Selective advantage of trisomic human cells cultured in non-standard conditions

Abstract

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.

Single-chromosome Gains Commonly Function as Tumor Suppressors

“…For example, trisomy of chromosome 21 predisposes individuals to leukemia (Seewald et al, 2012), and gain of chromosome 21 is a common occurrence in sporadic leukemia (Loncarevic et al, 1999; Ozery-Flato et al, 2011), but trisomy of chromosome 21 appears to protect against the development of many other cancer types, including breast, lung, and prostate cancers (Nižetić and Groet, 2012). Similarly, a recent report suggests that, while aneuploidy is typically detrimental to cell fitness, under certain conditions, such as hypoxia or chemotherapy treatment, aneuploid cells may proliferate better than euploid cells do (Rutledge et al, 2016). Thus, while the nine aneuploid lines that we examined hinder or are neutral with regard to tumor growth in every assay that we performed, it is conceivable that a wider survey of aneuploidies, oncogenes, or growth conditions would reveal unusual cases in which aneuploidy provides a fitness advantage.…”

Living in CIN: Mitotic Infidelity and Its Consequences for Tumor Promotion and Suppression

“…Similarly, one study found aneuploidy and CIN in murine liver promote regeneration after hepatic injury (Duncan et al, 2012), although two subsequent studies using single cell sequencing did not identify aneuploidy in wild type hepatocytes (Choi et al, 2016; Knouse et al, 2014). Human cells with an extra chromosome 7 or 13 have a proliferative advantage over diploid cells under multiple stresses (Rutledge et al, 2016). Together, these data suggest that aneuploidy and CIN generate phenotypic variation, which allows for adaptation to environmental stresses and could explain their prevalence in aggressive human cancers.…”

Role of chromosomal instability in cancer progression

“…This concept has been clearly demonstrated in single-celled organisms (Rancati et al 2008, Selmecki et al 2009, Pavelka et al 2010, Yona et al 2012, Chang et al 2013, however, demonstrating this in human cells has been more challenging. There is evidence that aneuploid human cells, although generally appearing less fit than their euploid counterparts under 'standard' conditions (Williams et al 2008, Thompson & Compton 2010 display advantages under selective conditions (Rutledge et al 2016) and that aneuploidy of pluripotent stem cells promotes their efficient adaptation to culture conditions (Barbaric et al 2014, Na et al 2014. Further, aneuploidy in murine liver cells promotes adaptation to chronic liver injury (Duncan et al 2012).…”