Tetraploidy/aneuploidy and stem cells in cancer promotion: The role of chromosome passenger proteins

Abstract

While polyploidy, a state of having fully duplicated sets of chromosomes per cell, has been described in normally developing bone marrow megakaryocytes or as an adaptive response in other cell types, aneuploidy is never detected in normal cells. Tetraploidy or aneuploidy can be induced by several signals and it is highly prevalent in different forms of cancers, suggesting a role for this cell cycle state in promoting cellular transformation. Investigations suggested that loss of heterozygosity of cancer-related genes in stem cells might contribute to genetic instability in progeny cells and to subsequent cancer development. Deregulated expression of chromosome passenger proteins, such as Aurora kinases or Survivin, is a hallmark of various cancers, and experimentally induced changes in these regulators can promote tetraploidy or aneuploidy and loss of heterozygosity. Our studies described an induction of tetraploidy/aneuploidy by a stable form of Aurora-B, leading to acquisition of transformation properties. It is intriguing to speculate that in some cancers, tetraploidy/aneuploidy induced by deregulated expression of a mitotic regulator represents a primary event that leads to unbalanced expression of a cluster of crucial genes and to cellular transformation.

Aurora A is differentially expressed and regulated in chromosomal and microsatellite instable sporadic colorectal cancers

“…13 As such, changes in proteins of the so-called chromosomal passenger complex and/or proteins involved in mitotic spindle function have been associated with the development of aneuploidy in cancer cells. [13][14][15][16][17][18][19][20][21] Moreover, proteins of the centrosomal complex have received substantial experimental attention as key regulators of cellular ploidy. 29,30 Alteration of the centrosomal kinase aurora A 31-34 by gene amplification and/or overexpression has been associated with induction of supernumerary centrosomes and/or aneuploidy in several gastrointestinal, eg esophageal, 59 gastric, 60 as well as gynaecological 53,61,62 carcinomas.…”

“…In addition, it is reasonable that the activation status of aurora A, controlled by phosphorylation as well as protein stability 64 , may introduce a further functional level affecting successful aurora (-A) inhibition and tumour cell death. 68 In this context, functional investigations of inactive/active aurora A protein levels as well as other centrosomal and chromosomal passenger complex [13][14][15][16][17][18][19][20][21] proteins in chromosomal and microsatellite instable colorectal tumour cell lines with specific reference to their interaction with the p53 66 and adenomatosis polyposis coli 24,25 pathways, will certainly be a worthwhile effort and are subject of our ongoing in vitro investigations.…”

“…Besides chromosome non-disjunction and/or telomere-related alterations, 11,12 gross defects in chromosome segregation during cell division may contribute to the development of chromosomal instability and aneuploidy. 13 Indeed, changes in proteins involved in chromosome segregation-so-called chromosomal passenger proteins [14][15][16][17][18] -and/or proteins involved in mitotic spindle [19][20][21] have been associated with the development of aneuploidy in cancer cells. Also, the adenomatosis polyposis coli protein, whose alteration is observed in early colorectal carcinogenesis, 22,23 has recently been implicated in the control of chromosome segregation during mitosis.…”

Stem cell-associated genes are extremely poor prognostic factors for soft-tissue sarcoma patients

“…In addition, it is a component of the chromosome passenger protein complex that has been proposed to regulate mitosis (Nguyen and Ravid, 2006). Therefore, it is considered as an interface molecule between regulation of apoptosis and control of cell proliferation (Altieri, 2003).…”

“…Therefore, it is considered as an interface molecule between regulation of apoptosis and control of cell proliferation (Altieri, 2003). Overexpression of survivin has been reported in many tumor tissues including leukemias, lymphomas, STS, colorectal cancers, astrocytic tumors, lung cancer, breast cancer and ovarian tumors (Altieri, 2003;Nguyen and Ravid, 2006). Overexpression of survivin in malignant tumors has been correlated with a poor prognosis (reviewed in Altieri, 2003).…”