Tetraploidy and tumor development

Tetraploid cells, which contain a doubled chromosomal content, are known to facilitate tumorigenesis [1]. Two specific characteristics of tetraploid cells play major roles in promoting neoplastic transformation. First, proliferating tetraploid cells are genomically unstable and accumulate both numerical and structural chromosomal abnormalities. Such chromosomal instability arises mainly due to the presence of supernumerary centrosomes that disrupt normal mitotic spindle assembly and chromosome segregation [2]. Second, extra copies of chromosomes in tetraploid cells act as a compensatory buffer against spontaneously arising deleterious mutations. This enables nascent tumor cells to continue proliferating in the presence of normally lethal genomic alterations [3]. Together, these two characteristics allow tetraploid cells to continuously sample multiple genetic permutations, ultimately giving rise to rare cells that have acquired growth advantages. Indeed, mounting evidence suggests that tetraploidy may have a significant and previously unappreciated role in the development of solid tumors. Computational analysis of sequencing data from ~4000 human cancers has indicated that approximately 40% of all human tumors have undergone a tetraploidization event at some point during their progression [4]. This is true even of mature tumors that ultimately stabilize with a near-diploid complement of chromosomes. As such, while near-tetraploid tumors are less commonly seen in the clinical setting than their neardiploid or triploid counterparts, these observations are not necessarily indicative of the extent to which tetraploidy drives tumor development in patients. However, several critical questions regarding tetraploid-driven tumor development remain unanswered. Though many tumors show evidence of having passed through a tetraploid stage at some point during the oncogenic process, it remains unclear how often such a stage acts as an intermediate preceding tumorigenesis, rather than arising as a secondary consequence of malignant transformation. It also remains unresolved how often, and by what mechanisms, tumor-initiating tetraploid cells arise in pre-neoplastic tissues. Tetraploidy generally arises as a result of three different pathways: endoreduplication, in which the genome is re-replicated without an intervening mitosis; cell fusion, which is often instigated by viral infections; and cytokinesis/mitotic failure. Of the three pathways, cytokinesis or mitotic dysfunction is thought to be the most common way by which human cells become tetraploid. This is due in large part to the fact that a Editorial