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Transgenic Mice: A Unique Model for Metastatic Squamous Cell Carcinoma1
Departments of Human Oncology [A. P. J., N. E. D., D. L. W., A. K. V.] and Pathology and Laboratory Medicine [E. G. V., T. D. O.], Medical School, University of Wisconsin, Madison, Wisconsin 53792, and Veterans Administration Hospital [T. D. O.], Madison, Wisconsin 53705
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ABSTRACT |
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 Top ABSTRACT IntroductionMaterials and MethodsResultsDiscussionREFERENCES |
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18-fold) epitope-tagged protein
kinase C-
(T7-PKC) protein in the epidermis provide a unique
murine model system for highly malignant/metastatic SCC. Skin tumors
were developed by the initiation-promotion protocol (initiation with
100 nmol 7,12-dimethyl-benz[a]anthracene; promotion
with 5 nmol
12-O-tetradecanoylphorbol-13-acetate twice
weekly). T7-PKC transgenic mice showed 92% suppression of papilloma
development compared with wild-type littermates after 23 weeks of tumor
promotion. However, within 15–20 weeks of
12-O-tetradecanoylphorbol-13-acetate promotion, 40% of
T7-PKC mice developed at least one carcinoma compared with 7% of
the wild-type mice. All carcinomas from T7-PKC mice appeared without
prior papilloma formation. Interestingly,
7,12-dimethyl-benz[a]anthracene alone resulted in the
development of squamous cell carcinomas in 22% of T7-PKC mice,
whereas wild-type littermates developed no tumors. Histopathological
analysis of tumors from multiple T7-PKC mice revealed moderately
differentiated SCC invading the dermal region with neoplasia appearing
to originate and invade from the hair follicle. Carcinomas of T7-PKC
mice rapidly metastasized to regional lymph nodes within 3 weeks of
appearance. In wild-type mice, the grade of the invading tumors,
originating from interfollicular epidermis, was pathologically
categorized as well-differentiated SCC and remained localized to the
dermis. The T7-PKC transgenic mice may provide a rapid and unique
in vivo model to investigate metastatic SCC. |
Introduction |
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TopABSTRACTIntroductionMaterials and MethodsResultsDiscussionREFERENCES |
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1 year (5
, 6)
.
The murine skin model system used at present lacks the capability to
study metastatic development in a timely manner (7, 8, 9)
.
To define the distinct role of individual PKC isoforms in the signal
transduction pathways resulting in mouse skin tumor promotion by TPA,
we reported generation of FVB/N transgenic mice expressing an
T7-epitope-tagged PKC
, PKC
, or PKC under the control of the
human keratin 14 promoter/enhancer (10, 11, 12)
. Transgenic
expression of T7-PKC did not affect tumor promotion susceptibility.
The T7-PKC- and T7-PKC-expressing transgenic mice exhibited
different sensitivities to the induction of mouse skin tumors by
initiation with DMBA and twice-weekly promotion with TPA. The increased
expression of T7-PKC protein in the epidermis (8-fold) suppressed
the formation of both skin papillomas and carcinomas by 70%
(11)
. In contrast, the increased expression of T7-PKC
protein in the epidermis (18-fold) almost completely suppressed
papilloma formation but still resulted in the development of SCC
(12)
.
Here we present evidence consistent with the hypothesis that T7-PKC
papilloma-independent carcinomas are pathologically distinguishable,
based on histogenesis, from wild-type mouse tumors. The invading
T7-PKC tumors were pathologically categorized as MDSC, which rapidly
metastasized to regional lymph nodes. In contrast, malignant tumors
from wild-type mice, pathologically categorized as WDSC, invaded the
dermis and s.c. tissues, but remain localized. In T7-PKC mice, the
tumors appeared to originate from the hair follicle within squamous
cells located near the sebaceous gland ("bulge region"). The bulge
cells are postulated to be progenitor or stem cells for the hair
follicle and epidermis (13
, 14)
. In contrast, WDSC derived
from papillomas in wild-type mice appeared to largely originate from
the interfollicular epidermis. The T7-PKC transgenic mouse provides
a unique opportunity to study the origin and events necessary for
malignant progression by using this new model of metastatic SCC.
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Materials and Methods |
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TopABSTRACTIntroductionMaterials and MethodsResultsDiscussionREFERENCES |
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Mice.
The generation of mice for the tumor promotion experiments was
performed by mating heterozygous F5 males with wild-type FVB/N mice.
The transgene was detected by dot blot analyses of genomic DNA from
tail biopsies using the radiolabeled EcoRV/BamHI
fragment from pGEM3Z-K14 ß-globin vector, which encompasses 1 kb
of the K14 promoter and the entire ß-globin intron.
Histology.
The tissue to be examined was excised promptly after euthanasia and
immediately placed in 10% neutral-buffered formalin. Normal tissue was
fixed for 1 h in formalin and then embedded in paraffin.
Carcinomas and lymph nodes required fixation times of 2–3 h. Sections
(4-µm thick) were cut for H&E staining. Carcinomas were examined by a
pathologist (T. D. O.). Previous studies demonstrated concordance
between gross classification of skin tumors (papilloma
versus carcinoma) and subsequent microscopic evaluation by a
pathologist (T. D. O.).
Tumor Induction Experiments.
For mouse skin tumor initiation, a single 100-nmol dose of DMBA in 0.2
ml of acetone was applied topically to the shaved backs of
7–9-week-old female mice. Two weeks after initiation, TPA (5 nmol) in
0.2 ml of acetone or acetone alone was applied twice weekly to skin for
the duration of the experiment. Tumor incidence and multiplicity were
observed weekly starting at 8 weeks of TPA promotion. The number of
mice for each group was as follows: DMBA+TPA, 15 wild-type mice, 15
T7-PKC mice; DMBA+acetone, 14 wild-type mice, 15 T7-PKC mice.
Carcinomas were recorded by gross observation as downward-invading
lesions. Carcinoma-bearing mice were observed for abnormal tumor growth
in the lymph nodes.
Statistical Analysis.
Analyses were performed using the MSTAT computer program, provided by
Dr. Norman Drinkwater, University of Wisconsin, Madison, WI.
Two-sided P values were calculated for tumor and metastasis
multiplicity by Wilcoxon’s rank-sum test. Two-sided P
values comparing tumor incidence were calculated using Fisher’s exact
test.
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Results |
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TopABSTRACTIntroductionMaterials and MethodsResultsDiscussionREFERENCES |
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Transgenic Mice. mouse line 215, which expressed T7-PKC protein at
concentrations 18-fold higher than endogenous PKC levels
(12)
, was further evaluated for the development of
carcinomas by the DMBA initiation and TPA tumor promotion protocol. In
this experiment, female wild-type and T7-PKC transgenic mice were
treated topically with 100 nmol of DMBA in 0.2 ml of acetone. Two weeks
later, 0.2 ml of acetone or 5 nmol of TPA in 0.2 ml of acetone was
applied twice weekly to the dorsal skin. At the beginning of the
experiment, the 7–9-week-old mice exhibited no phenotypic
abnormalities. Treatment with TPA for 23 weeks elicited an average of
12 papillomas/wild-type mouse (Table 1)
. However, in accordance with our previous findings (12)
,
the T7-PKC mice averaged <1 papilloma/T7-PKC mouse (Table 1)
.
The papillomas that developed in T7-PKC mice were also much smaller
than wild-type papillomas (data not shown). Despite the low papilloma
burden, the T7-PKC mice developed carcinomas independently of
papilloma development (Fig. 1
B). After 23 weeks of tumor promotion, 6 of 15 (40%)
transgenic mice were evaluated by gross examination as having at least
one carcinoma, compared with 1 of 15 (7%) of the wild-type mice (Table 1
and Fig. 1B
). Wild-type carcinomas developed from existing
papillomas. Additionally, 3 of 15 transgenic mice treated with
DMBA+acetone alone also developed papilloma-independent carcinomas
(Table 1
and Fig. 1A
). Wild-type mice treated with
DMBA+acetone developed no papillomas (Table 1
and Fig. 1A
).
Because the treatment parameters were identical between the current
experiment and our previously reported experiment (12)
, we
normalized and combined the experimental data to determine whether the
development of carcinomas in T7-PKC mice after DMBA initiation alone
was statistically significant. From the combined data, we determined
that DMBA+acetone treatment elicited carcinoma development in 7 of 31
(22%) T7-PKC mice, whereas wild-type mice never developed
carcinomas (Table 2)
. From the analysis of the combined data, we conclude that DMBA+acetone
is sufficient to induce carcinoma development in T7-PKC mice (Table 2)
.
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mice rapidly developed tumors in regional lymph nodes within
3 weeks after positive identification of carcinomas by gross
observation (Fig. 1B)
. Three of six mice positive for
carcinomas contained regional lymph nodes that bore tumors (Table 1)
.
The T7-PKC transgenic mice that developed carcinomas with
DMBA+acetone treatment did not have evidence of enlarged lymph nodes
(Fig. 1B)
. However, the positive identification of the
carcinomas was less than 3 weeks before the mice were sacrificed at the
conclusion of the experiment.
Primary Tumors Arising in T7-PKC Mice Are Derived from the Hair
Follicle.
Wild-type and T7-PKC mice that were positive for carcinoma formation
were sacrificed 1 week after the last treatment with TPA or acetone.
The carcinoma and surrounding uninvolved skin were removed, fixed, and
embedded. Regional lymph nodes with evidence of tumor growth by gross
observation were also isolated, along with apparently normal lymph node
in the same animal.
By gross observation, both wild-type mouse and T7-PKC mouse
carcinomas were identified by dark red color or the presence of blood
clot on the skin surface. As the lesions progressed, necrosis occurred
on the surface of the cancer, and surface ulceration resulted.
Microscopically, cancer cells were identified by the presence of large
pleomorphic nuclei with prominent nucleoli and frequent mitoses. Areas
of intracellular keratinization and focal extracellular keratin
deposits were identified. The cell cytoplasm was abundant, and the cell
surface exhibited intercellular bridges. Neutrophils were identified
focally adjacent to keratin pearls. The tumors from T7-PKC
transgenic mice were moderately MDSC based on a small number of focal
areas with typical squamous epithelium or keratin formation and a large
number of areas composed of largely undifferentiated cells. In
histological sections of MDSC from two T7-PKC mice initiated with
DMBA and treated for 23 weeks with 5 nmol of TPA, malignant cells were
seen streaming from the hair follicle, often in the region of the
sebaceous gland (Fig. 1, C–E)
. This process often involved
multiple adjacent hair follicles.
DMBA-initiated mice that had been treated for only 8 weeks with TPA or
acetone were also harvested to determine the origin of premalignant
lesions. After 8 weeks of TPA treatment, T7-PKC mice displayed focal
areas of increased hair follicle width, epidermal hyperplasia, and
hyperkeratosis. Possible premalignant lesions were identified arising
from hair follicles; these lesions had cells with enlarged nuclei and
prominent nucleoli and showed outward expansion from the hair follicle
(Fig. 2)
.
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transgenic mice exhibited enlarged regional lymph
nodes after the identification of primary tumor (Fig. 1B)
.
The lymphoid tissue, identified by the presence of numerous collections
of well-differentiated lymphocytic cells, was infiltrated by SCC (Fig. 1F)
. The carcinoma cells ranged in appearance from
undifferentiated clusters of epithelial cells to well-differentiated
squamous cells producing keratin ("keratin pearls"). Other areas
showed undifferentiated carcinoma cells with numerous mitoses
identified. The cell morphology was identical to that seen in the
primary cancer.
In contrast to T7-PKC MDSC, the carcinomas of wild-type mice were
classified as WDSC based on the observation that the majority of the
tumor cells had a squamous appearance with abundant keratin formation.
Microscopically, extensive areas of intracellular keratinization and
focal extracellular keratin deposits were identified. Malignant cells
were observed streaming from the epidermis of the papilloma, not from
the hair follicle (Fig. 1, G and H)
. Epidermal
hyperplasia was not observed in the uninvolved skin of wild-type mice.
All mice were harvested 1 week after the last TPA or acetone treatment;
therefore, the common transient effects of TPA treatment on mouse skin,
including epidermal hyperplasia and keratinization, should mostly have
subsided. This was the case with the uninvolved skin of wild-type mice,
which displayed no abnormalities (data not shown). However, the
uninvolved skin of T7-PKC mice 1 week after TPA treatment still
exhibited hyperplasia of all epidermal cell layers with minimal
hyperkeratosis, and small isolated foci of lymphocytic infiltrates were
identified within the dermis (data not shown).
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Discussion |
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TopABSTRACTIntroductionMaterials and MethodsResultsDiscussionREFERENCES |
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-expressing transgenic mice display almost no papilloma
development during treatment with the two-stage DMBA+TPA tumor
promotion protocol compared with wild-type littermates. However,
carcinoma development appears to be enhanced compared with wild-type
mice (12)
. In an effort to better understand the origin
and development of papilloma-independent carcinomas, T7-PKC mice
were further evaluated for the development of carcinomas by the
DMBA+TPA tumor promotion protocol. We infer three conclusions from the
most recent work. The first two conclusions are that
papilloma-independent carcinomas, which develop in T7-PKC mice,
arise from the hair follicle and have increased metastatic potential.
The third result was determined after combining our previous tumor
promotion results (12)
with our most recent experiments.
Using statistical analysis, we were able to conclude that initiation by
DMBA was sufficient for SCC development in T7-PKC mice.
Histopathological analysis of multiple T7-PKC mice indicated that
SCC of T7-PKC mice invaded the dermal region from the hair follicle.
The SCC of T7-PKC mice rapidly metastasized to regional lymph nodes
as soon as 3 weeks after positive identification of carcinoma by gross
observation. The tumors from T7-PKC transgenic mice were classified
as MDSC. By comparison, the carcinomas of wild-type mice, which
appeared to originate from the interfollicular epidermis of papillomas,
were classified as WDSC. WDSC derived from papillomas invaded the
dermal area with no evidence of metastatic progression.
The difference in metastatic potential and the different origin of
malignancy provided support for the original hypothesis that T7-PKC
papilloma-independent carcinomas were pathologically distinct from
wild-type mouse carcinomas. Although the papilloma-independent
carcinomas appeared to originate from the hair follicle, it was
possible that the origin of the tumor was not within the hair follicle.
The hair follicle might have been the easiest pathway for invasion.
However, this did not appear to be the case because we observed
neoplastic cells arising only from the hair follicle and not the
epidermis. By harvesting T7-PKC and wild-type mice after 8 weeks of
DMBA+TPA or DMBA+acetone treatments, we identified possible
premalignant areas in T7-PKC mice as early as 8 weeks after DMBA+TPA
treatment. The premalignant lesions originated within the hair
follicle.
The metastatic potential of a transformed keratinocyte appeared to
inversely correlate with the differentiation potential of that
keratinocyte in the limited number of tumors studied to date. This
conclusion was based on the location of invasion and pathological
categorization of T7-PKC mouse carcinoma compared with wild-type
mouse carcinoma. Bulge keratinocytes are located near the sebaceous
gland within the hair follicle. Evidence suggests that these cells
appear to be the stem or progenitor cells for both the hair follicle
and epidermis and, therefore, would be in a less-differentiated state
than epidermal cells (13
, 14)
. These properties may
increase the metastatic potential of these cells. The carcinomas of
T7-PKC mice that led to metastases were also less differentiated
than carcinomas from wild-type mice. Although this study was far from
conclusive, evidence suggested that malignant cells that invaded from
the hair follicle were less differentiated and had a higher metastatic
potential than cells that invaded from the epidermis.
Expression of T7-PKC has the ability to induce contradictory effects
in response to mouse skin tumor promotion (papilloma suppression with
carcinoma induction). Because label-retaining cells located in the
bulge region of the hair follicle gave rise to either a hair follicle
or epidermis, the bulge cells were concluded to be bipotent stem cells
(14)
. It is possible that T7-PKC overexpression has a
different outcome based on whether the transgene is expressed in
epidermal or follicular cells. This could be one reason that T7-PKC
expression from multiple transgenic lines consistently inhibits
papilloma formation but not carcinoma development. The multistep nature
of carcinoma development would also suggest that elevated PKC levels
may be able to alter the regulation of several different genes to mimic
the multiple molecular alterations known to occur during carcinoma
development. Transgenic expression of T7-PKC in the skin may alter
the cell cycle kinetics of stem and progenitor cells. The possibility
is highly unlikely that the tumor responses in the T7-PKC-expressing
mice are actually not the product T7-PKC expression but the result
of a disruption of a gene by transgenic insertion into the chromosome.
In this context, it is noteworthy that a second, lower-expressing
T7-PKC transgenic mouse line (line 224), which expresses 6-fold
increased PKC in the epidermis, displays the same papilloma
suppression with carcinoma induction as the higher-expressing
T7-PKC line (line 215) used in these experiments.
Several protocols are used to develop mouse skin tumors. The initiation-promotion protocol, which involves mouse skin initiation with DMBA and promotion with TPA, results in the development of mostly benign papillomas. More than 90% of papillomas regress after TPA treatment is stopped (15) , and only a small percentage of papillomas do progress to invasive SCC (15) . The initiation-promotion protocol has been further modified to enhance the conversion of skin papillomas to carcinomas, but metastatic potential is not increased (16, 17, 18, 19) .
In the mouse, present attempts to model metastasis in vivo use several experimental procedures (6) . This is necessary because metastatic development within mice is rare and requires a long latency period of 1 year (5) . However, the assays incompletely measure the metastatic capability of cancer cells. A classical assay involves the injection of cells into the tail vein of either immunocompromised or syngeneic mice. This assay models the latter stages of metastasis. However, the tail vein injection assay cannot be used to study the earlier invasive and angiogenic stages of malignant progression. In the use of immunocompromised mice, the importance of the immune system in metastatic progression cannot be analyzed. Subcutaneous injection of tumor cells into immunocompromised or syngeneic mice more readily evaluates the ability of tumors to invade, intravasate into the circular system, extravasate out of the circular system, invade the de novo organ site, and induce angiogenesis. However, these model systems do not allow for examination of the genesis of the cancer and ignore the complex interactions between tumor and host, especially at the tissue site where the carcinoma originated.
SCC and BCC are the most common forms of human skin cancer
(2)
. BCC is rarely life threatening because it is slow
growing and is mostly localized. SCC, unlike BCC, invades the nearby
tissues (3)
. The first site of metastasis usually is a
regional lymph node before metastatic growth in distant sites such as
the lung and brain. SCC is commonly encountered in a number of
epithelial tissues, including the oral cavity, esophagus, larynx,
bronchi, intestines, colon, genital tract, and skin (2
, 3)
. Effective management of SCC should include reliable
biomarkers (20)
for early detection of SCC and rationally
designed drugs for its prevention and treatment. The T7-PKC
transgenic mouse model for metastatic SCC may have selective advantages
over the in vivo mouse models used at present. The
carcinogen is applied topically. The procedure is convenient and
inexpensive, and carcinomas, which can be monitored over time, appear
rapidly within 15–25 weeks. This model could also be ideal for
screening agents that may prevent the induction of metastatic SCC. This
model also may be used in investigating the genesis and progression of
SCC and the molecular events associated with progression and
metastasis. The T7-PKC transgenic mouse model for metastatic SCC may
be a tool to achieve these goals.
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FOOTNOTES |
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1 This work was supported by NIH Grant CA35368. 
2 To whom requests for reprints should be
addressed, at Department of Human Oncology, K4/532, CSC, 600 Highland
Avenue, University of Wisconsin Comprehensive Cancer Center, Madison,
WI 53792. Phone: (608) 263-9136; Fax: (608) 262-6654; E-mail: akverma{at}facstaff.wisc.edu
3 The abbreviations used are: NMSC, nonmelanoma
skin cancer; BCC, basal cell carcinoma; SCC, squamous cell carcinoma;
PKC, protein kinase C; TPA,
12-O-tetradecanoylphorbol-13-acetate; DMBA,
7,12-dimethylbenz[a]anthracene; MDSC, moderately
differentiated SCC; WDSC, well-differentiated SCC.
Received 9/22/00. Accepted 12/ 4/00.
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REFERENCES |
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TopABSTRACTIntroductionMaterials and MethodsResultsDiscussionREFERENCES |
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, PKC, or PKC in the epidermis differ in susceptibility to two-stage chemical carcinogenesis and in response to TPA signaling for cell proliferation and differentiation. In: Keystone Symposium Proceedings. Protein Kinase C: Structure, Regulation and Cellular Function. Taos, NM, 2000.
in the epidermis are resistant to skin tumor promotion by 12-O-tetradecanoylphorbol-13-acetate.. Cancer Res., 59: 5710-5718, 1999. in their epidermis exhibit reduced papilloma burden but enhanced carcinoma formation after tumor promotion.. Cancer Res., 60: 595-602, 2000.This article has been cited by other articles:
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Y. Zhao, Y. Xue, T. D. Oberley, K. K. Kiningham, S.-M. Lin, H.-C. Yen, H. Majima, J. Hines, and D. St. Clair Overexpression of Manganese Superoxide Dismutase Suppresses Tumor Formation by Modulation of Activator Protein-1 Signaling in a Multistage Skin Carcinogenesis Model Cancer Res., August 1, 2001; 61(16): 6082 - 6088. [Abstract] [Full Text] [PDF]
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