Abstract
Centrosomes serve as the major microtubule organizing centers in cells and thereby contribute to cell shape, polarity, and motility. Also, centrosomes ensure equal chromosome segregation during mitosis. Centrosome aberrations arise when the centrosome cycle is deregulated, or as a result of cytokinesis failure. A long-standing postulate is that centrosome aberrations are involved in the initiation and progression of cancer. However, this notion has been a subject of controversy because until recently the relationship has been correlative. Recently, it was shown that numerical or structural centrosome aberrations can initiate tumors in certain tissues in mice, as well as invasion. Particularly, we will focus on centrosome amplification and chromosome instability as drivers of intra-tumor heterogeneity and their consequences in cancer. We will also discuss briefly the controversies surrounding this theory to highlight the fact that the role of both centrosome amplification and chromosome instability in cancer is highly context-dependent. Further, we will discuss single-cell sequencing as a novel technique to understand intra-tumor heterogeneity and some therapeutic approaches to target chromosome instability.
Highlights
Intra-tumor heterogeneity is a cancer hallmark that is characterized by the presence of different cell subpopulations within the same tumor[1,2]
A similar approach can be tested with the combination of paclitaxel and BubR1, Hec1, Nek2, or Sgol1 inhibitors because all of these proteins play an important role in proper SAC functioning and our studies have demonstrated their role in centrosome amplification and chromosome instability downstream of the E2F activators[35,162,201]
Failure to properly regulate the cell cycle and the centrosome cycle leads to centrosome aberrations
Summary
Intra-tumor heterogeneity is a cancer hallmark that is characterized by the presence of different cell subpopulations within the same tumor[1,2]. Albeit that study did not measure centrosome amplification and chromosome instability, it is tempting to propose this as an approach to suppress active generation of these processes in cancer cells, since we have shown that silencing or genetic ablation of Cdk in p53-null fibroblasts, in mammary epithelial cells expressing H-RasG12V or H-RasG12V and c-Myc, or in Her2+ breast cancer cells suppress these processes[25,104,174]. This approach neglects the fact that chromosome instability may occur by multiple mechanisms and multiple dysregulated proteins. These findings present us with multiple possibilities that together with advances in precise medicine and technologies such as SCS can be explored in cancer patients with specific tumor genotype/phenotype (intra-tumor heterogeneity) to develop better treatment
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