Chromosome segregation errors: a double-edged sword - TI Pharma

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heterogeneity and might therefore be an important factor in structural instability 264 .
4.2 Numerical Chromosomal Instability
Another striking hallmark of cancer cells is the presence of an abnormal chromosome
number 236,265,266 , termed aneuploidy, a state in which cells do not contain an exact multiple
of the haploid DNA content 267 . On average 25 percent of the genome of a cancer cell is affected
by numerical changes of either whole chromosomes or complete chromosomal arms 243 .
Aneuploidy can be stably inherited in a population of (tumor) cells 243,268,269 , but more often chromosome
numbers continuously change between cancer cells and their offspring 270 . This continuous change in
chromosome number is termed whole chromosomal instability (CIN) 231,270 and is associated with highgrade
tumors, metastasis and poor prognosis 271-277 Moreover, CIN has been associated with resistance
to chemotherapeutics, such as the widely used microtubule stabilizing agent Paclitaxel 278-280 . Various
hypotheses have been postulated on how CIN and aneuploidy could contribute to tumorigenesis 281-285
(see Discussion, Chapter 8). The general idea is that whole chromosome gains and losses during cell
division can, as suggested above for structural changes, result in loss and gain of tumor suppressors and
oncogenes respectively 286 , thereby providing a platform for cancer cells to adapt to their environment
and continuously divide 287,288 .
4.3 Causes of numerical CIN
Since the initial discovery of chromosomal instability in a variety of colon cancer cell lines in 1997
270 , many researchers have investigated the underlying cause of this striking phenotype, which was
later found to be present in many other tumor types as well 243 231,289 . Several mechanisms have been
proposed and tested using a variety of cancer cell lines and mouse models. However, it seems highly
unlikely that one single mechanism can be held responsible for the CIN observed in the different types
of tumors. Below we outline the different cellular causes that have been postulated and the genetic
defects that could underlie these phenotypes.
4.3.1 Mitotic checkpoint defects
Defects in mitotic checkpoint signaling directly lead to chromosome missegregations (Fig.6A). Indeed,
the hypothesis that has been investigated the most postulates that mitotic checkpoint defects could
underlie CIN 290 . Complete mitotic checkpoint loss is lethal to all dividing cell types studied thus far and
causes embryonic lethality 291-298 , likely because it results in continuous missegregations. Thus, even if
a viable daughter cell is generated during a first cell division, its genome is not properly propagated
in the subsequent cell division, resulting in growth arrest and cell death in the respective daughter
cells 291-298 . In contrast, partial checkpoint dysfunction results in mild chromosome segregation
errors, which can potentially generate new viable genotypes that are relatively stable. Partial mitotic
checkpoint activity could be responsible for this by allowing mitotic exit in the presence of one or
more unattached kinetochores 291,298-300 . In line with this, CIN cancer cell lines were initially thought
to have a weakened mitotic checkpoint due to mutations in the mitotic checkpoint kinase Bub1 301 .
However, other researchers could not reproduce these checkpoint defects in the same CIN cell lines
302 , which opened up the avenue for research on other possible causes of CIN. Although many CIN
lines do not show a weakened mitotic checkpoint when challenged with microtubule-targeting agents
302 , reduced levels or mutations in mitotic checkpoint genes have been identified in human cancer
73,282,303-315 . In one specific syndrome, Mosaic Variegated Aneuploidy (MVA), which is linked to cancer
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