Download Why do cancer cells have too many centrosomes?

Why do cancer cells have too many centrosomes?
Suzy Prosser and Andrew Fry
Department of Biochemistry, University of Leicester
Introduction
 Cell division is the biological basis of life, allowing a single fertilised egg cell to become a multicellular organism containing trillions of cells.
This process is strictly regulated as uncontrolled cell division results in cancer.
 A cell must duplicate its contents exactly and separate evenly into two daughter cells. One component of the cell that ensures that this is
completed properly is the centrosome. When the cell divides there are two centrosomes present, forming the two poles of a scaffold like
structure called the mitotic spindle.
 Each daughter cell inherits one centrosome and one set of chromosomes. Before the next division, the cell must duplicate its centrosome
so that there are again two present to form a bipolar spindle.
 If too many centrosomes are present, as is often the case in cancer cells, abnormal multipolar spindles are formed. This results in uneven
segregation of chromosomes leading to genetic instability. This drives cancer progression and resistance to therapies.
Normal cell division
Abnormal cell division
Centrosome at each spindle pole
(yellow)
DNA
(blue)
Centrosome
(yellow)
Spindle poles
(yellow)
Two new cells
Spindle
(red)
A cell before division
A bipolar spindle is formed to equally segregate the
genetic material between the two new cells
Two new cells are formed
Aims
Too many centrosomes lead to multipolar spindles
Centrosome duplication assay
 Establish a centrosome duplication assay to study what is one of the most
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poorly understood processes in cell biology
 Utilise this assay to investigate the steps in the pathway that result in the
accumulation of extra centrosomes in cancer cells
2 centrosomes
 Ultimately this may lead to the identification of potential targets to inhibit
4 centrosomes
8 centrosomes
Cells can be treated so that multiple centrosomes (yellow dots) form
over prolonged periods
centrosome accumulation in tumour cells
Results
We have identified a stepwise pathway by which centrosome overduplication occurs:
Nucleus
DNA replication
1
Cdk2
2
Centrosomal precursors
Nuclear export
4
3
MTs
5
MTs &
Dynein
Hsp90
Centrosome
1
Two centrosomes
(yellow) present in a cell
2
Centrosomal precursors
(green) appear in the nucleus
3
Centrosomal precursors
(green) seen round the
periphery of the nucleus
4
Precursors (green) cluster
around the existing
centrosome (red)
5
Precursors mature into
core centrosome
components (green)
Multiple functional
centrosomes have formed
By inhibiting those components highlighted in yellow, in conjunction with the centrosome duplication assay, we can deduce the contribution
o f each component to centrosome overduplication by observing the distribution pattern of different centrosomal proteins in cells by
immunofluorescence microscopy.
Discussion
The presence of too many centrosomes is a hallmark of cancer cells. These extra centrosomes lead to the formation of abnormal mitotic
spindles with multiple poles, the consequence of which is defective chromosome segregation. Understanding how centrosome number is
normally controlled and why cancer cells acquire extra centrosomes is therefore of profound importance. Using an experimental approach
that mimics the generation of multiple centrosomes in cells, we have identified some important and unexpected events in this process.
Ultimately, this may lead to the development of novel therapeutic approaches that can be taken to prevent the unwanted generation of
multiple centrosomes in cancer cells.