High levels of chromosomal instability facilitate the tumor growth and sphere formation. Issue 8 (30th June 2022)

• Record Type: Journal Article
• Authors: Iemura, Kenji; Anzawa, Hayato; Funayama, Ryo; Iwakami, Runa; Nakayama, Keiko; Kinoshita, Kengo; Tanaka, Kozo
• Is Part Of: Cancer science. Volume 113:Issue 8(2022)
• Page Start: 2727
• Page End: 2737
• Publication Date: 2022-06-30
• Subjects: chromosomal instability -- genetic heterogeneity -- HeLa cells -- K‐ras -- unfolded protein response; Cancer -- Periodicals; Neoplasms -- Periodicals; Research -- Periodicals; Electronic journals; 616.994005
• DOI: 10.1111/cas.15457
• Languages: English
• ISSNs: 1347-9032

Abstract

Abstract: Most cancer cells show chromosomal instability (CIN), a condition in which chromosome missegregation occurs at high rates. Growing evidence suggests that CIN is not just a consequence of, but a driving force for, oncogenic transformation, although the relationship between CIN and tumorigenesis has not been fully elucidated. Here we found that conventional two‐dimensional (2D) culture of HeLa cells, a cervical cancer‐derived cell line, was a heterogenous population containing cells with different CIN levels. Although cells with high‐CIN levels (high‐CIN cells) grew more slowly compared with cells with low‐CIN levels (low‐CIN cells) in 2D monolayer culture, they formed tumors in nude mice and larger spheres in three‐dimensional (3D) culture, which was more representative of the in vivo environment. The duration of mitosis was longer in high‐CIN cells, reflecting their higher mitotic defects. Single‐cell genome sequencing revealed that high‐CIN cells exhibited a higher karyotype heterogeneity compared with low‐CIN cells. Intriguingly, the karyotype heterogeneity was reduced in the spheres formed by high‐CIN cells, suggesting that cells with growth advantages were selected, although genomic copy number changes specific for spheres were not identified. When we examined gene expression profiles, genes related to the K‐ras signaling were upregulated, while those related to the unfolded protein response were downregulated in high‐CIN cells in 3D culture compared with 2D culture, suggesting the relevance of these genes for their survival. Our data suggested that, although CIN is disadvantageous in monolayer culture, it promotes the selection of cells with growth advantages under in vivo environments, which may lead to tumorigenesis. Abstract : In this work, Iemura et al. addressed the role of chromosomal instability (CIN), a condition in which chromosome missegregation occurs at high rates, on the acquisition of tumorigenic potential. They utilized HeLa cell clones exhibiting different levels of CIN, and compared their growth in two‐dimensional (2D) monolayer culture and three‐dimensional (3D) sphere culture, which is more representative of the in vivo environment. They found that although CIN is disadvantageous in monolayer culture conditions, it promotes the selection of cells with growth advantage under in vivo environments, which may lead to tumorigenesis.