Tetraploid cells from cytokinesis failure induce aneuploidy and spontaneous transformation of mouse ovarian surface epithelial cells

Abstract

Most ovarian cancers originate from the ovarian surface epithelium and are characterized by aneuploid karyotypes. Aneuploidy, a consequence of chromosome instability, is an early event during the development of ovarian cancers. However, how aneuploid cells are evolved from normal diploid cells in ovarian cancers remains unknown. In the present study, cytogenetic analyses of a mouse syngeneic ovarian cancer model revealed that diploid mouse ovarian surface epithelial cells (MOSECs) experienced an intermediate tetraploid cell stage, before evolving to aneuploid (mainly near-tetraploid) cells. Using long-term live-cell imaging followed by fluorescence in situ hybridization (FISH), we demonstrated that tetraploid cells originally arose from cytokinesis failure of bipolar mitosis in diploid cells, and gave rise to aneuploid cells through chromosome mis-segregation during both bipolar and multipolar mitoses. Injection of the late passage aneuploid MOSECs resulted in tumor formation in C57BL/6 mice. Therefore, we reveal a pathway for the evolution of diploid to aneuploid MOSECs and elucidate a mechanism for the development of near-tetraploid ovarian cancer cells.

Unrepaired DNA damage facilitates elimination of uniparental chromosomes in interspecific hybrid cells

“…Mouse ovarian surface epithelial cells (Mosec) were obtained and cultured as previously described. 68 Cells stably expressing red fluorescent protein-tagged histone 2B (H2B-mCherry) or enhanced green fluorescent protein-tagged histone 2B (H2B-EGFP) were generated by retroviral transduction. Human and mouse cells were trypsinized for harvesting and mixed together according to parental cell ratio 1:1, then overlaid cells were seeded on coverslips or chambers.…”

Death Domain-associated Protein DAXX Promotes Ovarian Cancer Development and Chemoresistance

“…The immortalized mouse ovarian surface epithelium (mOSE) was reported previously (15,16). All cells were cultured in DMEM (Invitrogen) supplemented with 10% fetal bovine serum (FBS; Hyclone) and 1% penicillin/streptomycin solution (Invitrogen) at 37°C in a humidified 5% CO 2 incubator.…”

Integrins Promote Cytokinesis through the RSK Signaling Axis

“…We have shown that RSK signaling promotes cytokinesis downstream of integrins in epithelial cells in culture, that RSK and a6 integrins regulate cytokinesis during tissue morphogenesis ex vivo and that RSK regulates cytokinesis in a cell-type-specific manner. Others have shown that cytokinesis failure can lead to aneuploidy and tumorigenesis and that tetraploid cells are present at early stages of tumors from different origins (Fujiwara et al, 2005;Galipeau et al, 1996;Ganem et al, 2007;Högnäs et al, 2012;Jonsdottir et al, 2012;Lv et al, 2012), suggesting that the proper interaction of cells with components of the ECM might contribute to maintaining genomic stability by promoting successful cytokinesis. More studies are needed to understand the significance of cell-type requirements for specific signaling pathways, the availability of redundant pathways, as well as integrin-dependent regulation of cytokinesis both in the context of developmental processes and tumorigenesis.…”

“…Our results demonstrate a novel role for integrin-regulated ERK and RSK signaling in promoting cytokinesis and suggest that integrins do so by regulating key events at the midbody necessary for abscission. Accumulating evidence links cytokinesis failure to tumorigenesis (Fujiwara et al, 2005;Galipeau et al, 1996;Ganem et al, 2007;Högnäs et al, 2012;Jonsdottir et al, 2012;Lv et al, 2012), suggesting a possible role for integrins as tumor suppressors owing to their ability to promote successful cytokinesis and thereby contribute to genomic stability.…”