Chromosome instability and deregulated proliferation: An unavoidable duo
The concept that aneuploidy is a characteristic of malignant cells has long been known; however, the idea that aneuploidy is an active contributor to tumorigenesis, as opposed to being an associated phenotype, is more recent in its evolution. At the same time, we are seeing the emergence of novel roles for tumor suppressor genes and oncogenes in genome stability. These include the adenomatous polyposis coli gene (APC), p53, the retinoblastoma susceptibility gene (RB1), and Ras. Originally, many of these genes were thought to be tumor suppressive or oncogenic solely because of their role in proliferative control. Because of the frequency with which they are disrupted in cancer, chromosome instability caused by their dysfunction may be more central to tumorigenesis than previously thought. Therefore, this review will highlight how the proper function of cell cycle regulatory genes contributes to the maintenance of genome stability, and how their mutation in cancer obligatorily connects proliferation and chromosome instability.
Available from: Anna V Roschke
- "The explanation is that activated oncogenes affect also the mitotic process that controls chromosome segregation. Emerging data show that W-CIN and the oncogenic signaling pathways responsible for driving tumor formation are closely interrelated, and novel roles for oncogenes and tumor-suppressor genes in genome stability are proposed [reviewed in Ref. (62, 86)]. These include genes participating in the RB pathway, the APC pathway, the WNT signaling pathway, the Ras signaling pathway, the TGF-beta signaling pathway, the NF-kB pathway, integrin signaling and cell adhesion, the Hippo signaling pathway, and the DNA damage response. "
[Show abstract] [Hide abstract]
ABSTRACT: Whole-chromosomal instability (W-CIN) - unequal chromosome distribution during cell division - is a characteristic feature of a majority of cancer cells distinguishing them from their normal counterparts. The precise molecular mechanisms that may cause mis-segregation of chromosomes in tumor cells just recently became more evident. The consequences of W-CIN are numerous and play a critical role in carcinogenesis. W-CIN mediates evolution of cancer cell population under selective pressure and can facilitate the accumulation of genetic changes that promote malignancy. It has both tumor-promoting and tumor-suppressive effects, and their balance could be beneficial or detrimental for carcinogenesis. The characterization of W-CIN as a complex multi-layered adaptive phenotype highlights the intra- and extracellular adaptations to the consequences of genome reshuffling. It also provides a framework for targeting aggressive chromosomally unstable cancers.
Available from: Bernardo Orr
- "This connection to CIN arises because they disrupt the careful orchestration of events required for accurate chromosome segregation during mitosis by decreasing the rate of correction of k-MT attachment errors and/or increasing the rate of formation of those errors through extra centrosomes or disruption of centromere geometry. The notion that tumor suppressor genes (and, by extension, oncogenes) combine their known roles in cell cycle progression, growth, and differentiation with the induction of genomic instability is not necessarily new and a substantial body of evidence supports this (reviewed in Coschi and Dick, 2012). The central point we are making here is that the molecular connections between these signaling pathways and CIN are becoming clearer as insights into the underlying mechanisms generating CIN are married to our understanding of these signaling pathways. "
[Show abstract] [Hide abstract]
ABSTRACT: Most solid tumors are characterized by abnormal chromosome numbers (aneuploidy) and karyotypic profiling has shown that the majority of these tumors are heterogeneous and chromosomally unstable. Chromosomal instability (CIN) is defined as persistent mis-segregation of whole chromosomes and is caused by defects during mitosis. Large-scale genome sequencing has failed to reveal frequent mutations of genes encoding proteins involved in mitosis. On the contrary, sequencing has revealed that most mutated genes in cancer fall into a limited number of core oncogenic signaling pathways that regulate the cell cycle, cell growth, and apoptosis. This led to the notion that the induction of oncogenic signaling is a separate event from the loss of mitotic fidelity, but a growing body of evidence suggests that oncogenic signaling can deregulate cell cycle progression, growth, and differentiation as well as cause CIN. These new results indicate that the induction of CIN can no longer be considered separately from the cancer-associated driver mutations. Here we review the primary causes of CIN in mitosis and discuss how the oncogenic activation of key signal transduction pathways contributes to the induction of CIN.
Available from: Stacy Donovan
- "As a tumor suppressor gene, Rb1 is well known for its role in regulating cell proliferation; however, recent data from a variety of different in vivo and in vitro model systems suggest that Rb1 may also play a role in the maintenance of genome stability (Knudsen et al., 2006; Manning and Dyson, 2011; Coschi and Dick, 2012). It has been proposed that the loss of Rb1 disrupts the coordinated transitions through the cell cycle and that compromised cell cycle checkpoints culminate in genomic change (Knudsen et al., 2006; Manning and Dyson, 2011; Coschi and Dick, 2012). In the present study, we found that multiple cell cycle checkpoints are compromised in Rb1-deficient horizontal cells before changes in horizontal cell size and ploidy were detected. "
[Show abstract] [Hide abstract]
ABSTRACT: The retinoblastoma tumor susceptibility gene, Rb1, is a key regulator of the cell cycle, and mutations in this gene have been found in many human cancers. Prior studies showed that retina-specific knock out of Rb1 in the mouse results in the formation of abnormally large horizontal cells, but the development, fate and genomic status of these cells remains unknown. In this study, we conditionally inactivate Rb1 in early retinal progenitors and show that the loss of Rb1 leads to the rapid degeneration of most retinal cells except horizontal cells, which persist as giant cells with aberrant centrosome content, DNA damage and polyploidy/aneuploidy. We observed inappropriate cell cycle entry of Rb1-deficient horizontal cells during the first postnatal weeks which dropped off abruptly by P30. Despite extensive DNA damage in Rb1-deficient horizontal cells, these cells can still enter mitosis. Adult Rb1-deficient horizontal cells display elevated DNA content (5N-34N) that varied continuously, suggesting the presence of aneuploidy. We also found evidence of supernumerary and disoriented centrosomes in a rare population of mitotic cells in the mutant retinas. Overall, our data demonstrate that horizontal cells are a remarkably robust cell type that can survive for months despite extensive DNA damage and elevated genome content.
Data provided are for informational purposes only. Although carefully collected, accuracy cannot be guaranteed. The impact factor represents a rough estimation of the journal's impact factor and does not reflect the actual current impact factor. Publisher conditions are provided by RoMEO. Differing provisions from the publisher's actual policy or licence agreement may be applicable.