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Carcinogenesis |
Cancer Genetics and Gynecological Oncology Programs, University of California San Francisco Cancer Center [D. A. E., R. R. R., A. L., J. M. A.], and the Department of Surgery [J. M. A.], University of California, San Francisco, California 94143; and the Biology Department, University of California, Santa Cruz, California 95064 [G. T., F. J. T.]
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ABSTRACT |
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 Top ABSTRACT INTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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INTRODUCTION |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Cervical carcinogenesis associated with HPV primarily affects metaplastic squamous epithelium in a specific anatomical location, the transformation zone. The topography and natural history of this region is complex and dynamic, affected by age, hormonal status, pregnancy, and parity (1) . In adult women, the transformation zone usually is on the vaginal surface of the cervix, an irregular line of demarcation dividing one type of epithelium from another (1) . Microscopically, columnar epithelium lines both the endocervical canal and associated endocervical glands, whereas squamous epithelium covers the outer cervix. During cervical squamous metaplasia, foci of squamous cells are detectable among the endocervical glandular columnar epithelium (1) . HPV appears to be tropic for the cervical transformation zone during infection and persistent disease. The transformation zone may have a unique estrogen metabolism compared with other reproductive tract epithelial cell types producing hormone metabolites with direct genotoxicity (9) .
We investigated mechanisms of multistage HPV-associated squamous
carcinogenesis in K14-HPV16 transgenic mice containing the entire HPV16
early region cloned behind the human keratin-14 promoter and expressing
viral oncogenes in basal squamous epithelial cells
(10, 11, 12, 13)
. Chronic estrogen treatment induced squamous
cancers predominantly in the vagina and outer cervix of transgenic mice
(14)
. In the present study, we discovered that a 5-fold
reduction in hormone dosage, compared with our original study
(14)
, produced multistage carcinogenesis restricted solely
to the cervical transformation zone of transgenic mice. Transformation
zone carcinogenesis exhibits a biology distinctive from that of our
previous model. Multifocal glandular squamous metaplasia develops in
the lower uterus, and metaplastic foci progress to high-grade dysplasia
and invasive cancers. Expansion of a basal squamous cell population
potentially expressing both estrogen receptor-
and the HPV transgene
may also underlie synergism between viral oncogenes and estrogen.
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MATERIALS AND METHODS |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Animal Sacrifice, Perfusion, and Dissection.
As described previously (13
, 15)
, mice received i.p.
injections of 100 mg/kg BrdUrd, and under Avertin anesthesia,
were sacrificed 2 h later by perfusion of the ascending aorta with
3.75% paraformaldehyde. Reproductive tracts and surrounding soft
tissue, including any lymph nodes, were dissected and postfixed
overnight at 4°C. The posterior wall of the vagina was removed, and
the tissues were rinsed in PBS, dehydrated through graded alcohols and
xylene, oriented with the cut vaginal surface facing downward, embedded
in paraffin, and 5-µm sections were stained with H&E.
Keratin Immunohistochemistry.
Immunoperoxidase staining for keratin-14 expression was performed as
described previously (11
, 15)
. Sections were incubated
with a rabbit antimouse K14 antibody (BAbCO), 1:10,000 in 3% BSA,
overnight at 4°C. Immunoperoxidase staining was performed using
3,3'-diaminobenzidine (cat. no. D5637; Sigma), and the sections
were counterstained with hematoxylin.
Tissue DNA Synthesis.
Immunohistochemistry to detect BrdUrd incorporation was performed as
described previously (13
, 15)
. The number of
diaminobenzidine-positive nuclei was counted in five adjacent x20
fields in the cervical canal and transformation zone.
Estrogen Receptor Expression.
Paraffin sections were melted at 55°C for 20 min, immediately
deparaffinized, rehydrated, and microwave-boiled for 10 min in 10
mM citrate buffer (pH 6.0). After cooling to room
temperature, sections were blocked in 10% BSA, incubated overnight at
4°C with ER-21 antibody (1:15,000 in 3% BSA; Geoffrey Greene,
University of Chicago, Chicago, IL), biotinylated goat antirabbit serum
(1:200 in BSA) for 1 h, followed by ABC-alkaline phosphatase
reagent for 1 h (Vector Labs, Burlingame, CA). Slides were
washed in 0.1 M Tris (pH 9.5) and incubated in the dark for
1.5 h in 5-bromo-4-chloro-3-indolyl phosphate/nitroblue
tetrazolium substrate reagent (SK-5400; Vector) with levamisole.
Serum Estrogen Levels.
Blood was collected by periorbital puncture into heparinized tubes and
centrifuged; serum estrogen was assayed using a RIA (Diagnostic
Products, Los Angeles, CA), modified for mouse serum (16)
.
In Situ Hybridization.
In situ hybridization for expression of HPV16 E6/E7 and
control mRNAs was performed as described previously (14
, 17)
. Sections were exposed for 1 month, developed, and
counterstained with H&E.
Microscopic Imaging and Statistical Analysis.
Microscopic images were captured using a Leica DMRXA microscope
equipped with a Spot digital camera (Diagnostic Instruments, Inc.).
Images were composed using Adobe Photoshop 5.5 (San Jose, CA).
Numerical data are presented as the mean ± SD, and were
analyzed statistically by two-way ANOVA and 
2
analysis, using Graph Pad 2 software (San Diego, CA).
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RESULTS |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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and Fig. 1
). Table 1
delineates the total number of transgenic and nontransgenic
mice starting treatment in each group and the subset of transgenic and
nontransgenic mice treated with each dose of 17ß-estradiol for 6
months. This part of the study was designed to delineate the location
of reproductive tract cancers; thus, derivation of cancer incidence
versus dose was not available. The frequency distribution of
the numbers of cancers occurring at different levels of the
reproductive tract was significantly different for mice treated
with either 0.25 or 0.10 mg/60-day 17ß-estradiol compared with
transgenic mice treated with 0.05 mg/60-day 17ß-estradiol (Fig. 1)
.
Transgenic mice treated with either 0.25 or 0.10 mg/60-day
17ß-estradiol predominantly developed squamous cancers of the vulva,
vagina, and lower/outer cervix (Fig. 1, a and c
,
and Fig. 1b
, panels 1–3, respectively). In
contrast, 0.05 mg/60-day 17ß-estradiol induced squamous cancers that
were almost exclusively localized to the transformation zone situated
between the upper cervix and the lower uterus (Fig. 1b
,
panel 4, and Fig. 1c
). Despite extensive invasion
into underlying stromal tissues, none of the transgenic mice treated
with any dose of 17ß-estradiol developed lymph node metastasis. The
0.01 mg/60-day 17ß-estradiol dose did not affect the reproductive
tract squamous epithelium of either transgenic or nontransgenic mice
when compared with placebo-treated controls matched for stages of
estrus (Fig. 1b
, panels 5 and 6, and
insets therein). Nontransgenic mice treated with each
17ß-estradiol dose developed squamous epithelial thickening
consistent with benign hyperplasia (Fig. 1)
. None of the nontransgenic
mice treated with any estrogen dose developed neoplasia or malignancy
(data not shown and Fig. 1
). Spontaneous reproductive tract pathology
did not develop in placebo-treated transgenic mice.
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. Mortality during estrogen treatment was due to urinary
bladder dilation in both transgenic and nontransgenic mice. Mice
severely affected by bladder dysfunction were sacrificed immediately
for reproductive tract histopathological analysis and were designated
as a "mortality." Deaths in the 0.25 mg/60-day 17ß-estradiol
groups occurred as early as after 2.5 months of treatment, whereas all
unscheduled deaths in the 0.1 and 0.05 mg/60-day 17ß-estradiol groups
occurred after 5–6 months of treatment. As such, calculation of
mortality for the entire group of mice encompassing the entire study
diluted mortality estimates for the lower estrogen doses because of
inclusion of early time points (Table 1)
. Therefore, we analyzed a
small subset of transgenic and nontransgenic mice treated with estrogen
for 6 months (Table 1)
. Mortality in the 0.25 and 0.10 mg/60-day
17ß-estradiol groups was greater than that reported previously for
this model (14)
and may have been due to modifier effects
of the FVN/n in-bred strain (see "Discussion"). Although there was
no statistically significant difference in mortality between groups,
there was a clear trend toward reduction in mortality in mice treated
with 0.05 mg/60-day 17ß-estradiol (see "Discussion"). Despite
step-sectioning of the bladder and the urethra, our analysis did not
reveal a discrete point of bladder obstruction (data not shown). There
was no significant difference in mortality between transgenic and
nontransgenic mice, and none of the mice treated with 0.01 mg/60-day
17ß-estradiol died (Table 1)
.
To determine the effect of each estrogen dose on blood hormone
levels, serum was obtained from transgenic and nontransgenic mice
treated for 7 weeks with 60-day release hormone or placebo pellets
(Fig. 2)
. Previous studies from the pellet manufacturer demonstrated constant
hormone release without "peak and trough" effects at the beginning
and end of the 60-day dosing interval (18)
. Compared with
placebo, the 0.25 and the 0.10 mg/60-day doses elevated serum estrogen
11–21-fold and 6–15-fold, respectively. Although there was no
statistically significant elevation of serum estrogen levels produced
by the 0.05 mg/60-day 17ß-estradiol dose compared with
placebo-treated mice in diestrus, the 50% elevation of serum hormone
levels in this group was most likely biologically significant (Fig. 2)
.
Moreover, cumulative reproductive tract histopathological analysis of
all transgenic and nontransgenic mice treated with 0.05 mg/60-day
17ß-estradiol revealed that this dose prevented estrus cycling,
whereas progesterone effects were seen in mice treated with 0.01
mg/60-day 17ß-estradiol.
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. Transformation zone cancers were first detected after 4 months of
treatment in 30% of transgenic mice, and increased to 60% after 5
months and 91% after 6 months of hormone treatment (Fig. 3a
, also see "Discussion"). Fig. 3b
illustrates the reproductive tract histopathology of
17ß-estradiol-treated nontransgenic (panels 1,
3, 5, and 7) and transgenic
(panels 2, 4, 6, and 8)
mice. After 1 and 4 months of treatment, there was a progressive
increase in the thickness and proximal extension of the squamous
epithelium into the lower uterus in the transgenic compared with the
nontransgenic mice (Fig. 3b
, panels 1–4). In
addition, squamous metaplasia was evident in lower uterine glands,
particularly in the reproductive tracts of transgenic mice (see
arrowhead in Fig. 3b
, panel 4).
Metaplastic lower uterine glands were separated from the anatomical
squamo-columnar junction by columnar epithelium (Fig. 3b
,
panels 4, 6, and 8). After 5 months of
17ß-estradiol treatment, the transformation zone of both
nontransgenic and transgenic mice displayed a profusion of lower
uterine glands. These glands were hyperplastic, with extensive branches
penetrating into the stroma (Fig. 3b
, panels 5
and 6, and Fig. 3c
). In the transgenic
mice, extensive squamous metaplasia was detectable in these
hyperplastic glands and was the source for high-grade dysplasia and
multifocal squamous carcinomas (Fig. 3b
, panel 6,
and Fig. 3c
, lower panel). After 6 months
of hormone treatment, there were further increases in the number and
stromal extension of transformation zone glands in nontransgenic mice
(Fig. 3b
, panel 7) and more extensive glandular
squamous metaplasia and stromal invasion by multifocal squamous
carcinomas in transgenic mice (Fig. 3b
, panel 8).
|
. After 1 month of 17ß-estradiol treatment, transformation zones in
both transgenic and nontransgenic mice demonstrated focal keratin-14
expression within two to three lower uterine glands (Fig. 4
,
panels 1 and 2). Metaplastic lower uterine glands
were separated from the cervical squamous epithelium by a considerable
length of intervening columnar epithelium (Fig. 4
, panels 1
and 2). After 6 months of hormone treatment, the
transformation zones in transgenic mice displayed an increase in the
frequency of metaplastic lower uterine glands (Fig. 4
, panel
4). Higher magnification of the transgenic transformation zone
revealed multifocal squamous metaplasia in several different lower
uterine glands as well as within individual lower uterine glands
(Fig. 4
, panel 5). Metaplastic foci appeared to arise from
single cells located at the epithelial-stromal interface (Fig. 4
,
panel 5 inset). In contrast, squamous metaplasia was
decreased at the transformation zone of nontransgenic mice (Fig. 4
,
panel 3).
|
). Representative immunohistochemical tissue sections demonstrated that
estrogen induced an increase in BrdUrd-positive cells within both the
squamous epithelium and the stroma in transgenic mice compared with
nontransgenic mice. Subcolumnar cells resembling reserve-like cells or
keratinocytes were more frequently in S-phase in estrogen-treated
transgenic compared with nontransgenic mice (Fig. 5
,
arrowheads).
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Estrogen Receptor Expression Patterns during Transformation
Zone Carcinogenesis.
Because estrogen receptor- is known to stimulate reproductive
tract proliferation (19
, 20)
, we investigated the
distribution of receptor expression immunohistochemically. Estrogen
receptor- protein was detected in both basal squamous epithelial and
underlying stromal cells in both nontransgenic and transgenic mice
after 1 month of 17ß-estradiol treatment (Fig. 6
, panels 1 and 2, respectively). After 6 months of
hormone treatment, the populations of basal and basaloid cells
expressing estrogen receptor- were markedly expanded in the
transgenic mice compared with the nontransgenic mice, particularly in
dysplastic squamous epithelium (Fig. 6
, panels 2 and
4 compared with panel 5). In metaplastic and
dysplastic lower uterine glands of transgenic mice in which columnar
epithelium was juxtaposed to squamous epithelium, estrogen receptor-
expression appeared to be greater in the former compared with the
latter. Estrogen receptor- expression was also evident in the
squamous epithelial component of transformation zone cancers (Fig. 6
,
panels 6 and 7).
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DISCUSSION |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Squamous metaplasia appears to be the first stage of transformation zone carcinogenesis in both our model and in clinical disease. Although the location of the transformation zone in mice is at the junction of the upper cervix and lower uterus, in contrast to the portio of the cervix in humans, there are data implicating the glandular reserve cells in human disease (28, 29, 30) , as we suspect in our transgenic mouse model. For example, both ectocervical and endocervical cells can be cultured from the human cervix (31) . Although endocervical cells are derived from endocervical glands lined by columnar epithelium, they also produce colonies that simultaneously express both the squamous marker keratin-14 and the columnar marker keratin-18 (31) . Transplantation of endocervical cells into immuno-deficient hosts elaborates monolayers resembling immature squamous metaplasia, whereas transplantation of ectocervical cells produces well-differentiated, stratified squamous epithelium (31) . The more commonly held view of the origins of glandular metaplasia is migration and replacement of glandular columnar epithelium by adjacent squamous cells. Recent data suggest that enhanced cell motility, possibly facilitated by HPV E6 binding to paxillin (32) , may contribute to this phenomenon. However, development of multifocal squamous metaplasia at a distance from the squamo-columnar junction in our model is consistent with the possibility that cervical carcinogenesis may originate from individual glandular reserve cells (29 , 31) .
Squamous metaplasia is also more extensive in estrogen-treated transgenic versus nontransgenic mice. Squamous metaplasia appears to be induced in the vagina and cervix by a decrease in pH (1) . Epithelial acidification occurs during adolescence as a result of increased estrogen production, vaginal bacterial flora alterations, and epithelial wounding (1 , 33) . Yeast two-hybrid screens have demonstrated binding of M2 pyruvate kinase to HPV16 E7 (34) . HPV E7 stabilizes the dimeric compared with the tetrameric form of M2 pyruvate kinase (34) . Substrate utilization by dimeric M2 pyruvate kinase shifts intracellular glucose metabolism to aerobic glycolysis rather than tricarboxylic acid cycle oxidation (34) . One hypothesis suggested by these biochemical data is that E7-mediated intracellular acidosis due to lactate accumulation may be a signal that contributes to a squamous rather than a columnar fate decision in glandular reserve cells in estrogen-treated transgenic mice.
Several features of our present model suggest that a combination
of cell autonomous and non-cell autonomous factors conspire to induce
transformation zone cervical carcinogenesis. Expression of estrogen
receptor- and the HPV oncogenes (14)
in the same basal
cell population suggest a cell autonomous contribution to squamous
epithelial dysplasia and subsequent invasive cancer. There are a number
of molecular scenarios, predominantly involving parallel pathways, for
estrogen receptor- signaling to synergize with the cellular effects
of the HPV16 oncoproteins. For example, increases in E2F activity
secondary to pRB destabilization by HPV E7 up-regulates a collection of
genes, including thymidylate kinase and dihydrofolate reductase,
increasing nucleotide pools required for DNA synthesis by estrogen
receptor- target genes (35)
. Synergism between estrogen
receptor- and HPV could also occur at the level of the epithelial
growth factor receptor, whose cell surface recycling is
increased by HPV E5 oncoprotein (36, 37, 38)
. Up-regulation of
estrogen receptor- transcriptional activity can be produced by
epithelial growth factor receptor-mediated activation of the MAP
kinase pathway, which can directly phosphorylate the hormone receptor
(39)
. Indirect interaction between the HPV oncoproteins
and estrogen receptor- transactivation may also occur at the level
of chromatin remodeling. Ligand-bound nuclear receptors recruit
coactivator(s) that possess histone acetylase activity to DNA
(40)
. Chromatin histone acetylation increases
transcription machinery access to DNA (40)
. Conversely,
retinoblastoma protein transcriptional repression is mediated by
recruitment of histone deacetylase to DNA (41)
. HPV E7
disrupts complex formation between histone deacetylase and the
retinoblastoma protein (42)
. Thus, HPV E7 may further
increase chromosomal DNA access at estrogen receptor response elements.
Non-cell autonomous cooperation between ligand-activated estrogen
receptor- and the HPV oncoproteins may also occur. Metaplastic
squamous epithelium emerges from highly branched, hyperplastic, lower
uterine glands induced by chronic low-dose estrogen treatment. These
structures likely form as a result of stromal-epithelial interactions
at the transformation zone of estrogen-treated mice, possibly
coordinated by transcription and release of growth factors from the
underlying stroma in response to activation of estrogen receptor- by
ligand. Induction of dysplasia in the overlying neoplastic squamous
epithelium of transgenic mice could be mediated by squamous epithelial
cell cycle dysregulation and altered genomic stability mediated by HPV
E7 and E6 (43)
.
Thus, similar to human disease, transformation zone
carcinogenesis in estrogen-treated K14-HPV16 transgenic mice cannot be
explained by a single molecular feature; rather, it is multifactorial
(Fig. 7)
. Chronic estrogen treatment stimulates development of hyperplastic
lower uterine glands. These glands become "fertile soil," fostering
squamous metaplasia and neoplastic progression. Glandular stem-like
reserve cells can express low levels of keratin-14 (31)
and, in transgenic mice, the HPV oncogenes. Interaction of HPV16 E7
oncoprotein with M2 pyruvate kinase could produce decreased
intracellular pH (34)
, potentially biasing glandular
reserve cell fate decision(s) toward metaplastic squamous rather than
columnar epithelium (Ref. 1
and Fig. 7
). Continuous HPV E6
and E7 oncogene expression can cause persistent cell cycle
dysregulation (44)
and facilitate genetic instability
(45)
. Estrogen receptor- signaling within squamous
epithelial cells, between glandular columnar and metaplastic squamous
cells, and elaborated from the underlying stroma may further contribute
to carcinogenesis. This study sets the stage to elucidate cell
autonomous and non-cell autonomous contributions to transformation zone
carcinogenesis, using either genetic complementation or pharmacological
treatments, either antineoplastic or chemopreventive, that target each
element of this model.
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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1 Supported by Grant R01-CA-71398 and in part by
Grant NO1-CN-75106, both from the National Cancer Institute. 
2 To whom requests for reprints should be
addressed, at UCSF Cancer Center, 2340 Sutter Street, Box 0808, San
Francisco, CA 94143-0808. Phone: (415) 502-3292; Fax: (415) 476-8218;
E-mail: jarbeit{at}cc.ucsf.edu
3 The abbreviations used are: HPV, human
papillomavirus; BrdUrd, 5-bromo-2-deoxyuridine.
Received 9/30/99. Accepted 1/ 5/00.
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