Illicit survival of cancer cells during polyploidization and depolyploidization

Abstract

Tetraploidy and the depolyploidization of tetraploid cells may contribute to oncogenesis. Several mechanisms have evolved to avoid the generation, survival, proliferation and depolyploidization of tetraploids. Cells that illicitly survive these checkpoints are prone to chromosomal instability and aneuploidization. Along with their replication, tetraploids constantly undergo chromosomal rearrangements that eventually lead to pseudodiploidy by two non-exclusive mechanisms: (i) multipolar divisions and (ii) illicit bipolar divisions in the presence of improper microtubule-kinetochore attachments. Here, we describe the regulation and the molecular mechanisms that underlie such a 'polyploidization-depolyploidization' cascade, while focusing on the role of oncogenes and tumor suppressor genes in tetraploidy-driven tumorigenesis. We speculate that the identification of signaling/metabolic cascades that are required for the survival of tetraploid or aneuploid (but not diploid) cancer cells may pave the way for the development of novel broad-spectrum anticancer agents.

The ratio of CD8+/FOXP3 T lymphocytes infiltrating breast tissues predicts the relapse of ductal carcinoma in situ

“…[11][12][13] One of the mechanisms increasing tumor cell adjuvanticity is linked to the very mechanism of oncogenesis, which often (in at least 40% of malignancies) involves a tetraploidization event (i.e., genome duplication), followed by a gradual depolyploidization due to chromosome loss. [14][15][16] Interestingly, tetraploid cells are characterized by an endoplasmic reticulum stress response (that leads to an increase in the phosphorylation of eukaryotic initiation factor 2a (eIF2a) 17 and enhanced surface exposure of the endoplasmic reticulum protein calreticulin (CRT) on the cell surface, facilitating immune recognition of the cells through an adjuvant effect. [18][19][20][21][22] As a result, downregulation of CRT exposure, eIF2a phosphorylation, and reduction in ploidy occur under the pressure of the immune system, generating near-to-diploid cells that can escape from immune control.…”

Entosis, a key player in cancer cell competition

“…On one hand, entosis carried out by 'winner' cells may constitute a competitive advantage of aggressive tumor cells, perhaps allowing the 'winners' to retrieve amino acids and other building blocks for anabolic reaction from their cannibalistic activity [9] or increasing their genomic instability subsequent to mitotic aberrations [2,10]. In this context, pharmacological suppression of entosis by Y27632, a ROCKI/II inhibitor, abolished the competitive advantage of transformed cells over their non-transformed siblings in mixed culture experiments [5].…”

Characterization of novel MPS1 inhibitors with preclinical anticancer activity

“…11 In addition, MPS1 may be required for centrosome duplication. 26 Finally, MPS1 has been implicated in surveillance mechanisms such as the G 2 /M checkpoint (by interacting with checkpoint kinase 2 and Bloom syndrome) 27,28 and the tetraploidy checkpoint (by phosphorylating the oncosuppressor protein p53), 29 which prevent the initiation of mitosis in cells with damaged or unreplicated DNA 30,31 and the proliferation/survival of illicitly generated polyploids, [32][33][34] respectively.…”