An abnormal chromosome number, a condition known as aneuploidy, is a ubiquitous feature of cancer cells. A number of studies have shown that aneuploidy impairs cellular fitness. However, there is also evidence that aneuploidy can arise in response to specific challenges and can confer a selective advantage under certain environmental stresses. Cancer cells are likely exposed to a number of challenging conditions arising within the tumor microenvironment. To investigate whether aneuploidy may confer a selective advantage to cancer cells, we employed a controlled experimental system. We used the diploid, colorectal cancer cell line DLD1 and two DLD1-derived cell lines carrying single-chromosome aneuploidies to assess a number of cancer cell properties. Such properties, which included rates of proliferation and apoptosis, anchorage-independent growth, and invasiveness, were assessed both under standard culture conditions and under conditions of stress (i.e., serum starvation, drug treatment, hypoxia). Similar experiments were performed in diploid vs. aneuploid non-transformed human primary cells. Overall, our data show that aneuploidy can confer selective advantage to human cells cultured under non-standard conditions. These findings indicate that aneuploidy can increase the adaptability of cells, even those, such as cancer cells, that are already characterized by increased proliferative capacity and aggressive tumorigenic phenotypes.
A link between aneuploidy and miscarriage or cancer in humans has been known for a long time. However, only in recent years the development of experimental models of whole-chromosome aneuploidy has allowed investigators to take a closer look at how aneuploidy affects individual cells. Collectively, recent studies using these models have shown that aneuploidy induces transcriptomic and proteomic changes, chromosomal instability, and adaptation. In this article, we discuss the findings from these recent studies and present current and emerging models on how aneuploidy may be deleterious in certain contexts, but beneficial in others.
Understanding how cells acquire genetic mutations is a fundamental biological question with implications for many different areas of biomedical research, ranging from tumor evolution to drug resistance. While karyotypic heterogeneity is a hallmark of cancer cells, few mutations causing chromosome instability have been identified in cancer genomes, suggesting a nongenetic origin of this phenomenon. We found that in vitro exposure of karyotypically stable human colorectal cancer cell lines to environmental stress conditions triggered a wide variety of chromosomal changes and karyotypic heterogeneity. At the molecular level, hyperthermia induced polyploidization by perturbing centrosome function, preventing chromosome segregation, and attenuating the spindle assembly checkpoint. The combination of these effects resulted in mitotic exit without chromosome segregation. Finally, heat-induced tetraploid cells were on the average more resistant to chemotherapeutic agents. Our studies suggest that environmental perturbations promote karyotypic heterogeneity and could contribute to the emergence of drug resistance.
BACKGROUND Science has made great advances due to the ability to manipulate biological processes in a controlled manner. One of the most notable achievements was the establishment of cell lines. The most famous cell line was established by G.O. Gey at Johns Hopkins in 1951, after deriving the cells from the cervical cancer of Henrietta Lacks (HeLa) (Gey and Coffman 1952, Jones et al. 1971). In the over halfcentury since, HeLa has made major contributions to science. Indeed a PubMed search for "HeLa" yields nearly 80,000 results. Shortly after HeLa was established, scientists began attempting to make other types of cell lines, but had little means of properly identifying cell types. Early classification methods were primitive, with one assay screening for the production of glucose-6-phosphate dehydrogenase (G6PD), an enzyme thought to be found almost entirely in African Americans (Gartler 1968). Gartler et al observed G6PD in 20 human aneuploid cells (most of which he knew were collected from Caucasians) and lead him to discover a massive international cell contamination (Gartler 1968). The contaminant was HeLa, and the discovery unveiled a pandemic of HeLa contamination (Culliton 1974). These hard lessons taught scientists the importance of accurately identifying cell lines and correctly attributing specific cellular properties to the appropriate corresponding cell line. Consequently, the HeLa contamination drove the development of better techniques for characterizing and differentiating between cells lines. Early cytogenetic analysis of HeLa cells relied on Giemsa staining to produce distinct chromosome bands and examine HeLa's genomic landscape (Chu and Giles 1958, Nelson-Rees and Flandermeyer 1976, Hsu and Moorhead 1956, Seabright 1973). This lead to the discovery of HeLa's numerous chromosome aberrations, and made identifying HeLa-specific marker chromosomes the highest priority (Lavappa, Macy, and Shannon 1976, Chen 2008). Today, most cytogenetic analysis of HeLa has been performed by FISH, and G-banding. (Francke,
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