EJD, vol. 21, Suppl. 2, May 2011
To cite this article: Mcnairn AJ, Guasch G. Epithelial Transition Zones: merging microenvironments, niches, and cellular transformation. Eur J Dermatol 2011;
21(Suppl. 2):21-28 doi:10.1684/ejd.2011.1267
Eur J Dermatol 2011; 21(Suppl. 2): 21-28
Adrian J. MCNAIRN
Division of Developmental Biology,
Cincinnati Children’s Hospital Medical
Reprints: G. Guasch
Article accepted on 12/20/2010
Epithelial transition zones: merging
microenvironments, niches, and cellular
Transition zones (TZs) are regions in the body where two different
types of epithelial tissue meet resulting in the appearance of a distinct
abrupt transition. These TZs are found in numerous locations within
the body, including the cornea-conjunctiva junction, esophagogastric
junction, gastro-duodenal junction, endo-ectocervix junction, ileocecal
with the development of cancer, in some cases due to viral transforma-
tion by the human papilloma virus (HPV). The underlying molecular
and cellular basis for this tumor susceptibiblity is unknown. The dis-
tinct epithelial morphology and location results in unique properties
being conferred upon this epithelial tissue, as different signaling cues
and cell surface markers are apparent. Importantly, the natural state of
TZs closely resembles that of a pre-lesional epithelium, as several pro-
teins that are induced during wounding are expressed specifically within
this region, which may contribute to transformation. This region may
also act as a stem cell niche, and as such, represents a key location
for cellular transformation by accumulated genetic mutations or viral
transformation resulting in tumor formation.
Key words: transition zones, stem cells, slow-cycling, microenviron-
ment, tumor susceptibility, keratinocytes
Transition zones and cancer prevalence
In humans, transition zones (TZs) are defined by the junc-
tion between two types of epithelia. They are readily
identifiable histologically, and can be found in numerous
places including the junctions between the esophagus and
the stomach, between the stomach and the duodenum, the
ileocecal junction between the final part of the small intes-
of the endocervix and ectocervix, the cornea and the con-
junctiva in the eye, and between the anal canal and the
rectum. For the purposes of this review, we shall focus
specifically on TZs also recognized as squamo-columnar
junctions and have exhibited a predilection for cancer for-
mation. These TZs are present in the cornea-conjunctiva
junction, and the anorectal junction (figure 1).
Stratified squamous epithelium versus simple
To understand the morphology of the TZ, we must first dis-
cuss the types of epithelium present in the TZ. Stratified
squamous epithelia are tissues that constitute the surface
covering of the body as well as the internal lining of the gut
and reproductive organs. They are subjected to more exten-
sive wear and tear than most tissues, and they compensate
by having reservoirs of stem cells that can replenish the
tissue when damaged . Stratified squamous epithelium
is composed of several layers of cells, with the outermost
layers having a characteristic flat appearance. The basal
layer, which is in contact with the basement membrane is
mitotically active and gives rise to all the cells of the epi-
dermis . The spinous layer is the outer population of
cells, the granular layer is characterized by the presence of
may be either keratinized or non-keratinized. In humans,
non-keratinized stratified squamous epithelium occurs in
the cornea, oral cavity, anal canal (figure 1B), and vagina,
Simple epithelium consists of a single cell layer and may
be either squamous, columnar or cuboidal. These types of
epithelium are typically found in glands or other secre-
tive tissues, including the stomach, intestines, rectum and
While the same TZs present in humans are present in other
species, thus enabling animal models to be used, there are
some differences. For instance, the vagina and anal canal
of mice have keratinized stratified squamous epithelium
the stratified squamous epithelium and simple epithelium.
In any species, the abrupt transition from one epithelia to
another can be readily detected histologically (figure 1)
EJD, vol. 21, Suppl. 2, May 2011
50 µm 100 µm
Figure 1. Transition zones. A, B) Hematoxylin and Eosin staining of mouse and human anorectal transition zones. The dentate
line separates the stratified squamous epithelium of the anal canal from the simple epithelium of the rectum. The dashed line
indicates the basement membrane. The stratified epithelium is keratinized in mice as depicted by the presence of the stratum
corneum layer (A) in contrast to human (B). This keratinization is due to the coarse diet of the mice. C) PAS staining of the
human corneal-limbal transition zone showing the stratified squamous epithelium of the conjunctiva and the simple columnar
epithelium of the cornea. Reproduced with the permission of Dr. Ursula Schlotzer-Schrehardt . D) Hematoxylin and Eosin
of an adult mouse esophageal-stomach junction. The keratinized stratified squamous epithelium meet the glandular part of the
stomach. E) Adult mouse cervical junction showing the demarcation between the squamous epithelium of the ectocervix and the
columnar epithelium of the endocervix. Reproduced and modified with the permission of Dr. Jeffrey M. Arbeit .
Abbreviations: TZ, transition zone; BL, basal layer; Sp, spinous layer, Gr, granular layer, Sc, stratum corneum.
and molecularly as each epithelium expresses characte-
ristic proteins [2-4]. Moreover, at the ultrastructural level,
the anorectal TZ show fewer desmosomes than anal cells
that connect between each other in the basal layer .
Desmosomes are intercellular junctions that confer strong
cell-cell adhesion . This is interesting in the context
of a cancer as a cancer cell need to migrate and invade
the mucosa to propagate. Having less desmosome between
these two cell types may give a migration and invasion
advantage already to these TZ cells.
Squamous cell carcinoma arise in stratified squamous
that develop in humans. They arise in epidermal kera-
tinocytes and may occur in the skin, head and neck (mouth,
nasopharynx), esophagus, lung, penis, vagina, prostate,
cervix, anorectal, and bladder. Interestingly, several human
[6-9]. In the cervix, cancers arise exclusively in the vagina-
cervical squamocolumnar junction [6, 10]. In anal cancers,
tumors in the TZ (anal canal tumors) are three times more
common than carcinoma of the anal margin, and the prog-
nosis is less favorable. In the eye, squamous cell carcinoma
frequently arise in the junction between the cornea and
the conjunctiva in a region called the limbus . As the
TZ represents a merger of two distinct epithelium, there
is likely be to an assortment of different signaling clues
present, which results in the cells of the TZ having unique
properties as well as providing a potential niche for stem
EJD, vol. 21, Suppl. 2, May 2011
The transitional epithelium: a niche for
putative stem cells?
Corneal limbus junction
The limbus is a TZ lying between the stratified squamous
epithelium of the cornea and the simple columnar epithe-
lium of the conjunctiva (figure 1C) [3, 11]. This region is
well studied for its role in maintaining proper eye function
and as a stem cell niche, but it is also a hot spot for tumor
relatively rare cancer, although studies have indicated that
nearly 80% of ocular surface squamous neoplasia involve
the limbus .
Epithelial stem cells are frequently described as part of a
population of slow-cycling cells based upon the fact that
stem cells divide less frequently than other differentiated
cells. The limbus has been identified to contain label-
retaining cells (LRCs) by BrdU incorporation, a method
to identify relatively quiescent cells that may represent
stem cells (figure 2A) . The limbal LRCs have sub-
sequently been shown to exhibit stem cell properties and
may be identified by the virtue of the ABCG2 cell surface
marker . Additional markers of the limbus include kera-
tin 19, vimentin, KGF-R, metallothionin, and integrin ?9
[2, 3]. The basal cells of the limbus also express slightly
higher levels of p63 than the corneal basal cells and keratin
17 is expressed in the limbus of adult human corneas .
These cells have been demonstrated to have the capacity
for self-renewal and can give rise to fast-dividing transit
amplifying cells, which act as progenitor cells for repair
and maintenance of the eye. The presence of stem cells
in a compartment which can give rise to tumors, suggests
that TZs may function not only as a stem cell reservoir to
maintain tissues, but may also be subject to environmental
stresses which result in genetic changes triggering cellular
Another region in which a TZ has been identified is at the
esophagogastric junction, which occurs where the esopha-
gus meets the stomach (figure 1D). This junction is also
mouse has identified the presence of LRCs at the squamo-
columnar junction of the stomach, which corresponds to
the human esophagogastric junction, that also express the
cell surface marker CD44 . CD44 has recently been
found associated with certain human cancers, including
breast, colon, head and neck squamous cell carcinoma, and
pancreas . Using a transgenic mouse model in which
Wnt-1, COX2, and microsomal prostaglandin E synthase 1
include the stomach, pancreas, and intestines, Ishimoto et
squamo-columnar junction and contained CD44 positive
cells . In wild-type cells, CD44 expressing cells were
limited to a gland near the squamo-columar junction, but
over-expression triggers the aberrant activation of the Wnt
signaling pathway, and Cox2 is involved in prostaglandin
biosynthesis and activates expression of PGE2 [16, 17].
3 weeks doxy chase
Figure 2. Slow-cycling cells at transition zones. A) In vivo
term labeling with BrdU detects LRC (red stained nuclei) and
a single pulse of tritiated thymidine detects the rapidly cycling
TA cells (arrows). All slow-cycling cells are preferentially
located in the limbal epithelium. The TA cells are predom-
inantly located in the corneal epithelium. Figure reproduced
with the permission of Dr. Robert M. Lavker . B-D) In
B) Schematic of BrdU and doxy pulse-chase experiments.
Small arrows represent ten intraperitoneal BrdU injections
at the indicated time points. To specifically label slow-
cycling epithelial cells in the stratified squamous epithelium,
bitransgenic mice which harbor a tetracycline (Tet) regulatory
(active in all mitotically active keratinocytes and myoepithe-
lia) (K5-TetVP16) and a histone H2B-GFP gene under control
of a Tet enhancer element  (TRE-H2BGFP) are used .
C) Utilizing this system, a population of slow-cycling cells
the tumors arise, i.e. between the stratified epithelia of the
anal canal and the intestinal type glandular mucosa of the anal
TZ . Anorectal sections of pTRE-H2B-GFPxK5tTA mice
before (26 days old) and after 4 week chase (43 days old).
Shown are epifluorescence of H2B-GFP (green) and
4?,6?-diamidino-2-phenylindole (DAPI) (blue), and indi-
rect immunofluorescence with BrdU (Rhodamine Red) .
C) Before the chase, at 26 days old (P26), all the epithelial
cells expressed H2B-GFP and most of the cells (including the
cells in the rectum) are labeled with an anti-BrdU antibody
showing the efficiency of the BrdU pulse. D) After the chase,
colocalization of H2B-GFP and BrdU-retaining cells.
Abbreviations: BrdU, bromodeoxyuridine; H2BGFP, his-
tone H2BGFP; LRC, Label Retaining Cells. TA, Transient
Amplifying cell, TZ, Transition Zone. The asterisk denotes
EJD, vol. 21, Suppl. 2, May 2011
PGE2 is an inflammatory mediator released at sites of
tissue inflammation and is known to trigger hematopoi-
etic stem cell expansion [18, 19]. As the squamo-columnar
junction represents a region prone to inflammation, it
is likely that the mix of signaling clues caused by the
presence of two distinct epithelia tissues creates an envi-
ronment favorable to cellular transformation and stem cell
expansion. While it remains to be determined if the same
population of cells exist in humans, this data is suppor-
tive of the concept of the TZs as a stem cell niche that
is subject to tumor formation in response to changes in
the endocervix and ectocervix where the thicker stratified
squamous epithelium of the ectocervix meets the glandu-
lar columnar epithelium of the endocervix (figure 1E) .
This transition is thought to be influenced by both estrogen
and the acidic pH of the vagina, resulting in the need for a
thicker epithelial surface. The TZ of the cervix, also known
as the transformation zone, is the common site of origin of
cervical cancers, which is the second most common cancer
in women worldwide and is triggered by human papilloma
virus (HPV) infection [6, 10]. This TZ is conserved in mice
(figure 1E) and is the site of squamous cell carcinoma for-
mation in transgenic animals containing the HPV genome
under the control of the keratin 14 promoter .
HPV is a diverse family of small double-stranded DNA
viruses known to infect epithelial tissues . Cellular
transformation by HPV is largely mediated by the action
of two virally encoded oncoproteins, E6 and E7. E6 binds
to a ubiquitin ligase (E6 associated protein (E6AP) which
targets p53 for proteasome mediated degradation resulting
in increased genetic instability . E6 also triggers the
activation of telomerase transcription (hTERT). E7 binds
the retinoblastoma (Rb) family of proteins, including pRb,
p130, and p107, thereby disrupting their interaction with
the E2F family of transcription factors . Similar to E6
and p53, the binding of E7 to the Rb proteins results in
their degradation by the proteasome. The E2F family of
transcription factors is important for the regulation of cell-
cycle genes, including genes regulating entry into S-phase
The question remains as to whether or not there are stem
cells within this TZ as the majority of research has been
for LRCs. However, populations of reserve cells have been
cells are positive for the expression of p63, a marker of the
basal epithelium, and keratin 17, which is also expressed in
other TZs, including the limbus, the anal canal (figure 3A)
cell population is thought to be the target cell for HPV
It is known that HPV infection typically occurs at the level
of the basal cell, although viral production is associated
with the differentiated layers .
The anorectal TZ occurs where the stratified squamous
epithelium of the anal canal meets the simple cuboidal
dentate line and below the suprazonal irregular line, span-
estimated to occur this year, nearly 85% of anal tumors are
squamous cell carcinomas . Anal cancer is more preva-
lent among women and homosexual males and there does
formation in these groups .
Significantly, in a mouse model in which the essential
receptor (TGFβ receptor II) for TGF? signaling is con-
ditionally knock-out in the stratified epithelium, results in
the spontaneous development of squamous cell carcinoma
in the juncture of the mucosal stratified squamous epithe-
lium of the anal canal and the simple layer of the anal
column [7, 28] but not in adjacent skin which is also TGF?
receptor II deficient [28, 29]. Moreover, this mouse cancer
model recapitulates epithelial cancer of human anogenital
exhibit reduced or non-detectable TGF? receptor II and
phosphorylated (active) Smad2 immunolabeling reflec-
tive of TGF? activity . This model demonstrates the
importance of the TGF? pathway in maintaining tissue
homeostasis and also may provide a model to study tran-
in a virus-free system.
An examination of the mouse anorectal TZ, revealed the
existence of a population of LRCs in the basal cell com-
partment of the squamous epithelium at the point where
the anal canal meets the anal TZ  (figure 2D). These
anorectal LRCs give rise to differentiated anal epithelium
a variety of pluripotent cells and tissue stem cells including
hair follicle bulge stem cells, esophageal stem cells, bron-
chioalveolar stem cells and muscle satellite cells [30-34].
Moreover, these slow-cycling cells also expressed several
other markers consistent with known stem cells such as
Sox2, p63 and Tenascin C (figure 3A) . While additional
research is necessary to determine the “stemness” of these
LRCs present in various TZs, it is apparent that TZs very
progenitor cells to maintain tissue homeostasis.
Transition zones: merging
A key factor in the development and maintenance of TZs
is the influence of the microenvironment. Several studies
have revealed the effects of cell signaling molecules on the
TZs, most of which result in the development of tumors.
The conditional deletion of the bone morphogenic protein
plastic lesions specifically at the squamocolumnar junction
of the stomach (homologous to the human esophagogas-
tric junction) . Moreover, there were alterations in the
differentiation of the epithelial cells in response to the loss
of BMP signaling . Similarly, conditional deletion of
TGF? receptor II in stratified squamous epithelium results
in the formation of spontaneous squamous cell carcinoma
in the anal canal and genital regions . Two other mouse
models disrupting TGF? signaling have also described the
EJD, vol. 21, Suppl. 2, May 2011
Figure 3. Wound and inflammatory markers at transition zones. Immunofluorescence microscopy of frozen tissue sections
revealed that the epithelium at transition zones naturally expresses many markers of a hyperproliferative state including keratin
17 (K17) and tenascin C (TnC). A) Mouse anorectal junction stained with TnC and K17 (B). Inflammatory macrophages (Mac1)
are prevalent in the stroma underlying the anal epithelium . C) TnC at the limbus of the human eye. propidium iodide
stains the nucleus of the cells. Figure reproduced with the permission of Dr. Ursula Schlotzer-Schrehardt . D-E) Mouse
esophagus-stomach junction showing the expressing of Tenascin C and K17 (Unpublished data). E’) Higher magnification of the
esophagus-stomach junction, showing the presence of K17.
Abbreviations: K17, Keratin 17; TnC, Tenascin C; K5, Keratin 5; Str, Stroma; PI, propidium iodide; ?6, ?6-integrin.
development of spontaneous anorectal tumors [36, 37].
Interestingly, loss of TGF? signaling in other regions that
are not TZ such as the oral, skin, pancreas or intestine, do
not induce the formation of squamous cell carcinoma but
activation of additional oncogene such as H-Ras and K-
Ras are required to develop tumors . These findings
EJD, vol. 21, Suppl. 2, May 2011
Anal Basal Layer
Loss of TGFβ signaling
in epithelial cells
Figure 4. The anorectal transition zone: a pre-lesional epithelium containing putative stem cells. The anal transition zone
represents a pre-lesional region where wound-induced markers (orange) are present and inflammatory cells are detected in the
mucosa (blue cells). We have previously characterized a population of slow-cycling cells or Label-retaining cells (LRC) in that
region that express the stem cell marker CD34. This cell surface marker is highly express in the hair follicle stem cell niche
(bulge) where LRC reside . When TGF? signaling is lost in epithelial cells, spontaneous tumors arise at the anorectal TZ,
invading the mucosa, whereas additional mutation such as activation of the oncogene H-RasV12is necessary to induce tumors in
the skin .
suggest that cells within this region are intrinsically more
prone to transformation or alternatively, that the environ-
ment is permissive for transformed cells. The influence of
the microenvironment on cell types and differentiation of
form the mouse hair follicle bulge, that, when cultured on
extracellular matrix found in the corneal limbus and com-
bined with conditioned media from limbal cells, results
in the differentiation of those stem cells into a corneal-
like epithelium . These combined results demonstrate
the importance of the microenvironment is regulating cell
growth and controlling proper cellular differentiation.
The transitional epithelium as a
Recent studies have demonstrated that epithelium found
in TZs naturally possesses many of the same features that
are displayed by the epidermis when it either responds to
wounding in normal individuals or exists in patients with
hyperproliferative skin disorders . For instance, wild-
type anal epithelium is not only substantially thicker and
hyperproliferative-associated suprabasal keratins, such as
Keratin 17, Tenascin C, and migratory-associated integrins
(?6-integrin) (figure 3A) . It is particularly interest-
ing that tenascin C and ?6-integrin are expressed at this
site as their expression is known to correlate with inva-
sive growth during wound healing and tumorigenesis .
Further reflective of an atypical hyperproliferative state is
the presence of a large number of macrophages within the
underlying anorectal stroma (figure 3B) suggesting that the
anorectal region may be a pre-lesional state . Similarly,
within the limbus TZ, the presence of ?9-integrin, which
mediates adhesion to tenascin-C, has been detected, poten-
tially indicating the pre-lesion status of the epithelium is
a conserved characteristic (figure 3C) . Interestingly, a
role for keratin 17 as an immunomodulator was recently
proposed as the deletion of Keratin 17 in mouse epidermis
reduces cytokine expression and inflammation responses
may more closely resembled that of the epidermis when
subjected to an imbalance in tissue homeostasis due to an
injury, microbial infection, inflammation or pre-cancerous
lesions [43, 44] (figure 4).
Conserved genetic pathways to cancer?
pathway to the formation of a cancer cell. In vivo stu-
dies have shown that over-expression of Epidermal Growth
factor (EGF) receptor and loss of TGF? mediated growth
inhibition occur in cervical cancer . Both effects are
likely mediated by HPV infection, which can result in
the downregulation of TGF? receptor I . Interestingly,
mouse models which have deletions or mutations in the
TGF? pathway form spontaneous tumors, most commonly
in the anorectal or genital area [28, 36, 37, 47]. The effects
has not been fully examined. In a mouse model in which
TGF? receptor II had been deleted in fibroblasts, there was
no consistent change apparent among several knock-outs
. It will of interest to examine the expression of EGF in
EJD, vol. 21, Suppl. 2, May 2011
the spontaneous tumors formed in other TGF? conditional
knock-out models to determine how closely this perturba-
tion matches the effects of HPV transformation.
A second parallel apparent in the TZ spontaneous tumors
versus HPV mediated transformation is the effect on cMyc
expression. cMyc is a known oncogene and is one of the
factors required to facilitate the formation of an induced
pluripotent stem cell . cMyc is expressed in the basal
layer of stratified squamous epithelium in both humans and
mouse . Over-expression of cMyc in mouse models
has resulted in tumor formation, stem cell depletion, or
hyper-proliferation . cMyc overexpression has been
identified in HPV positive carcinomas of both the cervix
and anal canal [50, 51]. With increased expression asso-
ciated with tumor invasiveness [50, 51]. In the case of
HPV transformation, this upregulation is mediated largely
by gene duplication, with multiple copies of the cMyc
tional changes in cMyc . Increased cMyc expression
has also been detected in TGF? mouse models by western
blot and quantitative PCR, respectively [28, 47]. In addi-
tion, the disruption of the TGF? pathway down-regulates
the expression of the cyclin-dependent kinase inhibitors,
p27 and p2 [28, 47]. In HPV infected cells, the E7 protein
from HPV-16 has been shown to bind and inactivate both
p21 and p27 [53, 54]. This combination of events removes
cMyc expression by either viral transformation or pertur-
bation of TGF? can trigger a downstream cascade further
driving the cells towards transformation.
mix of signals present where the two types of epithelium
are joined (figure 4). Interestingly, the HPV E6 protein has
been found by microarray analysis of primary human lines
stably transformed with the HPV-16 E6 to exhibit upregu-
repair and is present in transitional epithelium of the anal
canal, the limbus and the esophagus [2, 28, 55] (figures
3A-C-D). While it is important to note that not all tumors
associated with TZs are HPV positive, nor have all been
demonstrated to have a defect in a key signaling pathway,
a significant number do have one or the other. Potentially,
the existing inflammation and wound response already in
place within TZs, creating greater cell stress leading to an
accumulation of signaling miscues or genetic mutations
resulting in the formation of a cancer cell (figure 4).
Thus, there appears that there are conserved, intersecting,
pathways which may affect the frequency at which cells
of the TZ become tumorigenic in response to oncogenic
viruses or genetic perturbations. ?
Disclosure. Acknowledgements: The authors would like to
thank Laura Runck for providing Figure 3A, Dr. Alberto
Pe˜ na and Dr. Marc A. Levitt from the Colorectal Cen-
ter Group at Cincinnati Children’s Hospital for providing
human anorectal TZ, Dr. Ursula Schlotzer-Schrehardt, Dr.
Robert M. Lavker, Dr. Jeffrey M. Arbeit for allowing their
figures to be reproduced in this review and Dr. Pierre
Coulombe for providing his keratin 17 antibody. Financial
support is provided by, CCHMC Trustee Grant Award, part
by PHS Grant P30 DK 078392 and The Concern Founda-
tion Grant. Conflicts of interest: none.
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