Centrosome dysfunction contributes to chromosome instability, chromoanagenesis, and genome reprograming in cancer

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Abstract

The unique ability of centrosomes to nucleate and organize microtubules makes them unrivaled conductors of important interphase processes, such as intracellular payload traffic, cell polarity, cell locomotion, and organization of the immunologic synapse. But it is in mitosis that centrosomes loom large, for they orchestrate, with clockmaker's precision, the assembly and functioning of the mitotic spindle, ensuring the equal partitioning of the replicated genome into daughter cells. Centrosome dysfunction is inextricably linked to aneuploidy and chromosome instability, both hallmarks of cancer cells. Several aspects of centrosome function in normal and cancer cells have been molecularly characterized during the last two decades, greatly enhancing our mechanistic understanding of this tiny organelle. Whether centrosome defects alone can cause cancer, remains unanswered. Until recently, the aggregate of the evidence had suggested that centrosome dysfunction, by deregulating the fidelity of chromosome segregation, promotes and accelerates the characteristic Darwinian evolution of the cancer genome enabled by increased mutational load and/or decreased DNA repair. Very recent experimental work has shown that missegregated chromosomes resulting from centrosome dysfunction may experience extensive DNA damage, suggesting additional dimensions to the role of centrosomes in cancer. Centrosome dysfunction is particularly prevalent in tumors in which the genome has undergone extensive structural rearrangements and chromosome domain reshuffling. Ongoing gene reshuffling reprograms the genome for continuous growth, survival, and evasion of the immune system. Manipulation of molecular networks controlling centrosome function may soon become a viable target for specific therapeutic intervention in cancer, particularly since normal cells, which lack centrosome alterations, may be spared the toxicity of such therapies. Cancer is an evolutionary multistep process arising in single cells resulting from accumulation of non-lethal mutations that increase, decrease, deregulate, or interfere with the function of critical genes, leading to autonomous growth and loss of homeostasis. Cancer cells fail to execute programed cell death when required, fail to exit the cell cycle when prompted, or to differentiate in response to appropriate external or internal regulatory signals. This dynamic "renegade" behavior (1), which was elegantly codified by Hanahan and Weinberg in a series of publications addressing the Hallmarks of cancer cells (2, 3), lay at the core of cancer biology and dispels the notion of sporadic cancer as a simple, oligogenic somatic genetic disease. Cancer is indeed a family of complex evolutionary somatic genetic disorders resulting from dynamic and ongoing reprograming of the genome, the nature of which will continue to challenge our ingenuity for years to come. © 2013 Pihan.

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APA

Pihan, G. A. (2013). Centrosome dysfunction contributes to chromosome instability, chromoanagenesis, and genome reprograming in cancer. Frontiers in Oncology, 3 NOV. https://doi.org/10.3389/fonc.2013.00277

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