-regulated during cancer development. In particular, cells with abnormally high numbers of centrioles are common in tumors and cancer-derived cell lines, and have been recently identified in pre-neoplastic tissues (8)(9)(10)(11)(12). Interestingly, within a single population of cancer cells, individual cells often carry different numbers of centrioles.…”

“…Interestingly, within a single population of cancer cells, individual cells often carry different numbers of centrioles. However, the number of centrioles per cell in the population seems to display a specific distribution depending on the cell type (9)(10)(11)(12). The source of this variability within and between cell populations is still poorly understood and calls for the development of quantitative approaches.…”

“…Here, we develop mathematical models of centriole overproduction and selection against centrosome amplification that are predicated on different assumptions on how supernumerary centrioles are produced and how selection operates. We use these models to analyze recently published data on representative cell lines of the progression from Barrett's esophagus to gastroesophageal adenocarcinoma (9) and the NCI-60 panel of cancer cell lines (10). These two data sets provide us with the opportunity to study how centriole number distributions vary along cancer progression, from pre-malignant to malignant stages, in the case of the Barrett's esophagus data set, and between different cancer types, in the NCI-60 data set.…”

Evidence that polyploidy in esophageal adenocarcinoma originates from mitotic slippage caused by defective chromosome attachments

“…A previous study reported that centrosome amplification occurred early in the progression of BE into EAC, and that this was dependent upon p53 loss (16). As supernumerary centrosomes can cause mitotic defects, we analyzed their presence in our BE cell lines and in the two EAC cell lines, FLO and JH-Eso-Ad1, that had the highest percentage of mitotic defects ( Fig.…”