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Oncogene (2008) 27, 6994–7002
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REVIEW
Drosophila asymmetric division, polarity and cancer
J Januschke1 and C Gonzalez1,2
1
Cell Division Group, IRB-Barcelona, PCB, c/Baldiri Reixac 10-12, Barcelona, Spain and 2Institucio Catalana de Recerca i Estudis
Avanc¸ats, Passeig Lluis Companys 23, Barcelona, Spain
A limited number of adult stem cells (SCs) maintain the
homoestasis of different tissues through the lifetime of the
individual by generating differentiating daughters and
renewing themselves. Errors in the SC division rate or in
the fine balance between self-renewal and differentiation
might result in tissue overgrowth or depletion, two
potentially lethal conditions. A few types of SCs have
been identified in Drosophila. These include the SCs of the
adult intestine and malpighian tubes, (Micchelli and
Perrimon, 2006; Ohlstein and Spradling, 2006; Singh
et al., 2007), the prohematocytes that maintain the
population of cells involved in the immunoresponse (Lanot
et al., 2001; Lemaitre and Hoffmann, 2007), the SC of the
follicle epithelia in the ovary (Nystul and Spradling,
2007), germ line SCs (GSCs) of both sexes (Fuller and
Spradling, 2007) and neuroblasts (NBs), the fly neural
SCs (Yu et al., 2006; Chia et al., 2008; Knoblich, 2008).
Drosophila SCs have proved a fruitful model system to
unveil some aspects of the molecular logic that sustains
SC function. This review focuses on results obtained in the
last few years from the study of NBs, particularly from
the standpoint of the possible functional connection
between asymmetric SC division and cancer.
Oncogene (2008) 27, 6994–7002; doi:10.1038/onc.2008.349
Keywords: stem cells; asymmetric division; centrosomes;
cell-of-origin; neuroblasts; cancer
Tumours in Drosophila
A recent and increasing body of literature suggests that
adult stem cells (SCs) might be the cells-of-origin for
certain human cancers, but conclusive evidence is still
lacking (Reya et al., 2001; Beachy et al., 2004; Huntly
and Gilliland, 2005; Kelly et al., 2007). Interestingly,
such a connection was suggested by results obtained in
Drosophila 30 years ago (Gateff, 1978). Naturally
occurring tumours have not been reported in Drosophila
or other insects (Harshbarger and Taylor, 1968; Mechler
et al., 1991), although neither have they been conclusively ruled out. However, experimentally induced loss
of function for a number of Drosophila genes results in
Correspondence: Professor C Gonzalez, Cell Division Group, IRBBarcelona, PCB, c/Baldiri Reixac 10-12, 08028 Barcelona, Spain.
E-mail: [email protected]
the growth of tumours that range from benign
hyperplasias to malignant neoplasms that are invasive
and lethal to the host (Gateff, 1978; Woodhouse et al.,
1998), thus showing that tumours can develop from fly
cells. Notably, tumours caused by one of such fly
tumour suppressors (TSs), lethal giant larvae (lgl), were
observed to originate from larval NBs (Gateff and
Schneiderman, 1967). This and other types of tumours
described in Drosophila over the years strongly suggest
that failed key developmental decisions may be the
initial cause of tumour formation (Potter et al., 2000;
Harris, 2005). Interestingly, lgl mutant alleles are
widespread in Drosophila wild-type populations, probably due to increased fitness under environmental stress
conditions (Golubovsky et al., 2006). It is, therefore,
reasonable to suspect that flies in these populations
might be affected by tumours caused by the loss of
heterozygosity for mutant alleles of lgl, something that,
no doubt, could be extrapolated to other fly populations
and TS genes.
The first Drosophila TSs, were identified in situ by the
massive growth of the brain in mutant third-instar
larvae (Gateff, 1978). However, most mutant alleles of
TS genes cause early lethality, and homozygous
individuals do not reach such a late stage. In these
cases, TS activity is detected by the overgrowth of clones
of mutant cells induced in heterozygous individuals
(Bilder, 2004). Dozens of genes are now known to fulfil
this definition, particularly in imaginal discs tissue.
However, the tumours caused by the loss of function for
most of these TSs are not invasive and cease to
proliferate as they undergo terminal differentiation
together with the surrounding wild-type tissue. Typically, the final consequence of mutation in such TSs is
limited to an ectopic lump of dead cuticle that has no
effect on the performance and lifespan of the affected
individual (Watson et al., 1994; Bilder, 2004). Therefore,
such tissue overgrowths bear little resemblance to cancer
(Hanahan and Weinberg, 2000). How can a given type
of in situ overgrowth in a fly tissue be characterized as
malignant? In Drosophila, as in vertebrate cancer
models, the best established assay is to implant the
affected tissue into a healthy host (allograft culture, also
known as ‘dauer’ culture) (Gateff, 1978; Gonzalez,
2007). Upon implantation, wild-type tissue never overgrows, and benign hyperplasias grow slowly, and do not
invade other tissues and retain the capacity for
differentiation. Malignant neoplasms, in contrast,
Asymmetric division and cancer
J Januschke and C Gonzalez
6995
display autonomous growth, the ability to migrate to
and colonize distant organs, and result in lethality to the
host. Moreover, malignant neoplasms frequently become immortal and can be expanded limitlessly
through successive rounds of implantation into healthy
hosts. Thus, in addition to its diagnostic potential,
allograft culture circumvents the short time window
imposed by Drosophila development and can be used to
age tumours for months, or years, thus providing a
means to test for changes that might occur during longterm tumour progression. Another advantage of allograft culture is that it provides extra time that may be
critical for the growth of tumours that might not be able
to develop within the time constraints of larval
development.
Drosophila NBs as SC models
Drosophila NBs originate as cells that delaminate from
the embryonic neuroepithelium. Acquisition of NB
identity imposes a self-renewing asymmetric mitosis
mode, whereby each of the two daughter cells acquires
one of the two possible developmental fates: NB or
ganglion mother cell (GMC; Chia et al., 2008; Doe,
2008; Gonczy, 2008; Knoblich, 2008). GMCs can be
considered as intermediate progenitors to use the
terminology that is common in vertebrates, that divide,
normally just once, to generate cells that eventually
differentiate into neurons or glia. Therefore, some of the
key processes that characterize SCs occur in Drosophila
NBs. Nevertheless, it is worth pointing out that, as in
any other model, there are some limitations here.
Firstly, NBs are SCs that operate exclusively during
development. Unlike adult SCs that ensure homoestasis
through the lifetime of the individual, NBs are
programmed to disappear once neurogenesis is completed and are not immortal (Truman and Bate, 1988;
Ito and Hotta, 1992; Maurange et al., 2008). Secondly,
whereas asymmetric NB division is self-renewing, in the
sense that one of the daughters retains NB identity and
will continue the programme of asymmetric mitoses,
self-renewal might not be complete and daughter NBs
might be more restricted than their mother NBs in terms
of the cell types that they can generate. Such progressive
restriction in competence has been demonstrated in
embryonic NBs (Isshiki et al., 2001; Pearson and Doe,
2003), and cannot be excluded in larval NBs as well
(Doe, 2008). Finally, another potentially significant
difference between Drosophila larval NBs and adult
SCs is the dependence on an SC niche. The SC niche can
be defined as the specific anatomic location that
regulates how SCs participate in tissue generation,
maintenance and repair (Scadden, 2006). Drosophila
GSCs fulfil this definition because they are totally
dependent on direct contact with a niche of specialized
cells to the extent that GSCs that abandon their niche
lose SC identity and differentiating daughter cells that
establish ectopic contact with the niche might acquire
SC identity (Brawley and Matunis, 2004; Kai and
Spradling, 2004). Indeed, NBs occupy defined anatomical
positions during development and are in close contact
with neighbouring cells: their most recent daughters on
the basal side (Truman and Bate, 1988), and cortex glial
cells on their apical and lateral sides (Dumstrei et al.,
2003). Moreover, NBs are not insensitive to their
neighbours and are definitively responsive to signals
like Anachronism or Activin, which are secreted by
larval glia (Ebens et al., 1993; Zhu et al., 2008) as
well as to Notch, and other signalling pathways that
control the number of proliferating NBs in the larval
brain (Park et al., 2003; Wang et al., 2006; Lee et al.,
2006a). However, the presence of a cell niche necessary
for maintaining the NB self-renewing asymmetric
division programme has not been demonstrated
(Doe, 2008). If anything, the ability of isolated
embryonic and larval NBs to continue dividing in a
self-renewing asymmetric manner, when cultured in vitro
strongly argues the contrary (Wu et al., 1983; Broadus
and Doe, 1997; Feiguin et al., 1998; Ceron et al.,
2006).
The asymmetric division machinery of Drosophila NBs
Self-renewing asymmetric division of Drosophila NBs
relies on the tight coordination of two processes: (i) the
differential sorting of several protein complexes that
leads to the generation of cortical asymmetry within
these cells (Chia et al., 2008; Gonczy, 2008; Knoblich,
2008) and (ii) the controlled positioning of the plane of
cytokinesis that leads to the unequal segregation of
those cortical protein complexes between the daughter
cells (Gonzalez, 2007). Clearly, both of these processes
are necessary, but neither of them is sufficient.
Complexes sorted to the apical cortex and inherited
by the daughter cell that retains NB identity include the
Par and Pins (Partner of inscuteable or Rapsynoid)
complexes, which can interact through the bridging
protein Insc (Kraut et al., 1996; Schober et al., 1999;
Schaefer et al., 2000; Petronczki and Knoblich, 2001).
The core components of the Par complex include
Bazooka (Baz/Par3), Par6 and Atypical protein kinase
C (aPKC; Wodarz et al., 1999; Petronczki and
Knoblich, 2001; Rolls et al., 2003). The main partners
complexed with Pins are Galphai and Mushroom body
defect (Mud; Parmentier et al., 2000; Schaefer et al.,
2000; Yu et al., 2003; Izumi et al., 2004, 2006; Bowman
et al., 2006; Siller et al., 2006). Both complexes contain
known auxiliary modulators (Chia et al., 2008; Knoblich, 2008), the number of which is steadily increasing
(Atwood et al., 2007; Chabu and Doe, 2008; Speicher
et al., 2008). Proteins sorted to the basal cortex, and
hence inherited by the daughter cell that is primed to
lose NB identity and to enter the differentiation
programme, include Staufen, Prospero and Brain
tumour (Brat) that are in a complex with the scaffolding
protein Mira, and the Partner of Numb (Pon)-Numb
complex (Doe et al., 1991; Ikeshima-Kataoka et al.,
1997; Li et al., 1997; Shen et al., 1997; Lu et al., 1998;
Betschinger et al., 2006; Lee et al., 2006c; Caussinus and
Hirth, 2007). Other elements of this intricate molecular
Oncogene
Asymmetric division and cancer
J Januschke and C Gonzalez
6996
machinery are the protein kinases CDK1 (cdc2), Polo
and Aurora A (Tio et al., 2001; Wang et al., 2006, 2007;
Lee et al., 2006a), and the cortical proteins Discs large
(Dlg), Lgl and Scribbled (Scrib; Ohshiro et al., 2000;
Peng et al., 2000; Albertson and Doe, 2003; Humbert
et al., 2003). These last three genes, dlg, lgl and scrib
were previously known by their TS activity.
Sorting the apical and basal protein complexes that
control NB asymmetric division would serve no
purpose, if cytokinesis did not ensure the unequal
distribution of these complexes between the two
daughter cells. Controlled orientation of the plane of
cleavage, which is governed by the orientation of the
mitotic spindle, is therefore an integral part of the
asymmetric division machinery (Kraut et al., 1996;
Kaltschmidt et al., 2000). Perhaps not surprisingly, some
of the cortex-bound polarized cues take part in spindle
alignment. In particular, the Pins–Galphai–Mud complex is thought to anchor the aster of one of the spindle
poles during mitosis (Bowman et al., 2006; Izumi et al.,
2006; Siller et al., 2006). Combined live imaging of
spindle assembly and centrosome function has shown
that spindle orientation in larval NBs is determined, at
least partially, from early interphase, much earlier than
any of the known polarized markers can be seen at the
apical cortex of the cell (Rebollo et al., 2007; Rusan and
Peifer, 2007). Soon after cytokinesis, both centrosomes
migrate to the nearest cortex, which roughly coincides
with the region where apical markers were last localized.
A few minutes later, the two centrosomes start to
display a markedly asymmetric behaviour. One of them
stays fixed at the apical cortex organizing an aster that
will be the main microtubule network during most of the
NB interphase. Orientation of the future mitotic spindle
can be accurately predicted from the position of this
apical aster and can, therefore, be considered predetermined at such an early stage of the cell cycle. The second
centrosome, which has little, if any, pericentriolar
material (PCM) and does not display any significant
microtubule organisation activity, moves extensively
throughout the cytoplasm, mainly on the apical side
first, more basally later, and until shortly before mitosis,
it slows down near the basal cortex, recruits PCM and
organizes the second mitotic aster. Thus, the two
centrosomes of an NB are very different structurally
and functionally. They are also unequal in fate as the
apical centrosome remains in the SC, whereas the other
centrosome goes into the differentiating daughter.
How the centrosome identifies the presumptive apical
cortex is not known (Figure 1). Polarized cortical
markers are not detected after mitosis, and the first sign
of them getting back to the cortex occurs very late in the
cell cycle, when mitosis starts, with the accumulation of
Baz in prophase (Siller et al., 2006). It is possible that
still unknown polarization markers tag the apical cortex
for the entire length of the cell cycle and serve as cues for
the migration of the centrosome to the cortex. Alternatively, the positioning of the centrosome at the cell
cortex might contribute to triggering the sorting of the
apical markers at each cell cycle. Maintenance of the
active microtubule organisation centre at its fixed
Oncogene
Figure 1 The timing of polarity markers during the cell cycle of
larval NBs. Markers that are asymmetrically localized at the apical
(blue) or basal (red) cortex have been observed during mitosis,
from prophase to late telophase. No such markers have been
observed during interphase, thus opening the question of how cell
polarity is maintained or reestablished from one cell cycle to the
next. The microtubule network of these cells (green), that remains
highly polarized through most of the interphase with its microtubule organizing centre (orange) tightly bound to the presumptive
apical cortex could be part of the answer. NBs, neuroblasts.
cortical position requires Pins (Rebollo et al., 2007).
However, the mechanism by which Pins might exert this
function that is required much earlier than the apical
crescent of Pins can be detected remains unclear. A
suspected regulator of this process is Polo (Rusan and
Peifer, 2007), which also controls the apical sorting of
aPKC and Numb (Wang et al., 2007). Interestingly,
cultured individual NBs show the same asymmetric
centrosome behaviour as NBs observed ‘in toto’,
strongly suggesting that the regulation of such stereotyped behaviour does not depend on the cross talk
between NBs and their neighbouring cells (Rebollo
et al., 2007).
Self-renewing asymmetric division of NBs and tumour
suppression
The possible functional link between failed NB asymmetry and tumour growth was first suggested by the
identification of known TS genes, such as lgl or dlg, as
key regulators of NB asymmetry (Wodarz, 2005). Direct
demonstration of such a link came, when pieces of larval
brain tissue mutant for any of several elements that
regulate NB asymmetry, including notably all known
cell-fate determinants, were shown to develop malignant
tumours when transplanted to the abdomen of adult
hosts (Caussinus and Gonzalez, 2005). Since then, many
more of these proteins have been shown to be TSs, both
in allograft culture and in situ in the larval brain
(Table 1).
Protein complexes sorted to the basal cortex contain
cell-fate determinants that negatively regulate NB selfrenewal and promote neuronal differentiation. The
transcription factor Prospero is normally segregated to
the GMC, where it enters the nucleus and regulates
Asymmetric division and cancer
J Januschke and C Gonzalez
6997
Table 1 Tumour suppressor activity of asymmetric cell division genes
Mutant a
Overgrowth
In situ
Clonal
analysis
aPKC
aPKC GOF
pins
mira
brat
References
Allograft culture
NB
duplicationb
Immortal, invasive
metastatic
growth
Limited
growth
potential
+
+
+
+
+
+
+
pros
+
+
numb
lgl
dlg
mud
sas6
sas4
sak
sak GOF
asl
cnn
aurA
polo
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
Lee et al., 2006c; Caussinus and Gonzalez, 2005
Lee et al., 2006c
Rebollo et al., 2007; Lee et al., 2006c; Caussinus and Gonzalez, 2005
Betschinger et al., 2006; Caussinus and Gonzalez, 2005
Lee et al., 2006b; Betschinger et al., 2006; Bello et al., 2006;
Caussinus and Gonzalez, 2005; Gateff, 1978
Lee et al., 2006b; Choksi et al., 2006; Betschinger et al., 2006;
Caussinus and Gonzalez, 2005
Lee et al., 2006a; Bowman et al., 2006; Caussinus and Gonzalez, 2005
Lee et al., 2006c; Betschinger et al., 2006; Gateff, 1978
Gateff, 1978
Siller et al., 2006; Bowman et al., 2006; Izumi et al., 2006
Castellanos et al., 2008
Castellanos et al., 2008; Basto et al., 2006
Castellanos et al., 2008
Basto et al., 2008
Castellanos et al., 2008; Rusan and Peifer, 2007
Lucas and Raff, 2007
Castellanos et al., 2008; Lee et al., 2006a; Wang et al., 2006
Castellanos et al., 2008; Wang et al., 2007
a
GOF: gain of function, all other situations refer to loss of function.
Symmetric NB divisions reported by live imaging.
b
genes that are crucial for cell-cycle repression or
initiation of neuronal differentiation (Knoblich et al.,
1995; Broadus et al., 1998; Li and Vaessin, 2000; Choksi
et al., 2006). Likewise Brat, which is also sorted into the
GMC, is a translational repressor with dozens of
possible targets, which is required to restrain cell growth
(Sonoda and Wharton, 2001; Frank et al., 2002; Loop
et al., 2004). Larval brain tissue mutant for prospero or
brat develop massive malignant tumours in allograft
culture (Caussinus and Gonzalez, 2005) and displays
significant overgrowth in situ (Bello et al., 2006;
Betschinger et al., 2006; Choksi et al., 2006; Lee et al.,
2006c). Sorting of Brat and Pros to the GMC is
mediated by the adaptor protein, Mira. Consistently,
Mira loss of function also leads to overgrowth in situ
(Betschinger et al., 2006) and malignant tumour growth
in allograft cultures (Caussinus and Gonzalez, 2005).
Another key cell-fate determinant is Numb, best known
by its activity as a regulator of Notch signalling
(Schweisguth, 2004; Le Borgne et al., 2005). Following
its segregation into GMCs, Numb promotes differentiation and inhibits NB self-renewal (Wang et al., 2006; Lee
et al., 2006a). Like the loss of function for other cell-fate
determinants, allograft culture of Numb mutant clones
causes massive malignant tumours (Caussinus and
Gonzalez, 2005). Consistently, expression of an activated form of Notch yields increased NB number (Wang
et al., 2006), although Notch regulatory signalling seems
to be restricted to NBs in the optic lobes and to be
inactive in the ventral ganglion (Almeida and Bray,
2005).
Some elements of the apical cortex complexes can
also, if disrupted, cause overgrowth. Ectopic cortical
localization of aPKC inhibits cortical localization of
basal protein complexes (Betschinger et al., 2003; Rolls
et al., 2003; Smith et al., 2007), and leads to a dramatic
increase in NB numbers in situ (Lee et al., 2006b).
Consistently, loss of aPKC function leads to NB cellcycle arrest (Rolls and Doe, 2004), and does not result in
tumour growth in allograft cultures (Caussinus and
Gonzalez, 2005). Spindle misorientation in NBs with
otherwise normal cortical polarity can also cause overgrowth, as it has been proposed to occur in mud mutant
NBs (Bowman et al., 2006; Izumi et al., 2006; Siller
et al., 2006).
The behaviour of pins mutant larval brain tissue is
intriguing. In situ, loss of Pins function causes a
reduction in the number of NBs in late larval stages
(Lee et al., 2006b). However, pins mutant NBs have been
observed to divide symmetrically by live imaging
(Rebollo et al., 2007), and malignant tumours develop
from pins mutant tissue in allograft culture (Caussinus
and Gonzalez, 2005). The reason for this discrepancy is
unknown. Interestingly, all cases of mutants in which
symmetric NB division has been observed cause tumour
growth, benign or malignant, in allograft culture (Basto
et al., 2006, 2008; Siller et al., 2006; Lee et al., 2006a;
Lucas and Raff, 2007; Rusan and Peifer, 2007;
Castellanos et al., 2008) (Table 1).
Finally, some of the main kinases that regulate the
process are also TSs. Both AurA and Polo are necessary
to constrain aPKC to the apical cortex and regulate the
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Asymmetric division and cancer
J Januschke and C Gonzalez
6998
basal localization of Numb, and are required for spindle
alignment (Wang et al., 2006, 2007; Lee et al., 2006a).
Larval brain mutants for polo or aurA have supernumerary NBs (Wang et al., 2006; Lee et al., 2006a) and
develop as malignant tumours when implanted in adult
hosts (Castellanos et al., 2008).
Cell-of-origin of larval brain tumours
Several working models have been put forward as to what
are the cells-of-origin of the larval brain tumours and to the
mechanistic interpretation of how such a cell gets transformed (Figure 2). The simplest working model suggests
direct expansion of NBs (Siller et al., 2006; Lee et al.,
2006b). A second model calls on reversion from GMC to
NB fate (Betschinger et al., 2006; Lee et al., 2006c). Finally,
a third model proposes that overgrowth results from the
expansion of transient amplifying cell (Bello et al., 2008;
Bowman et al., 2008; Boone and Doe, 2008).
Direct NB expansion might apply to cases in which
uncoupling of spindle orientation from the apico-basal
axis of the cell results in cleavage planes that bisect the
NB in two halves that are symmetric, both in terms of
the cell-fate determinants that they contain and in size.
This has been proposed to occur in mud-mutant NBs
(Bowman et al., 2006; Izumi et al., 2006; Siller et al.,
2006). This model implies that the presence of apical
cortex components like aPKC is read by the system as
dominant over the presence of basally localized differentiation promoting determinants, as cells that inherit
both retain SC identity. This opens the question of how
intermediate situations are read by the system, for
example, how much aPKC a GMC can tolerate. This
model might also apply to situations in which aPKC is
ectopically localized over most of the NB cortex, as
reported in cases like expression of aPKC-CAAX, or the
combined loss of lgl and pins function (Lee et al.,
2006b). In these cases, the two daughter cells receive
aPKC, but no cortically localized cell-fate determinants.
Reversion of GMCs to an NB fate has been proposed to
explain tumour growth in pros and brat mutants as, in
their absence, GMCs cannot start their programme of
repression of self-renewal and activation of differentiation pathways (Betschinger et al., 2006; Choksi et al.,
2006; Lee et al., 2006c). This model implies that the
system interprets the loss of pros or brat as a dominant
situation to revert back to SC fate, and ignores other
determinants of differentiation like Numb. Finally,
some cases of overgrowth have been proposed to result
from alterations in the recently identified NB lineage
that produces transient amplifying cells (Bello et al.,
2008; Bowman et al., 2008; Boone and Doe, 2008).
Loss of Brat or Numb function in this lineage is thought
to inhibit the maturation of Asense-negative transient
amplifying cells into Asense-positive cells causing
them to overproliferate uncontrollably (Bowman et al.,
2008).
Unequivocal identification of the cell-of-origin of
these tumours will require data obtained by direct
imaging of mutant cells expressing a battery of markers
Oncogene
Figure 2 Models of the origin of Drosophila larval brain tumours.
(a) In most larval NBs (wt) asymmetric division self-renews the NB,
and creates a GMC (red) that divides into two daughters that
differentiate into neurons (black). Situations like uncoupling of
spindle alignment and polarity cues (1) or ectopic widespread
cortical localization of aPKC (2) are thought to give rise to equal
daughters that retain NB identity. In the absence of pros or brat,
the newborn GMC has been proposed to revert back to NB
identity (3). In all three cases, the result would be a net increase in
the number of NBs. (b) Asymmetric division of certain larval NBs
self-renews the NBs and creates transient amplifying cells (white).
After maturation (grey), these cells can enter mitosis generating
more of their kind and GMCs (red) that divide into two daughters
that differentiate into neurons. Loss of Brat or Numb function in
this lineage is thought to inhibit the maturation process and to
result in the uncontrolled growth of the immature cells (Bowman
et al., 2008). aPKC, atypical protein kinase C; GMC, ganglion
mother cell; NBs, neuroblasts.
for asymmetrically sorted proteins, spindle orientation
and cell type identity (Doe, 2008). Whichever the model
of overgrowth is, it will be essential to define the nature
of the overgrowing cells and what makes them different
from normal NBs or GMCs. This might require a
comprehensive quantitated understanding of the regulatory circuitry of the system with all its integrating
elements, which we do not have at the moment.
Genome instability and centrosome dysfunction in larval
brain tumours
The possibility of creating experimentally induced
tumours in Drosophila is being exploited to tackle some
fundamental questions pertaining to the origin of
tumours. One example is Boveri’s old proposal to
explain the origin of human tumours–supernumerary
Asymmetric division and cancer
J Januschke and C Gonzalez
6999
centrosomes cause chromosome instability that triggers
tumourigenesis (Boveri, 2008). Indeed, different types of
genome instability (GI), including chromosome instability and centrosomal alterations are common traits in
human cancer (Lengauer et al., 1998; Duensing, 2005).
However, Boveri’s proposal, as originally stated or in its
more modern versions that accommodate for a wider
range of centrosome abnormalities, remains hypothetical, and direct experimental proof is still lacking (Nigg,
2006).
This hypothesis has recently been tested in Drosophila
by assaying the tumourigenic potential of cells that have
been genetically manipulated to contain centrosome
abnormalities that phenocopy those proposed as potentially tumourigenic (Basto et al., 2008; Castellanos et al.,
2008). Several types of centrosome dysfunction, including supernumerary centrosomes, were found to be
potent tumourigenic conditions in larval brains kept in
allograft culture. Interestingly, both benign tumours
that had a limited growth potential, and malignant
neoplasms that grew unrestrainedly, spreading over
different parts of the host’s anatomy and killing the
host were observed (Basto et al., 2008; Castellanos et al.,
2008). These results provide the first direct demonstration of a causative relation between abnormal centrosomes and cancer. However, GI is unlikely to be the key
event that initiates these tumours because genome
alterations that phenocopy those found in vertebrate
tumours are poorly tumourigenic, if at all, in the absence
of abnormal centrosomes in Drosophila (Castellanos
et al., 2008). Consistently, tumourigenic activity and GI
do not seem to correlate. Sak overexpression results in
supernumerary centrosomes, but the initial multiple
spindle poles cluster in two and eventually bipolar
spindles are assembled (Basto et al., 2008), and
chromosome segregation occurs faithfully in most cells.
Likewise acentriolar dsas4 mutant cells often manage to
assemble acentrosomal spindles and equal chromosome
segregation occurs in most cells (Basto et al., 2006). Yet,
despite the relatively low levels of chromosome instability caused by Sak overexpression or loss of dsas-4,
these conditions often cause malignant neoplasms
(Basto et al., 2006; Castellanos et al., 2008).
It is important to stress that whereas these results
strongly suggest that the tumours caused by centrosome
dysfunction in Drosophila cannot be accounted for
solely by GI, they cannot be taken as evidence to discard
a possible role of GI in tumourigenesis. Moreover, GI is
a common trait in Drosophila tumours that develop in
allograft cuture (Caussinus and Gonzalez, 2005; Castellanos et al., 2008). Regardless of whether the
mutation that originated the tumour causes a certain
level of GI in situ, like aurA or dsas-4 mutant alleles do,
or none at all, like pros, mira and others, tumours that
grow in allograft culture eventually display significant
levels of chromosomal alterations that affect both
chromosome integrity and number (Caussinus and
Gonzalez, 2005; Castellanos et al., 2008). As allograft
culture per se does not cause GI (Remensberger, 1968),
such tumour-associated GI might reflect a downstream
consequence of tumourigenesis. It will be interesting to
determine whether such tumour-associated GI contributes to the worsening of malignant traits displayed by
some of these tumours.
It is still uncertain how centrosome dysfunction
generates tumours in larval brains, but the simplest
hypothesis is that it does so by perturbing the
segregation of cell-fate determinants, a condition known
to cause tumour growth in these cells (Gonzalez, 2007).
Consistent with this interpretation, different degrees of
perturbed NB self-renewing asymmetric division have
been reported in the centrosome dysfunction conditions
that cause tumours in larval NBs, and the extent of such
perturbations correlates well with the ability to generate
tumours (Basto et al., 2006; Castellanos et al., 2008).
Moreover, the tumourigenic activity of centrosome
dysfunction is negligible in imaginal discs (Castellanos
et al., 2008), which do not grow by the self-renewing
asymmetric division of SCs. There are different mechanisms by which centrosome dysfunction can be envisaged
to perturb self-renewing NB asymmetric division. An
obvious one is by compromising the alignment of the
spindle along the apico-basal axis of the NB (Basto et al.,
2006; Bowman et al., 2006; Izumi et al., 2006; Siller et al.,
2006). Loss of function of some centrosomal proteins that
directly control the sorting of some of the elements of the
asymmetric self-renewing machinery might also impair
this process (Wang et al., 2006, 2007; Lee et al., 2006a).
Finally, centrosome dysfunction could affect the mechanisms that establish robust NB polarity after each round of
mitosis (Siegrist and Doe, 2005; Rebollo et al., 2007;
Rusan and Peifer, 2007).
Therefore, rather than being linked to chromosome
segregation, the tumourigenic activity of centrosome
function in Drosophila seems to be directly related to
self-renewing asymmetric SC division, thus adding
further support to the view that the initial event that
triggers tumourigenesis in this model system might be
failed developmental decisions. The possibility that
centrosome dysfunction might cause tumours when
affecting SC is tantalizing given the increasing evidence
suggesting that adult SCs may be the cell-of-origin of
certain tumour types (Beachy et al., 2004).
Acknowledgements
This study was supported by EU and Spanish Grants:
ONCASYM-037398 FP6, BFU2006-05813, SGR2005 Generalitat de Catalunya and Consolider-Ingenio2010 CENTROSOME_3D CSD2006-23.
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