Abstract
Polyploidy is a hallmark of cancer, and closely related to chromosomal instability involved in cancer progression. Importantly, polyploid cells also exist in some normal tissues. Polyploid hepatocytes proliferate and dynamically reduce their ploidy during liver regeneration. This raises the question whether proliferating polyploids are prone to cancer via chromosome missegregation during mitosis and/or ploidy reduction. Conversely polyploids could be resistant to tumor development due to their redundant genomes. Therefore, the tumor-initiation risk of physiologic polyploidy and ploidy reduction is still unclear. Using in vivo lineage tracing we here show that polyploid hepatocytes readily form liver tumors via frequent ploidy reduction. Polyploid hepatocytes give rise to regenerative nodules with chromosome aberrations, which are enhanced by ploidy reduction. Although polyploidy should theoretically prevent tumor suppressor loss, the high frequency of ploidy reduction negates this protection. Importantly, polyploid hepatocytes that undergo multiple rounds of cell division become predominantly mononucleated and are resistant to ploidy reduction. Our results suggest that ploidy reduction is an early step in the initiation of carcinogenesis from polyploid hepatocytes.
Highlights
Polyploidy is a hallmark of cancer, and closely related to chromosomal instability involved in cancer progression
Genome-wide analysis indicates that proliferation of polyploid hepatocytes give rise to regenerative nodules (RNs) with allelic imbalances (AIs), which are enhanced by ploidy reduction
Chromosomal aberrations during liver injury were further explored using SNP-informative Hgd+/−Fah−/− mice, and whole-chromosome loss of the Hgd wild-type chromosome 16 in RNs was readily detected (Supplementary Fig. 3). This is consistent with previous studies showing that polyploidyfacilitated aneuploidy of chromosome 16 causes loss of Hgd and protects hepatocyte adaptation from Fah deficiency[15,16]. These findings indicate that proliferating polyploid hepatocytes in injured livers undergo chromosome aberrations and that ploidy reduction is associated with this process
Summary
Polyploidy is a hallmark of cancer, and closely related to chromosomal instability involved in cancer progression. Polyploid cells can generate ploidy-reduced progeny via multipolar mitosis[11], which efficiently contributes to organ development as well as regeneration[5,12]. Human pan-cancer analysis frequently detected punctuated bursts of chromosome aberrations during tumorigenesis in both polyploid and neardiploid tumors[14] This implies the existence of a critical mechanism to generate near-diploid tumor cells with extensive chromosome aberrations in a single mitosis, which would reasonably be ploidy reduction via multipolar mitosis. It remains unclear how the dynamic ploidy alterations of normal hepatocytes impact cancer transformation. Ploidy reduction is a previously unappreciated mechanism linking normal cells to cancer development
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
