Download CONTRIBUTION OF STEM CELLS AND DIFFERENTIATED CELLS

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CONTRIBUTION OF STEM CELLS
AND DIFFERENTIATED CELLS TO
EPIDERMAL TUMOURS
David M. Owens and Fiona M. Watt
The outer covering of the skin — the epidermis — is subject to sustained environmental
assaults. As a result, many cells acquire potentially oncogenic mutations. Most cells are lost
through differentiation, and only long-term epidermal residents, such as stem cells, accumulate
the number of genetic hits that are necessary for tumour development. So, what genetic and
environmental factors determine whether a mutant stem cell forms a tumour and what type of
tumour will develop?
APOCRINE GLAND
A tubular gland of secretory cells
that functions primarily to
produce scent.
ECCRINE GLAND
A tubular gland of secretory cells
that functions primarily in heat
regulation through the
production of sweat.
KERATINOCYTE
The most abundant cell type in
the epidermis. Keratinocytes are
epithelial cells and produce hair
follicles, sweat and sebaceous
glands, and the outer covering of
the skin.
Cancer Research UK,
London Research Institute,
Keratinocyte Laboratory,
44 Lincoln’s Inn Fields,
London WC2A 3PX, UK.
Correspondence to F.M.W.
e-mail:
[email protected]
doi:10.1038/nrc1096
444
The epidermis — the outer covering of the skin — comprises a multilayered epithelium (known as the interfollicular epidermis (IFE)) and associated hair follicles,
sebaceous glands and sweat glands (FIG. 1a). The epidermis
is maintained throughout adult life by stem cells that selfrenew and also generate progeny that undergo terminal
differentiation1. The single terminal differentiation pathway within the IFE eventually leads to the production of
the dead, cornified epidermal layers that provide a protective covering for the skin. The terminally differentiated
cells of the sebaceous gland are lipid-filled sebocytes that
burst and release their contents onto the skin surface. The
hair follicle is a more complex structure, comprising eight
different cell lineages; the visible culmination of terminal
differentiation within the follicle is the production of
hairs that project from the surface of the skin (FIG. 1a).
There are two types of sweat glands — APOCRINE and
ECCRINE — but their relationship with the stem-cell compartment is less well defined, and in mouse skin they are
confined to non-hair-bearing regions.
Epidermal stem cells are able to differentiate along
each of the epidermal lineages (reviewed in REFS 2,3).
Stem cells in the hair follicle can give rise to sebocytes
and the IFE4,5, whereas, with appropriate mesenchymal
stimuli, cells of the IFE can be induced to differentiate
into hair and sebocyte lineages6,7. Although any epidermal stem cell can generate all of the epidermal lineages
(FIG. 2a), it is our view that stem cells feed only one or a
subset of lineages under steady-state conditions, the
choice of lineage being determined by the specific
location or microenvironment of the cell3,8 (FIG. 2b).
Stem cells are not the only cells within the epidermis
that are capable of proliferation. Stem-cell progeny that
are destined to undergo terminal differentiation can
divide a small number of times before they irreversibly
exit the cell cycle; these are known as transit (or transient)
amplifying cells1,9. Divisions of transit amplifying cells
increase the number of terminally differentiated cells that
are produced by each stem-cell division. As a result, stem
cells divide infrequently in undamaged, steady-state
epidermis, even though they have a high capacity for selfrenewal. The differentiation potential of transit amplifying cells has only been examined extensively in cultured
human epidermis in which the sole detectable differentiated lineage is the IFE10,11. It is therefore unclear whether
transit amplifying cells are restricted to a single terminal
differentiation pathway — in other words, they are committed progenitors by analogy with the haematopoietic
system12 — or whether they have the ability to differentiate along all of the epidermal lineages and differ from
stem cells only in self-renewal ability.
Stem cells and the genesis of epidermal tumours
The role of the epidermis is to protect our bodies from
a wide range of environmental assaults, including
ultraviolet (UV) irradiation, chemical carcinogens,
and the entry of viruses and other pathogens. As a
result, epidermal KERATINOCYTES have a high risk of
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INTEGRINS
Summary
Heterodimeric transmembrane
glycoproteins that are receptors
for extracellular-matrix proteins.
DMBA
(7,12Dimethylbenz[a]anthracene).
Bay-region diol-epoxide-type
chemical carcinogen. Induces an
A→T transversion of codon 61
in Hras.
TUMOUR PROMOTER
Induces epigenetic changes that
select for clonal expansion of
mutated cells. The phorbol ester
type, TPA, is the most widely
used tumour promoter in
mouse skin carcinogenesis
models.
• Epidermal stem-cell progeny give rise to the
differentiated cells of the interfollicular epidermis
(IFE), hair follicles and sebaceous glands.
• Multipotent epidermal stem cells are likely to be the
main target cells for the various types of epidermal
tumour.
• Differentiated cells can regulate the clonal expansion
of mutant stem-cell clones.
• Epidermal cancer comprises many different tumour
types, including basal-cell carcinoma (BCC),
squamous-cell carcinoma (SCC), trichofolliculoma,
pilomatricoma and sebaceous adenoma.
• Factors responsible for the genesis of specific tumour
types have been identified. Some, such as RAS and p53,
are important for growth, and others, such as
β-catenin, are important for determining
differentiated characteristics.
acquiring an oncogenic mutation. However, relatively
few skin cancers develop because most cells that acquire
mutations are lost through the normal process of terminal differentiation, and it takes more than one genetic
lesion to cause a tumour. Most tumours are clonal in
origin13 and it has been estimated that five events in
humans, and two or three in rodents, are required to
transform a normal cell into a cancer cell14,15. So, only
long-term residents of the epidermis, and therefore presumably stem cells, have the ability to accumulate the
number of genetic hits that are necessary to result in
tumour formation.
a Normal skin
b Squamous-cell carcinoma
IFE
HF
SG
c Trichofolliculoma
d Sebaceous adenoma
Figure 1 | Diversity of epidermal tumours reflects the range of differentiated cell types in
normal epidermis. a | Normal skin, showing interfollicular epidermis (IFE), hair follicle (HF) and
sebaceous gland (SG). b | Squamous-cell carcinoma, showing IFE differentiation.
c | Trichofolliculoma, showing aberrant hair-follicle differentiation. d | Sebaceous adenoma, with
numerous differentiated sebocytes. All images are haematoxylin- and eosin-stained sections of
mouse tissue. Scale bar: 100 µm.
This principle is well illustrated in the case of UVlight-induced TP53 mutations in human IFE16.
Numerous cells with TP53 mutations can be found in
sun-exposed, clinically normal human epidermis. Both
scattered single cells and clonal patches of mutated cells
are observed throughout exposed epidermis17–19 (FIG.
3a,b). The single mutated cells are predominantly
suprabasal, terminally differentiating cells19 (FIG. 3b). The
size and distribution of TP53-mutated patches can be
compared with the distribution of stem and transit
amplifying cells (identified on the basis that stem cells
have relatively higher β1 INTEGRIN expression and tend
not to be actively cycling)19. Some clones are small and
are restricted to the transit amplifying compartment (FIG.
3b), indicating that they have arisen from a transit amplifying cell founder. Other clones are larger and their location is consistent with a stem-cell founder19 (FIG. 3b).
Some of these large clones encompass several clusters of
stem cells (FIG. 3c). In each case, the boundaries between a
TP53-mutant clone and neighbouring wild-type cells
were found to lie in the transit amplifying compartment19 (FIG. 3b,c). As the location of large patches of TP53mutated cells is selective for stem-cell-rich regions, this
would indicate that only epidermal stem cells have the
capacity to substantially propagate UV-light-induced
genetic alterations.
The chances of a single stem cell that has sustained
a TP53 mutation subsequently acquiring additional
oncogenic changes are extremely low; however, if that
cell undergoes clonal expansion, the probability that
one of its progeny will acquire an additional mutation is increased20 (FIG. 3c). Zhang et al.21 have examined whether, in mouse epidermis, Trp53 mutation is
sufficient for clonal expansion, or whether sustained
irradiation with a carcinogenic dose of UV-B is
required. They found that Trp53-mutant clones only
grew during chronic UV-B exposure and that sustained exposure to UV light was sufficient for Trp53mutant keratinocytes to colonize adjacent stem-cell
compartments. These stem-cell compartments could
act as physical barriers to clonal expansion; this fits
well with the observation in human epidermis that
the boundaries between clones lie in the transit
amplifying compartment19 (FIG. 3c).
The importance of clonal expansion is also illustrated by the process of chemical carcinogenesis in
mouse skin. One treatment with 7,12-dimethylbenz
[a]anthracene (DMBA) induces mutations in Hras; however, these cells only undergo clonal expansion after
repeated applications of a TUMOUR PROMOTER, such as 12O-tetradecanoylphorbol-13-acetate (TPA). As discussed
by Perez-Losada and Balmain in this issue22, the effects
of the tumour promoter include induction of growth
factors and enhanced inflammation, which stimulate
the proliferation of mutant cells. So, tumour promoters
increase the target-cell population that can acquire
additional oncogenic mutations23. Experimental evidence for this comes from subjecting DMBAinitiated/TPA-promoted epidermis to a second dose of
DMBA before any tumours have developed; this results
in a substantially increased incidence of carcinomas23.
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a
b
HF
stem cell
SG
stem cell
IFE
stem cell
Transit amplifying cells
Spinous layers
Sebaceous
progenitor cells
Hair matrix
cells
Contribution of differentiated cells to cancer
ORS
progenitors
Granular layers
IRS
progenitors
Hair-shaft
progenitors
Henle Huxley Cuticle
Cuticle Cortex Medulla
Companion
layer
Outer root
sheath
Sebocytes
Cornified
layers
c
Trichofolliculoma
Pilomatricoma
Basal-cell carcinoma
Sebaceous
adenoma
Papilloma
Squamous-cell
carcinoma
Figure 2 | The epidermal stem-cell compartment gives rise to distinct cell lineages and
tumour types. a | Illustrates the concept that epidermal stem cells that reside in the hair follicle (HF),
sebaceous gland (SG) or interfollicular epidermis (IFE) are interchangeable and functionally
equivalent3. b | Nevertheless, the progeny of IFE stem cells differentiate into the cornified layers of
skin, whereas the progeny of sebaceous-gland stem cells eventually form sebocytes and those of
hair-follicle stem cells go on to form the cells of the outer root sheath (ORS), inner root sheath (IRS)
and hair shaft. The differentiation potential of a given stem cell is directed by its local
microenvironment3. c | The differentiated characteristics of specific tumour types can be correlated
with different epidermal lineages. Tumours with differentiated characteristics of the apocrine and
eccrine glands are not shown because, in the mouse, the glands are found in non-hair-bearing skin.
Further evidence that the consequences of an oncogenic assault depend on the cell that sustains it comes
from experiments in which the same oncogene is
expressed in different layers of the epidermis of transgenic mice. When mice are constructed with a Ras
oncogene that is driven by promoters that are selectively
expressed during terminal differentiation, the only
tumours to form are benign papillomas that tend to
regress24–26. However, if Ras is driven by a truncated
keratin-5 promoter that is expressed exclusively in the
proliferating cells of the hair follicle, the mice develop
malignant carcinomas22,26.
The consequences of activating the c-Myc protooncogene in different epidermal compartments has
been examined using a chimeric gene (MycER) that is
under the control of cell-type-specific promoters.
MycER is activated by topical application of the drug
4-hydroxy-tamoxifen (4-OHT), and this allows
temporal control of Myc activity in addition to the
spatial control conferred by the use of different
446
promoters. Activation of Myc in the suprabasal,
terminally differentiated epidermal layers results in
neoplastic changes that are completely reversed when
4-OHT treatment is stopped27. By contrast, when
MycER is activated in the basal layer of the epidermis
via the keratin-14 promoter, a single application of
4-OHT is as effective as repeated treatments in profoundly altering epidermal proliferation and differentiation28. One reason why c-Myc induces irreversible
changes in basal keratinocytes is that many of the
genes that are repressed by c-Myc are cell-adhesion
molecules such as integrin extracellular-matrix receptors29–31: decreased extracellular-matrix adhesion is a
potent epidermal differentiation stimulus32,33.
Although the stem-cell compartment is the primary target for the accumulation of oncogenic mutations, the
differentiation compartment can also contribute to the
development of tumours. First, transit amplifying
cells34, and even post-mitotic, terminally differentiating
keratinocytes27, can undergo sustained proliferation in
response to an oncogene, although formation of a
malignant tumour has not been reported. There are
clear parallels between these observations and studies of
leukaemia. The cells that are capable of initiating
human acute myeloid leukaemia when transplanted
into immunocompromised mice have a phenotype that
is similar to haematopoietic stem cells35; however, it is
also possible to generate myeloid leukaemia, in a more
benign form, by targeting restricted progenitors36.
Second, the differentiated cells of the epidermis can
influence whether a genetically altered stem cell is able
to proliferate and create a tumour or whether its
tumorigenic potential is held in check (FIG. 4a,b).
The influence of the differentiation compartment is
illustrated by experiments in which integrin extracellular-matrix receptors are expressed in the differentiating
cell layers in order to mimic the aberrant patterns of
integrin expression that are seen in a range of benign
hyperproliferative conditions and also in some squamous-cell carcinomas (SCCs)33. None of these mice
develop spontaneous tumours and there are no obvious
effects on epidermal differentiation or adhesion.
However, when subjected to two-stage chemical carcinogenesis with DMBA and TPA, it is clear that the integrins
profoundly influence the response of the epidermis.
Suprabasal α3β1 integrin expression reduces the conversion of papillomas to SCCs37. The α6β4 integrin, which
is correlated with poor prognosis in both mouse and
human SCCs33, leads to increased papillomas, SCCs and
metastases (D.M.O. and F.M.W., unpublished observations). Finally, suprabasal expression of the α2β1 collagen receptor has no effect on the incidence or frequency
of benign papillomas or SCCs37.
How do terminally differentiated keratinocytes
communicate with the stem-cell compartment to
influence tumour development either positively or
negatively? One potential mechanism is via secreted
factors. Keratinocytes synthesize a large number of
growth factors and there are numerous examples of
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Terminally
differentiating cells
a
Suprabasal
layers
Stem
cells
Basal
layer
Transit
amplifying cells
b
c
suprabasal keratinocytes and also triggers skin inflammation39. Suprabasal expression of c-Myc promotes
skin angiogenesis by increasing vascular endothelial
growth factor (VEGF) secretion by keratinocytes27.
Finally, terminally differentiating keratinocytes produce
transforming growth factor-β (TGF-β)40, which
inhibits epidermal proliferation41 and can therefore
potentially put a brake on clonal expansion.
Direct cell–cell contact might also be important in
communication between epidermal stem cells and
differentiated cells. Deletion of the gene that encodes
α-catenin, which results in defective assembly of
ADHERENS JUNCTIONS, is sufficient to cause epidermal
hyperproliferation and pre-cancerous lesions 42,43.
Perturbed GAP-JUNCTIONAL communication is also associated with carcinogenesis in human and mouse
skin44–46. In vitro experiments show that high expression of the transmembrane Notch ligand, Delta1, by
human epidermal stem cells signals to neighbouring
cells to differentiate47,48, whereas the stem cells themselves are protected from this signal 47. Notch signalling also stimulates differentiation of mouse
epidermal cells49, and ablation of Notch1 predisposes
the epidermis to development of tumours50. Although
Notch is not generally regarded as a cell-adhesion
receptor, Delta1 promotes clustering of human epidermal stem cells by restricting motility via an effect
on the actin cytoskeleton47,48.
Diversity of epidermal tumours
Figure 3 | Models of epidermal lineage and clonal expansion in human interfollicular
epidermis. a | The proposed locations of stem cells (purple), transit amplifying cells (green) and
suprabasal, terminally differentiating cells (pink) in human interfollicular epidermis. Arrows
represent the relationship between each cell compartment and the movement of cells to the
surface of the skin as they undergo terminal differentiation. This model applies to epidermis from
most body sites, but not to the thickened epidermis of the palms and soles1,19. b | TP53
mutations can be acquired by post-mitotic, terminally differentiated cells (red), transit amplifying
cells (dark green) or stem cells (dark purple). Terminally differentiating cells that acquire such a
mutation do not divide and are therefore represented as single cells (red). A transit amplifying cell
has limited proliferative ability and therefore will only pass on the mutation to other transit
amplifying cells and to their terminally differentiating daughter cells (represented here as a small
clone of dark green and red cells). A stem cell will pass on a TP53 mutation to progeny that are
stem cells, transit amplifying cells and terminally differentiating cells (represented as a clone of
dark red, green and purple cells). c | Clonal expansion of a mutant stem cell is illustrated by the
increased number of stem (dark purple), transit amplifying (dark green) and terminally
differentiating (red) cells bearing the mutation compared with b. The boundary between the
mutant clone (dark coloured cells) and the normal cells (light colours) is shown as lying in the
transit amplifying compartment19,21.
ADHERENS JUNCTION
A cell–cell adhesive junction that
contains classical cadherins.
GAP JUNCTION
A cell–cell junction that
mediates intercellular
communication.
the impact of these factors on various cell compartments within the skin. So, keratinocyte cytokines influence fibroblasts in the underlying connective tissue;
these, in turn, alter growth-factor production by keratinocytes38. Suprabasal β1 integrin expression results
in increased keratinocyte expression of IL-1α, which
activates ERK/MAPK (extracellular-signal-regulated
kinase/mitogen-activated protein kinase) in basal and
The most common epithelial tumours of the skin are
basal-cell carcinomas (BCCs) and SCCs in humans,
and papillomas and SCCs in mice. However, these are
only three examples of the wide variety of epidermal
tumours. The full range of epidermal tumours reflects
the range of differentiated lineages that are followed
by stem-cell daughters (FIG. 2c). There are tumours with
elements of sebaceous-gland differentiation (FIG. 1d),
tumours that have characteristics of the hair lineages
(FIG. 1c), tumours that have aspects of IFE differentiation (FIG. 1b) and tumours with characteristics of
apocrine and eccrine glands51,52.
In FIG. 2c, we have listed some types of epidermal
tumours and attempted to ascribe them to specific differentiated lineages. SCCs and, in the mouse, their
benign precursors, papillomas, have elements of interfollicular epidermal differentiation and are thought to arise
from the IFE (FIG. 1b). The histology of BCCs is harder to
interpret because it shows an accumulation of cells that
are negative for markers of terminal differentiation.
However, as mutations that affect Sonic Hedgehog
(SHH) signalling result in BCC formation and SHH
activity is confined to hair follicles53,54, it is now generally
believed that BCCs arise from the undifferentiated follicle outer root sheath (FIG. 2b,c). Sebaceous adenomas arise
from the upper region of the hair follicle and comprise a
proliferative outer layer of keratinocytes and an inner
differentiation compartment of sebocytes52 (FIGS 1d and
2b,c). Trichofolliculomas (FIG. 1c) and pilomatricomas
show evidence of differentiation towards the hair-shaft
and inner-root-sheath lineages (FIG. 2b,c). There are also
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Table 1 | Mutations associated with epidermal tumours
Mutation
Tumour
Species
SHH signalling, including
PTCH
Basal-cell carcinoma
Mice, humans
β-Catenin
Trichofolliculoma
Mice, humans
LEF1
Sebaceous adenoma
Mice
RAS
Squamous-cell carcinoma
Mice
TP53
Squamous-cell carcinoma
Basal-cell carcinoma
Mice, humans
Humans
MSH2, MLH1
Sebaceous adenoma and carcinoma
Mice, humans
CYLD
Cylindroma (apocrine and eccrine
differentiation)
Humans
PTEN
Trichilemmoma, papilloma,
squamous-cell carcinoma
Mice, humans
Folliculin
Fibrofolliculoma
Humans
COWDEN DISEASE
Autosomal-dominant disease
that features multiple
trichilemmomas.
GORLIN’S SYNDROME
A hereditary predisposition to
basal-cell carcinomas.
mixed-lineage tumours, such as sebeomas, which have
elements of both sebaceous and squamous differentiation, and sebaceous trichofolliculomas in which there are
differentiated sebocytes and aberrant hair shafts.
What does this tell us about the founding cells of
tumours and the pathways that control lineage commitment? There are two issues to be considered: the
malignant potential of the tumour and its differentiated characteristics. It is possible that an epidermal
tumour is more likely to be malignant if it arises from a
stem cell and to be benign if it arises from a committed
progenitor, as has been indicated for myeloid
leukaemias12,35,36. It is also possible that a tumour arising from a stem cell would show mixed-lineage differentiation, whereas one that has elements of only one
lineage could be derived from a committed progenitor.
a Positive growth stimulus from differentiated cells
However, the case of SCCs throws doubt on the latter
hypothesis. SCCs, which are the most malignant keratinocyte tumours, are characterized by only IFE differentiation. The differentiated characteristics of a tumour
will depend not only on the nature of the founding cell,
but also on the specific genetic lesions and their impact
on lineage commitment.
RAS and the genesis of SCCs
Two proteins that are of undisputed importance in the
genesis of epidermal tumours are p53 and RAS. TP53
mutations are found in most human BCCs and SCCs16,
and RAS can contribute to the development of human
SCCs55. Induction of Ras mutations in mouse skin, by
chemical carcinogens, also results in the formation of
SCCs22, as does perturbation of signalling upstream
and downstream of wild-type Ras56–59.
It is notable that even when mutant Ras is targeted
to the hair follicle, the only tumour type to develop has
an IFE differentiation phenotype26. In cultured keratinocytes, overexpression of RAS can promote IFE
differentiation under some circumstances60,61, but a
direct role in lineage commitment has not been
shown, and inducible activation of RAS in adult
mouse epidermis indicates that RAS is primarily a proproliferative, differentiation-suppressive signal62,63.
What is clear, however, is that the combination of RAS
mutations with other genetic changes can result in
tumours with a diverse range of epidermal differentiation phenotypes. For example, the combination of Ras
mutations and mutations of the tumour-suppressor
gene Pten 64,65 in mouse skin results in sebaceous carcinomas and sweat-gland adenocarcinomas, in addition
to papillomas and SCCs66. A similar range of skin
tumours is observed in patients with the hereditary
cancer syndrome COWDEN DISEASE64,65, which is caused by
PTEN mutations (TABLE 1).
SHH signalling
Suprabasal
layers
Basal
layer
b Negative growth stimulus from differentiated cells
Suprabasal
layers
Basal
layer
Figure 4 | Contributions of differentiated cells to epidermal cancer. Signals from
differentiated cells in the suprabasal layers can either enhance (a) or inhibit (b) the clonal
expansion of mutant stem-cell clones. The colours represent individual cells within a single mutant
stem-cell clone (see FIG. 3b).
448
SHH, its receptor complex Patched (PTCH) and
Smoothened (SMO), and downstream transcription
factors of the GLI family (FIG. 5), are required for hairfollicle development and the post-natal hair growth
cycle67–69. PTCH is mutated in human nevoid BCC
syndrome (also known as GORLIN’S SYNDROME) 70,71. Its
mutation in mice results in the overexpression and
activation of Gli1, which leads to the development of
BCCs72,73. BCCs are also induced by constitutive activation of SHH signalling in human and transgenic
mouse skin54,74,75. SMO is required for activating the
transcription of SHH target genes, and constitutively
active SMO results in tumours similar to those
caused by SHH overexpression 76. When SHH signalling is blocked, some markers of follicular differentiation are still expressed, so SHH is thought to be
primarily required for growth, rather than differentiation. This might explain the undifferentiated
phenotype of BCC68.
Hedgehog signalling synergizes with other genetic
changes in the development of BCCs. There is a high
frequency of both PTCH and TP53 mutations in
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SHH
Membrane
PTCH
SMO
Cytoplasm
Nucleus
GLI
Transcription
GLI target genes
Figure 5 | The Sonic Hedgehog pathway. Sonic
Hedgehog (SHH) acts on the membrane–receptor complex
that is formed by Patched (PTCH) and Smoothened (SMO)
to inhibit the repression of SMO by PTCH. SMO then
signals intracellularly to activate GLI, and hence
transcription of its target genes.
individual human BCCs, whether inherited or
sporadic77. Notch1 deficiency in mouse epidermis results
in the development of BCC-like tumours, and this seems
to be due to the unregulated expression of Gli2 (REF. 50).
overexpressed in the epidermis, SHH transcription is
increased80. Conversely, SHH expression is inhibited
by the deletion of β-catenin82 or overexpression of
the secreted WNT inhibitor Dickkopf1 (REF. 85).
Patched is upregulated in the sebaceous tumours of
mice that express ∆NLef1 (REF. 84), and this is correlated with expression of Indian Hedgehog (Catherin
Niemann and F.M.W., unpublished observations). In
addition, activation of SHH in human BCCs leads to
altered WNT expression89.
The level of β-catenin signalling therefore determines lineage choice both in normal epidermis and in
tumours. This raises the issue of whether perturbation
of β-catenin signalling is a primary oncogenic event in
the epidermis, or whether β-catenin synergizes with
additional oncogenic pathways to determine the type of
tumour that is formed.
Conclusions
All cells within the epidermis can sustain oncogenic
mutations. Although a committed progenitor can potentially result in tumour formation, the stem-cell compartment is probably the most significant because the cells
are long-term residents of the epidermis and have the
potential for clonal expansion. Nonetheless, terminally
differentiated cells can exert a crucial influence on
whether or not a mutant stem cell will go on to develop
into a tumour. The type of tumour that develops, and
whether it is benign or malignant, depends on the nature
of the oncogenic changes and the cell that sustained
β-Catenin and lineage regulation
MUIR–TORRE SYNDROME
A condition that results in
multiple sebaceous tumours and
multiple visceral carcinomas.
MISMATCH REPAIR
A genomic system that detects
and repairs incorrectly paired
nucleotides that are introduced
during DNA replication.
Proteins involved include MSH2
and MLH1.
WNT
Frizzled
β-Cat
Autosomal dominantly
inherited syndrome in which
tumours have eccrine or
apocrine glandular
differentiation.
Dickkopf
β-Cat
FAMILIAL CYLINDROMATOSIS
A diverse repertoire of WNTs is expressed in different
regions of the epidermis78,79, resulting in activation of
β-catenin signalling and transcription of target genes of
the LEF/TCF family (FIG. 6). When β-catenin levels are
increased, new hair follicles form in post-natal IFE80,81.
Conversely, when β-catenin is absent, or its activity is
blocked with dominant-negative forms of the downstream transcription factor LEF1, hair follicles are converted into cysts of IFE with associated sebocytes82–84. So,
the level of β-catenin signalling has a crucial role in
post-natal lineage selection, with high levels promoting
hair-follicle formation and low levels stimulating the
differentiation of IFE and sebocytes82–85.
Overexpression of β-catenin in the epidermis of
transgenic mice results in the development of spontaneous tumours and the differentiated characteristics of
those tumours reflect the role of β-catenin in normal
lineage selection. So, transgenic mice that overexpress a
stabilized form of β-catenin in the epidermal basal layer
develop trichofolliculomas and pilomatricomas, and,
indeed, activating mutations in β-catenin have been
found at high frequency in human pilomatricomas80,86.
Conversely, mice that express amino-terminally truncated Lef1 (∆NLef1), which blocks β-catenin signalling,
develop spontaneous tumours that show sebaceous
and squamous differentiation, rather than hair-follicle
differentiation84.
There is good evidence for crosstalk between
Hedgehog and WNT signalling both in normal
development87 and in tumours88. When β-catenin is
Dishevelled
GSK3β
APC
Axin/conductin
β-Cat
LEF
Transcription
Figure 6 | The WNT pathway. When WNT, which can be
inhibited by Dickkopf, binds to the Frizzled receptor, a signal is
sent via Dishevelled to inhibit GSK3β (glycogen synthetase
kinase-3β). This prevents the phosphorylation and degradation
of β-catenin (β-Cat), so β-catenin accumulates and is able to
enter the nucleus, bind to its partner LEF and activate
transcription of its target genes.
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MICROSATELLITE INSTABILITY
Characterized by the
accumulation of somatic
alterations in the length of
simple, repeated nucleotide
sequences (called
‘microsatellites’).
BIRT–HOGG–DUBE SYNDROME
A condition that is characterized
by hair-follicle and kidney
tumours.
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
11.
12.
13.
14.
15.
16.
17.
18.
19.
20.
21.
450
them (stem or committed progenitor). More work is
needed to define the relationships between normal stem
cells and tumour stem cells12,90.
Although some of the proteins that are important
in the genesis of epidermal tumours, such as p53, RAS,
SHH and β-catenin, have been identified, there are
other genes that are mutated in skin cancers and that
affect tumour type for unknown reasons (TABLE 1).
For example, CYLD is responsible for FAMILIAL
CYLINDROMATOSIS, and resulting tumours tend to have
Watt, F. M. Stem cell fate and patterning in mammalian
epidermis. Curr. Opin. Genet. Dev. 11, 410–417 (2001).
Panteleyev, A. A., Jahoda C. A. & Christiano A. M. Hair
follicle predetermination. J. Cell Sci. 114, 3419–3431 (2001).
Niemann, C. & Watt, F. M. Designer skin: lineage
commitment in postnatal epidermis. Trends Cell Biol. 12,
185–192 (2002).
Taylor, G., Lehrer, M. S., Jensen, P. J., Sun, T. T. & Lavker, R. M.
Involvement of follicular stem cells in forming not only the
follicle but also the epidermis. Cell 102, 451–461 (2000).
Puts the case that the IFE and sebaceous glands are
derived from hair-follicle stem cells.
Oshima, H., Rochat, A., Kedzia, C., Kobayashi, K. &
Barrandon, Y. Morphogenesis and renewal of hair follicles
from adult multipotent stem cells. Cell 104, 233–245 (2001).
Reynolds, A. J. & Jahoda, C. A. Cultured dermal papilla cells
induce follicle formation and hair growth by
transdifferentiation of an adult epidermis. Development 115,
587–593 (1992).
Ferraris, C., Bernard, B. A. & Dhouailly, D. Adult epidermal
keratinocytes are endowed with pilosebaceous forming
abilities. Int. J. Dev. Biol. 41, 491–498 (1997).
Ghazizadeh, S. & Taichman, L. B. Multiple classes of stem
cells in cutaneous epithelium: a lineage analysis of adult
mouse skin. EMBO J. 20, 1215–1222 (2001).
Presents evidence for the existence of discrete stemcell populations in the IFE, sebaceous glands and hair
follicles.
Lavker, R. M. & Sun, T. T. Epidermal stem cells: properties,
markers, and location. Proc. Natl Acad. Sci. USA 97,
13473–13475 (2000).
Barrandon, Y. & Green, H. Three clonal types of keratinocyte
with different capacities for multiplication. Proc. Natl Acad.
Sci. USA 84, 2302–2306 (1987).
Jones, P. H. & Watt, F. M. Separation of human epidermal
stem cells from transit amplifying cells on the basis of
differences in integrin function and expression. Cell 73,
713–724 (1993).
Reya, T., Morrison, S. J., Clarke, M. F. & Weissman, I. L.
Stem cells, cancer, and cancer stem cells. Nature 414,
105–111 (2001).
Nowell, P. C. The clonal evolution of tumor cell populations.
Science 194, 23–28 (1976).
Hahn, W. C. et al. Creation of human tumour cells with
defined genetic elements. Nature 400, 464–468 (1999).
Hahn, W. C. & Weinberg, R. A. Rules for making human
tumor cells. N. Engl. J. Med. 347, 1593–1603 (2002).
Brash, D. E. & Pontén, J. Skin precancer. Cancer Surv. 32,
69–113 (1998).
Jonason, A. S. et al. Frequent clones of p53-mutated
keratinocytes in normal human skin. Proc. Natl Acad. Sci.
USA 93, 14025–14029 (1996).
Ren, Z. P. et al. Benign clonal keratinocyte patches with p53
mutations show no genetic link to synchronous squamous
cell precancer or cancer in human skin. Am. J. Pathol. 150,
1791–1803 (1997).
Jensen, U. B., Lowell, S. & Watt, F. M. The spatial
relationship between stem cells and their progeny in the
basal layer of human epidermis: a new view based on
whole-mount labelling and lineage analysis. Development
126, 2409–2418 (1999).
Brash, D. E. Sunlight and the onset of skin cancer. Trends
Genet. 13, 410–414 (1997).
Zhang, W., Remenyik, E., Zelterman, D., Brash, D. E. &
Wikonkal, N. M. Escaping the stem cell compartment:
sustained UVB exposure allows p53-mutant keratinocytes
to colonize adjacent epidermal proliferating units without
incurring additional mutations. Proc. Natl Acad. Sci. USA
98, 13948–13953 (2001).
Examines the role of UV-B irradiation in driving clonal
expansion of cells with TP53 mutations.
eccrine or apocrine glandular differentiation 91.
Similarly, in MUIR–TORRE SYNDROME, patients have mutations in DNA MISMATCH-REPAIR GENES (and therefore have
92–94
MICROSATELLITE INSTABILITY
) and are predisposed to
developing sebaceous tumours 95. Hair-follicle and
kidney tumours are a feature of BIRT–HOGG–DUBE SYNDROME, in which a novel gene product, named folliculin, is altered96. In these cases, the tumours might
inform work on normal epidermis rather than the
other way round.
22. Perez–Losada, J. & Balmain, A. Stem cell hierarchy in
epithelial cancers. Nature Rev. Cancer 3, 432–441 (2003).
23. Owens, D. M., Wei, S.-J. C. & Smart, R. C. A multihit,
multistage model of chemical carcinogenesis.
Carcinogenesis 20, 1837–1844 (1999).
24. Bailleul, B. et al. Skin hyperkeratosis and papilloma
formation in transgenic mice expressing a ras oncogene
from a suprabasal keratin promoter. Cell 62, 697–708
(1990).
25. Greenhalgh, D. A. et al. Induction of epidermal hyperplasia,
hyperkeratosis, and papillomas in transgenic mice by a
targeted v-Ha-ras oncogene. Mol. Carcinog. 7, 99–110
(1993).
26. Brown, K., Strathdee, D., Bryson, S., Lambie, W. & Balmain, A.
The malignant capacity of skin tumours induced by
expression of a mutant H-ras transgene depends on the cell
type targeted. Curr. Biol. 8, 516–524 (1998).
27. Pelengaris, S., Littlewood, T., Khan, M., Elia, G. & Evan, G.
Reversible activation of c-Myc in skin: induction of a
complex neoplastic phenotype by a single oncogenic lesion.
Mol. Cell 3, 565–577 (1999).
28. Arnold, I. & Watt, F. M. c-Myc activation in transgenic mouse
epidermis results in mobilization of stem cells and
differentiation of their progeny. Curr. Biol. 11, 558–568
(2001).
29. Gandarillas, A. & Watt, F. M. c-Myc promotes differentiation
of human epidermal stem cells. Genes Dev. 11, 2869–2882
(1997).
30. Waikel, R. L., Kawachi, Y., Waikel, P. A., Wang, X. J. & Roop,
D. R. Deregulated expression of c-Myc depletes epidermal
stem cells. Nature Genet. 28, 165–168 (2001).
31. Frye, M., Gardner, C., Li, E. R., Arnold, I. & Watt, F. M.
Evidence that Myc activation depletes the epidermal stem
cell compartment by modulating adhesive interactions with
the local microenvironment. Development 130, 2793–2808
(2003).
References 27–31 show the differing roles of c-MYC in
epidermal stem cells and differentiated cells.
32. Evans, R. D. et al. A tumor-associated β1 integrin mutation
that abrogates epithelial differentiation control. J. Cell Biol.
160, 589–596 (2003).
33. Watt, F. M. Role of integrins in regulating epidermal
adhesion, growth and differentiation. EMBO J. 21,
3919–3926 (2002).
34. Barrandon, Y., Morgan, J. R., Mulligan, R. C. & Green, H.
Restoration of growth potential in paraclones of human
keratinocytes by a viral oncogene. Proc. Natl Acad. Sci.
USA 86, 4102–4106 (1989).
35. Bonnet, D. & Dick, J. E. Human acute myeloid leukemia is
organized as a hierarchy that originates from a primitive
hematopoietic cell. Nature Med. 3, 730–737 (1997).
36. Traver, D., Akashi, K., Weissman, I. L. & Lagasse, E. Mice
defective in two apoptosis pathways in the myeloid lineage
develop acute myeloblastic leukemia. Immunity 9, 47–57
(1998).
37. Owens, D. M. & Watt, F. M. Influence of β1 integrins on
epidermal squamous cell carcinoma formation in a
transgenic mouse model: α3β1, but not α2β1, suppresses
malignant conversion. Cancer Res. 61, 5248–5254 (2001).
38. Szabowski, A. et al. c-Jun and JunB antagonistically control
cytokine-regulated mesenchymal-epidermal interaction in
skin. Cell 103, 745–755 (2000).
39. Hobbs, R, M. & Watt, F. M. Regulation of interleukin-1α
expression by integrins and epidermal growth factor
receptor in keratinocytes from a mouse model of
inflammatory skin disease. J. Biol. Chem. (in the press).
40. Akhurst, R. J., Fee, F. & Balmain, A. Localized production of
TGF-β mRNA in tumour promoter-stimulated mouse
epidermis. Nature 331, 363–365 (1988).
41. Akhurst, R. J. TGF-β antagonists: why suppress a tumor
suppressor? J. Clin. Invest. 109, 1533–1536 (2002).
| JUNE 2003 | VOLUME 3
42. Vasioukhin, V., Bauer, C., Degenstein, L., Wise, B. & Fuchs, E.
Hyperproliferation and defects in epithelial polarity upon
conditional ablation of alpha-catenin in skin. Cell 104,
605–617 (2001).
43. Perez-Moreno, M., Jamora, C. & Fuchs, E. Sticky business.
Orchestrating cellular signals at adherens junctions. Cell
112, 535–548 (2003).
44. Sawey, M. J., Goldschmidt, M. H., Risek, B., Gilula, N. B. &
Lo, C. W. Perturbation in connexin 43 and connexin 26 gapjunction expression in mouse skin hyperplasia and
neoplasia. Mol. Carcinog. 17, 49–61 (1996).
45. Yamakage, K., Omori, Y., Zaidan-Dagli, M. L., Cros, M. P. &
Yamasaki, H. Induction of skin papillomas, carcinomas, and
sarcomas in mice in which the connexin 43 gene is
heterologously deleted. J. Invest. Dermatol. 114, 289–294
(2000).
46. van Steensel, M. A., van Geel, M., Nahuys, M., Smitt, J. H. &
Steijlen, P. M. A novel connexin 26 mutation in a patient
diagnosed with keratitis-ichthyosis-deafness syndrome.
J. Invest. Dermatol. 118, 724–727 (2002).
47. Lowell, S., Jones, P., Le Roux, I., Dunne, J. & Watt, F. M.
Stimulation of human epidermal differentiation by DeltaNotch signalling at the boundaries of stem-cell clusters.
Curr. Biol. 10, 491–500 (2000).
48. Lowell, S. & Watt, F. M. Delta regulates keratinocyte
spreading and motility independently of differentiation.
Mech. Dev. 107, 133–140 (2001).
49. Rangarajan, A. et al. Notch signaling is a direct determinant
of keratinocyte growth arrest and entry into differentiation.
EMBO J. 20, 3427–3436 (2001).
50. Nicolas, M. et al. Notch1 functions as a tumor suppressor in
mouse skin. Nature Genet. 33, 416–421 (2003).
51. Lever, W. F. & Schaumburg–Lever, G. Histopathology of the
Skin 6th edn (J.B. Lippincott Company, Philadelphia, 1983).
52. Bogovski, P. in Pathology of Tumours in Laboratory
Animals 1–45 (eds Turusov, V. & Mohr, U.) Vol. 2 (IARC,
Lyon, 1994).
53. Dahmane, N., Lee, J., Robins, P., Heller, P. & Ruiz i Altaba, A.
Activation of the transcription factor Gli1 and the Sonic
hedgehog signalling pathway in skin tumours. Nature 389,
876–881 (1997).
54. Oro, A. E. et al. Basal cell carcinomas in mice overexpressing
sonic hedgehog. Science 276, 817–821 (1997).
This study was the first to show the tumorigenic
consequences of altered SHH signalling in an
experimental mouse model.
55. Dajee, M. et al. NF-kappaB blockade and oncogenic Ras
trigger invasive human epidermal neoplasia. Nature 421,
639–643 (2003).
56. Vassar, R., Hutton, M. E. & Fuchs, E. Transgenic
overexpression of transforming growth factor alpha
bypasses the need for c-Ha-ras mutations in mouse skin
tumorigenesis. Mol. Cell. Biol. 12, 4643–4653 (1992).
57. Dominey, A. M. et al. Targeted overexpression of
transforming growth factor alpha in the epidermis of
transgenic mice elicits hyperplasia, hyperkeratosis, and
spontaneous, squamous papillomas. Cell Growth Differ. 4,
1071–1082 (1993).
58. Sibilia, M. et al. The EGF receptor provides an essential
survival signal for SOS-dependent skin tumor development.
Cell 102, 211–220 (2000).
59. Malliri, A. et al. Mice deficient in the Rac activator Tiam1 are
resistant to Ras-induced skin tumours. Nature 417,
867–871 (2002).
60. Roper, E. et al. P19(ARF)-independent induction of p53 and
cell cycle arrest by Raf in murine keratinocytes. EMBO Rep.
2, 145–150 (2001).
61. Lin, A. W. & Lowe, S. W. Oncogenic ras activates the
ARF-p53 pathway to suppress epithelial cell
transformation. Proc. Natl Acad. Sci. USA 98, 5025–5030
(2001).
www.nature.com/reviews/cancer
© 2002 Nature Publishing Group
REVIEWS
62. Dajee, M., Tarutani, M., Deng, H., Cai, T. & Khavari, P. A.
Epidermal Ras blockade demonstrates spatially localized
Ras promotion of proliferation and inhibition of differentiation.
Oncogene 21, 1527–1538 (2002).
63. Tarutani, M., Cai, T., Dajee, M. & Khavari, P. A. Inducible
activation of Ras and Raf in adult epidermis. Cancer Res.
63, 319–323 (2003).
64. Li, J. et al. PTEN, a putative protein tyrosine phosphatase
gene mutated in human brain, breast, and prostate cancer.
Science 275, 1943–1947 (1997).
65. Liaw, D. et al. Germline mutations of the PTEN gene in
Cowden disease, an inherited breast and thyroid cancer
syndrome. Nature Genet. 16, 64–67 (1997).
References 64 and 65 provide the identification and
molecular characterization of a critical tumoursuppressor gene through the discovery of
hereditary mutations that are linked to certain
human cancers.
66. Suzuki, A. et al. Keratinocyte-specific Pten deficiency results
in epidermal hyperplasia, accelerated hair follicle
morphogenesis and tumor formation. Cancer Res. 63,
674–681 (2003).
67. Oro, A. E. & Scott, M. P. Splitting hairs: dissecting roles of
signaling systems in epidermal development. Cell 95,
575–578 (1998).
68. Callahan, C. A. & Oro, A. E. Monstrous attempts at
adnexogenesis: regulating hair follicle progenitors through
Sonic hedgehog signaling. Curr. Opin. Genet. Dev. 11,
541–546 (2001).
69. Mill, P. et al. Sonic hedgehog-dependent activation of Gli2 is
essential for embryonic hair follicle development. Genes
Dev. 17, 282–294 (2003).
70. Toftgård, R. Hedgehog signalling in cancer. Cell. Mol. Life
Sci. 57, 1720–1731 (2000).
71. Bonifas, J. M. et al. Activation of expression of hedgehog
target genes in basal cell carcinomas. J. Invest. Dermatol.
116, 739–742 (2001).
72. Nilsson, M. et al. Induction of basal cell carcinomas and
trichoepitheliomas in mice overexpressing GLI-1. Proc. Natl
Acad. Sci. USA 97, 3438–3443 (2000).
73. Grachtchouk, M. et al. Basal cell carcinomas in mice
overexpressing Gli2 in skin. Nature Genet. 24, 216–217
(2000).
74. Gailani, M. R. et al. The role of the human homologue of
Drosophila patched in sporadic basal cell carcinomas.
Nature Genet. 14, 78–81 (1996).
75. Fan, H., Oro, A. E., Scott, M. P. & Khavari, P. A. Induction of
basal cell carcinoma features in transgenic human skin
expressing sonic hedgehog. Nature Med. 3, 788–792 (1997).
76. Xie, J. et al. Activating Smoothened mutations in
sporadic basal-cell carcinoma. Nature 391, 90–92
(1998).
77. Ling, G. et al. PATCHED and p53 gene alterations in
sporadic and hereditary basal cell cancer. Oncogene 20,
7770–7778 (2001).
78. DasGupta, R. & Fuchs, E. Multiple roles for activated
LEF/TCF transcription complexes during hair follicle
development and differentiation. Development 126,
4557–4568 (1999).
79. Reddy, S. et al. Characterization of Wnt gene expression in
developing and postnatal hair follicles and identification of
Wnt5a as a target of Sonic hedgehog in hair follicle
morphogenesis. Mech. Dev. 107, 69–82 (2001).
80. Gat, U., DasGupta, R., Degenstein, L. & Fuchs, E. De novo
hair follicle morphogenesis and hair tumors in mice
expressing a truncated β-catenin in skin. Cell 95, 605–614
(1998).
The first study to show the tumorigenic effects of
misregulated β-catenin signalling in skin and to
indicate a role for β-catenin in post-natal epidermal
lineage commitment.
81. Jamora, C., DasGupta, R., Kocieniewski, P. & Fuchs E.
Links between signal transduction, transcription and
adhesion in epithelial bud development. Nature 422,
317–322 (2003).
82. Huelsken, J., Vogel, R., Erdmann, B., Cotsarelis, G. &
Birchmeier, W. β-Catenin controls hair follicle
morphogenesis and stem cell differentiation in the skin. Cell
105, 533–545 (2001).
83. Merrill, B. J., Gat, U., DasGupta, R. & Fuchs, E. Tcf3 and
Lef1 regulate lineage differentiation of multipotent stem cells
in skin. Genes Dev. 15, 1688–1705 (2001).
84. Niemann, C., Owens, D. M., Hulsken, J., Birchmeier, W. &
Watt, F. M. Expression of ∆NLef1 in mouse epidermis results
in differentiation of hair follicles into squamous epidermal
cysts and formation of skin tumours. Development 129,
95–109 (2002).
85. Andl, T., Reddy, S. T., Gaddapara, T. & Millar, S. E. WNT
signals are required for the initiation of hair follicle
development. Dev. Cell 2, 643–653 (2002).
86. Chan, E. F., Gat, U., McNiff, J. M. & Fuchs, E. A common
human skin tumour is caused by activating mutations in βcatenin. Nature Genet. 21, 410–413 (1999).
87. Ingham, P. W. & McMahon, A. P. Hedgehog signaling in
animal development: paradigms and principles. Genes Dev.
15, 3059–3087 (2001).
88. Taipale, J. & Beachy, P. A. The Hedgehog and Wnt signaling
pathways in cancer. Nature 411, 349–354 (2001).
NATURE REVIEWS | C ANCER
89. Mullor, J. L., Dahmane, N., Sun, T. & Ruiz i Altaba, A. Wnt
signals are targets and mediators of Gli function. Curr. Biol.
11, 769–773 (2001).
90. Al-Hajj, M., Wicha, M. S., Benito-Hernandez, A., Morrison, S. J.
& Clarke, M. F. Prospective identification of tumorigenic
breast cancer cells. Proc. Natl Acad. Sci. USA 100,
3983–3988 (2003).
91. Bignell, G. R. et al. Identification of the familial
cylindromatosis tumour-suppressor gene. Nature Genet.
25, 160–165 (2000).
Description of the CYLD gene, which is mutated in
apocrine- and eccrine-gland tumours.
92. Reitmair, A. H. et al. Spontaneous intestinal carcinomas and
skin neoplasms in Msh2-deficient mice. Cancer Res. 56,
3842–3849 (1996).
93. Fong, L. Y. et al. Muir–Torre-like syndrome in Fhit-deficient
mice. Proc. Natl Acad. Sci. USA 97, 4742–4747 (2000).
94. Kruse, R. et al. ‘Second hit’ in sebaceous tumors from
Muir–Torre patients with germline mutations in MSH2: allele
loss is not the preferred mode of inactivation. J. Invest.
Dermatol. 116, 463–465 (2001).
95. Johnson, P. J. & Heckler, F. Muir–Torre syndrome. Ann.
Plast. Surg. 40, 676–677 (1998).
96. Nickerson, M. L. et al. Mutations in a novel gene lead to
kidney tumors, lung wall defects, and benign tumors of the
hair follicle in patients with Birt–Hogg–Dubé syndrome.
Cancer Cell 2, 157–164 (2002).
Identification of folliculin, which is mutated in
fibrofolliculomas — hair-follicle tumours in which
epithelial strands extend from the infundibulum (neck) of
the hair follicle into hyperproliferative connective tissue.
Acknowledgements
The authors are grateful to Cancer Research UK and a European
Union Quality of Life Network grant for financial support. We thank
C. Lo Celso, D. Prowse and C. Niemann for providing micrographs
for figure 1 and S. Lyle for his advice.
Online links
DATABASES
The following terms in this article are linked online to:
LocusLink: http://www.ncbi.nih.gov/LocusLink/
α-catenin | β-catenin | CYLD | Delta1 | folliculin | Gli1 | Hras | IL-1α |
Indian Hedgehog | α3β1 integrin | α6β4 integrin | β1 integrin | Lef1 |
LEF1 | Myc | Notch1 | PTCH | Pten | RAS | SHH | SMO | TGF-β |
TP53 | Trp53 | VEGF
Access to this interactive links box is free online.
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