ARTICLE
Auteur(s) : Agnès Bernet, Patrick Mehlen
Apoptosis, Cancer and Development Laboratory, Laboratoire
labellisé ‘La Ligue’, CNRS FRE2870, Centre Léon Bérard, 69008 Lyon,
France
Whilst the classic view for receptor function is mono-sided, i.e. a
receptor is inactive until bound and activated by its ligand,
during the last decade it has been suggested that some receptors
may display two sides, à la Jeckyll and Hyde: In the presence of
ligand, these receptors transmit positive signals of
differentiation, proliferation or migration, whereas in the absence
of ligand, they turn into deadly weapons driving cells to commit
suicide. Such a feature should lead cells expressing such receptors
to become dependent on the presence of their ligand for survival.A
growing number of so-called dependence receptors are being
identified: the low-affinity neurotrophin receptor
P75ntr[1], the androgen receptor AR [2], the DCC
receptors [3], RET (rearranged during transfection) [4], UNC5H [5],
Patched [6], neogenin [7], and integrins such as
αvβ3 and α5β1[8].
Interestingly, whereas these receptors are known to be involved in
the development of the nervous system when bound by their ligand,
they each have the ability to trigger apoptosis in the absence of
ligand. We propose to focus on the role of some of the receptors
most extensively studied so far: the dependence receptors for
netrin-1. Netrin-1 is a laminin-related molecule (figure 1) initially
discovered as a diffusible molecule produced by a ventral structure
in the developing spinal cord, i.e. floor plate, that attracts
commissural axons [9]. Netrin-1 is a member of a family of
homologous molecules like netrin-2, netrin-G1, netrin-G2 and
netrin-4/β-netrin. Although next to nothing is known about these
latest molecules, netrin-1 has been extensively described,
particularly by Tessier-Lavigne and collaborators. As such,
netrin-1 was shown to act as a chemoattractive or chemorepulsive
cue for many migrating axons and neurons. This effect is believed
to pass through two main families of type 1 transmembrane
receptors: DCC (for deleted in colorectal cancer) and its homolog
neogenin and the UNC5H-UNC5 homolog-receptors (UNC5H1, UNC5H2,
UNC5H3, UNC5H4) (figure
1). Because netrin-1 and its receptors have already been
reviewed for their role in neuronal guidance [10-12], we will
mainly describe here the implications of netrin-1, DCC and UNC5H in
apoptosis and consider the consequences on tumor escape mechanisms.
Role of DCC and UNC5H as dependence receptors
The role of DCC and UNC5H as receptors for netrin-1, a molecule
involved in axon guidance and neuron migration, suggested that
signal transduction occurred only in the presence of the ligand
netrin-1. Yet, we and others have shown that both DCC and UNC5H are
much more complex. Indeed, we have suggested these molecules to act
as dependence receptors, that are also active in the absence of
their ligand. Various cell transfection or viral infection
experiments have demonstrated that UNC5H or DCC, when expressed in
the absence of netrin-1, can induce cell death, whereas the
presence of netrin-1 is sufficient for blocking this pro-apoptotic
activity [3, 5, 13-17].
Little is known about the exact mechanism underlying the
pro-apoptotic activity of DCC and UNC5H. However, they both seem to
be cleaved by major proteases of the apoptotic pathway, caspases.
Caspases are cysteine proteases that cleave intracellular proteins
on the carboxyl side of an aspartate residue. Caspases involved in
apoptosis can be split into two groups: initiator caspases (e.g.,
caspases-8 and 9) and effector caspases (e.g., caspases-3, 6 and
7). Initiator caspases are activated by a death receptor pathway
(caspase-8) or a mitochondrial pathway (caspase-9). Their
activation initiates a proteolytic cascade that results in
activation of the effector caspases, thus rapidly triggering the
execution of apoptosis and ultimately leading to cell death.
The cleavage sites of UNC5H and DCC receptors are recognized in
vitro by caspase-3 (at position 412 for UNC5H and 1290 for DCC,
(figure 1)),
which does not necessarily imply that caspase-3 is responsible for
the cleavage of these receptors in vivo [3, 5]. Mutations of the
cleavage site prevent the pro-apoptotic activity of these
receptors, suggesting that cleavage is a prerequisite for cell
death induction by releasing/exposing a pro-apoptotic domain named
ADD (addiction dependence domain) lying in the intracellular domain
of DCC or UNC5H.
In UNC5H, the ADD domain is thought to be located downstream of
the caspase cleavage site and to encompass a death domain very
similar to that of proteins like Fas and TNFR receptors, that are
generally considered to mediate apoptotic signaling [5]. How the
death domain of UNC5H induces apoptosis is yet unknown, even though
it is probable that other death domain-containing proteins are
required. Along this line, we recently demonstrated that UNC5H2
interacts with a death domain containing serine/threonine kinase
protein named DAPK (death associated protein kinase) and that DAPK
is required for UNC5H2-induced cell death [18]). Besides the death
domain described above, UNC5H receptors harbor another domain, also
involved in cell death, ZU-5 domain. This domain is homologous to
zona occludens-1, an intercellular junction protein involved in
signaling. Recently, NRAGE, a protein of the MAGE (melanoma
antigen) family known to be a regulator of apoptosis, has been
identified as a specific binding partner of UNC5H1. The interaction
between NRAGE and UNC5H1 could activate the apoptotic pathway by
promoting the degradation of the survival protein XIAP (X-linked
inhibitor of apoptosis), or by activating the JNK (c-jun N-term
kinase) pathway [19].
In DCC, the ADD is located upstream of the caspase cleavage site
and is probably exposed through conformational changes after the
caspase-dependent release of the C-terminal domain [3]. The DCC ADD
domain has been shown to interact with caspase-9 in the absence of
netrin-1 [3, 13]. As evidenced in vitro so far [3], this
interaction is hypothesized to activate effector/downstream
caspases, thus forming an amplification loop leading to more DCC
cleavage and apoptotic cell death. Alternatively, other proteins
may also interact with the ADD of DCC, as recently shown by Chen
and colleagues. Indeed, DIP13 (DCC-interacting protein-13) has been
shown to interact with DCC ADD and to mediate DCC-induced cell
death [14].
Results obtained in vivo in netrin-1 knockout mice have
confirmed that cells expressing DCC and UNC5H are dependent on
netrin-1 for survival. Indeed In the absence of netrin-1, brainstem
cells, especially those expressing DCC and/or UNC5H genes, undergo
massive apoptosis [5]. Along the same line, while looking for a
role of UNC5H in neuronal axon guidance in Xenopus, Tessier-Lavigne
and collaborators used a UNC5H mutant deleted of its death domain
because expression of the wild-type receptor induced cell death
[20].
The physiological relevance of the “negative” face of these
receptors in the absence of netrin-1 can be dual. Indeed, whilst
DCC and UNC5H have been shown to impact positively on axon guidance
by acting as receptors for netrin-1, a negative control by these
receptors, i.e. cell death, can also occur. In this respect, the
dynamic regulation of axons during CNS development may result of
the combination of two opposite (negative and positive) control
mechanisms. The negative effect would be a “surveillance” mechanism
capable of eliminating cells that strayed beyond the ligand source.
In CNS cells, the growth and orientation of neurons would follow
receptor-mediated chemoattraction/repulsion pathways (depending on
the receptor expressed at the cell surface) in response to the
source of netrin-1. This response is dependent on the capacity of
receptors to bind netrin-1. When neurons migrate away from the
netrin-1 source, receptors that have become “unoccupied” may induce
cell death, thus preventing cells to migrate to “unwanted”
sites.
The second possible role in vivo is to regulate cellular
lifespan as recently proposed in intestinal villi. Indeed, the
expression profiles of netrin-1 and DCC in the normal intestine and
colon might suggest that cell survival regulation is dependent on
the DCC/netrin-1pair. In these tissues, the production of netrin-1
is restricted to the base of the intestinal crypt, whereas DCC is
distributed throughout the villi [21, 22]. This goes well with the
classic view of highly proliferative cells in the base of the
intestinal crypt that differentiate whilst moving to the distal
part of the villi/crypt and that eventually detach and die or die
and detach (figure
2). In this view, proliferating crypt cells that express
DCC in a netrin-1-rich environment would be protected from cell
death, whereas epithelial cells that have stopped proliferating to
differentiate and move towards the villus tip would progressively
be placed into a netrin-1-deprived environment, leading to
apoptotic cell death (figure 2). In that
respect, we have shown that overexpressing netrin-1 throughout the
intestinal epithelium contributes to reducing apoptosis by
approximately 50 % [22]. One may speculate that the apparent
proximal-to-distal netrin-1 gradient may function as a regulatory
system that limits the lifespan of cells that undergo (i) multiple
proliferative steps within the crypt, and (ii) repeated mechanical
and chemical insults originating from the intestinal lumen, two
conditions that may increase the risk of cell damage and resultant
aberrant behavior. Consequently, induction of cell death due to
absence of superficial netrin-1 expression, together with the
mechanical detachment of cells in the lumen, may represent key
factors for limiting the initiation of malignant
transformation.
Role of dependence receptors UNC5H and DCC in colorectal
tumorigenesis
Due to the dependence mechanism described above, DCC and UNC5H
could potentially be involved in tumor suppression. The
receptor/netrin-1 pairs may indeed limit tumor development by
inducing apoptosis of cells that have acquired transforming
capacities. Any tumor cell submitted to an inadequate/abnormal
environment (highly proliferative cells in a environment with
limited and constant netrin-1 concentration, migration to other
tissues because of metastatic propensities) would display unbound
dependence receptors, thus triggering the pro-apoptotic activity of
DCC and/or UNC5H, which would ultimately lead to cell death and
subsequent tumor regression. In cancer, the deletion of genes
coding for DCC and UNC5H would induce loss of the pro-apoptotic
signal, thus providing a selective advantage for tumor escape.
Along this line, in the early 90s, the DCC gene was proposed as
a putative tumor suppressor gene. Data supporting this proposal
included observations that a DCC allele, located on chromosome 18q,
was deleted in over 70 % of colorectal cancers and a number of
other tumors [23, 24]. Interestingly, in most reports, allelic
losses of 18q are infrequent in early stage tumors (e.g. small
adenomas), but are common in primary colorectal carcinomas and
nearly 100% of hepatic metastases arising from colorectal
primaries, implying that chromosome 18q LOH (loss of
heterozygosity) may contribute more to progression rather than
initiation of colorectal cancer. In more than 90 % of primary
colorectal cancers with LOH of chromosome 18q, DCC is included in
the region of allelic loss [24, 25]. Most studies have linked
chromosome 18q LOH in colorectal cancers to a reduction in DCC
expression both at the RNA level [25] and at the protein level
[26]. LOH of chromosome 18q and/or decreased DCC expression have
also been seen in various other cancers, including gastric,
prostate, endometrial, ovarian, esophageal, breast, testicular,
glial, neuroblastoma, and hematologic malignancies [10].
Chromosome 18q LOH has been associated with poor prognosis in
colorectal cancer patients lacking lymph nodes or distant
metastases at the time of surgery (so-called stage II), as well as
in patients who have lymph nodes but no distant metastases at the
time of surgery (stage III) [27, 28]. In other studies, chromosome
18q LOH has also been associated with decreased responsiveness to
5-fluorouracil-based adjuvant chemotherapy regimens in stage III
colorectal cancer patients [29, 30]. Loss of DCC expression was
often associated with poor prognosis and increased risk of
metastasis [31, 32]. The data indicating that 18q allelic loss and
decreased DCC expression are associated with poor prognosis and
possibly decreased response to adjuvant chemotherapy in colorectal
cancer patients are interesting and of potential clinical
significance. Nevertheless, the findings do little to establish
whether DCC loss/inactivation is a critical factor in tumorigenesis
or merely an epiphenomenon. Some evidence that DCC inactivation may
in fact be associated with tumorigenic growth properties in colon
and other cancers has been obtained. For example, introduction of
an intact copy of chromosome 18 into a colorectal cancer cell line
lacking endogenous DCC expression yielded detectable levels of DCC
transcripts and resulted in suppression of growth in soft agar and
tumorigenicity in nude mice [33]. Also, ectopic expression of DCC
in a tumorigenic keratinocyte cell line lacking endogenous DCC
expression was shown to suppress tumorigenic growth of the cells in
nude mice [34]. Interestingly, in this study, it was observed that
tumorigenic reversion was associated with loss of DCC expression
and loss or rearrangement of the transfected DCC expression vector
[34]. Several more recent studiesalso indicate that restoration of
DCC expression can suppress tumorigenic growth properties in vitro
or in nude mice [35, 36]. More recently, an interesting study
suggestsARRAY(0x218c8c) that the DCC/netrin-1 pair is important in
endometrial carcinogenesis because (i) DCC is lost in nearly all
the endometrial cancer cell lines tested and (ii) re-expression of
DCC in these cell lines drives apoptosis, a phenomenon blocked by
the presence of netrin-1 [37]. However, beside these numerous
arguments towards a role of DCC as a tumor suppressor gene, various
concerns, such as the rarity of point mutations identified in DCC
coding sequences, the absence of DCC germline mutations involved in
a heritable cancer predisposition or the lack of a tumor
predisposition phenotype in mice heterozygous for Dcc inactivating
mutations, together with the presence of other known and candidate
tumor suppressor genes on chromosome 18q, have raised questions
about the role of DCC. However, as discussed in detail in another
review [10], none of these concerns appears sufficient to discard
the hypothesis that DCC acts as a tumor suppressor gene.
Similarly, it has been observed that the expression of UNC5H is
strongly reduced in more than 90 % of colorectal cancers, as
well as in many other tumors. In colorectal cancers, this reduction
has been mostly associated with UNC5H1 and UNC5H3 [16]. In this
case, allelic losses have been observed, but it is tempting to
attribute the loss of UNC5H expression to epigenetic mechanisms
such as promoter methylation [16]. Moreover, UNC5H2 has been shown
to be a direct transcriptional target of the p53 tumor suppressor
gene whose pro-apoptotic activity is known to be dependent on the
p53-dependent expression of UNC5H2 and can be antagonized by the
presence of netrin-1 [15]. Moreover, several in vitro experiments
have shown that DCC and UNC5H compromise the hallmark features of
cell transformation: anchorage-independent growth and ability to
invade through a Matrigel matrix [10-16].
To evaluate the role of DCC and UNC5H receptors in tumorigenesis
and to avoid the usual bias of using inactivating strategies
(knock-out) in which both the positive (netrin-1 dependent signals)
and the negative (apoptosis in the absence of netrin-1) pathways
are inactivated, we have developed an alternative method. Indeed
theorically, there are two mechanisms by which dependence receptors
might cause cancer: either the receptors are inactivated or deleted
somehow so that cell death is no longer promoted when there is
little or no ligand, or the ligand is present in excess or in the
wrong location, so that inapropriate cell survival is
encouraged;
We then chose to generate mice that overexpress netrin-1 in the
intestinal epithelium, in order to prevent receptor-induced cell
death (figure
2B). We indeed have observed that the targeted
overexpression of netrin-1 throughout the digestive tract can
produce approximately 50 % cell death inhibition in the
intestinal epithelium [22]. This inhibition of cell death, in
agreement with the model proposed for cell lifespan regulated by
netrin-1 control of DCC-induced cell death, is associated with the
formation of numerous focal hyperplasias (compared to control mice)
and of adenomas [22]. Thus, inhibition of cell death by netrin-1 is
associated with an increased initiation of colorectal
tumorigenesis. Because DCC loss in humans is very often considered
as a late event, netrin-1-overexpressing mice are backcrossed in a
mouse model in which colorectal tumorigenesis is initiated by a
mutation in adenomatous polyposis coli (APC) [38]. Interestingly,
while APC mutated mice develop low grade adenomas, the development
of tumors in the APC/netrin-1 mice was pushed toward high grade
adenoma and adenocarcinoma [22] (figure 3). The above
results demonstrate that blocking cell death induced by netrin-1
overexpression is associated with both an initiation and a
progression of colorectal tumorigenesis [22], thus confirming that
dependence receptors expressed in the digestive tract play a role
in tumorigenesis.
Several key issues remain to be answered. First, which is the
receptor involved? Indeed, whether it is DCC or UNC5H1-3 remains to
be shown. Interestingly, UNC5H and DCC proteins display a distinct
localisation inside the intestinal villi: UNC5H2 and DCC appear to
be present along the whole intestinal villi while UNC5H3 is present
only within the crypt [22]. Together with the fact that
overexpression of netrin-1 in the mouse model described above shows
two “time window” effects, one during early phase of tumorigenesis,
as illustrated by the adenomas and focal hyperplasias observed in
these mice, and one late effect with the formation of
adenoma-carcinomas in the APC/netrin-1 mice-, this would point to
regulatory functions of these dependence receptors at different
times of colorectal tumorigenesis. A second question is related to
netrin-1 expression in human colorectal tumors, as it would be
expected that a similar selective advantage for a tumor is either
to lose receptor expression (as it occurs for DCC and/or UNC5H) or
to gain netrin-1 expression. A preliminary set of data has shown
that overexpression of netrin-1 is only rarely associated with
human colorectal cancer (7 % of the tested tumors) [22],
therefore suggesting that gain of netrin-1 or loss of the receptor
do not represent a similar selective advantage. Further work will
have to analyse whether this effect is restricted to colorectal
cancers or if it is general to cancer development.
More work has to be performed to discard that the effect seen in
netrin-1 overexpressing mice is indeed due to the inhibition of DCC
or UNC5H-induced cell death by netrin-1 and not to the fact that
netrin-1 overexpression leads to over-stimulation of alternative
receptors, such as integrins or A2b, nore to the fact that netrin-1
has a positive effect on tumor development due to
chemoattrative/chemo-repulsive activities. Indeed, it was recently
suggested that UNC5H2 plays a role in embryonic angiogenesis, even
though this probably occurs independently of netrin-1 [39]. It was
also shown that netrin-1 can enhance angiogenesis in a
DCC/UNC5H-independent mechanism [40]. However, it is fair to say
that netrin-1 receptors such as DCC and UNC5H are probably involved
in tumor growth control and can thus be seen as tumor suppressors,
even though their pro-activities in low netrin-1 presence largely
differ from the growth inhibitory activity of other known tumor
suppressors such as Rb that constitutively repress cell cycle. DCC
and UCN5H only acquire their suppressive activity when cells grow
abnormally and/or migrate to “unwanted” sites where the ligand
concentration is low. Dependence receptor-initiated apoptosis then
represents a novel paradigm for the controlled removal of malignant
cells that have strayed beyong region of ligand availability. This
is why we have named these receptors “conditional” tumor
suppressors. Whether these conditional tumor suppressors or their
pro-apoptotic signaling pathways will turn out to be interesting
targets for cancer therapy remains now to be investigated.
Acknowledgments
We wish to thank H. Bilak for critical reading of the manuscript.
The work performed in Mehlen’s laboratory is supported by the Ligue
Contre le Cancer, the Centre National de la Recherche Scientifique,
the Ministère de la Recherche et de la Technologie (ACI), the
Association pour la Recherche contre le Cancer (ARC), the Fondation
de la Recherche Médicale (FRM), the National Institute of Health
(NIH).
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