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Laboratory of Animal Developmental Biotechnology, Korea Research Institute of Bioscience and Biotechnology, Taejon 305-333, Korea [H-Y. H., M-S. N., T-H. L., K-K. L., D-Y. Y.]; Research Institute of Medical Science, Catholic University of Korea, Seoul 137-040, Korea [J-W. L., Z-Y. R.]; Departments of Pathology [H-B. M.] and Surgery [B-J. S.], School of Medicine, Wonkwang University, Iksan 570-749, Korea; Department of Molecular Virology and Oncology, Cancer Research Institute, Kanazawa University, Kanazawa 920, Japan [H. S.]; and Department of Cancer Cell Research, Institute of Medical Science, University of Tokyo, Tokyo 108-639, Japan [M. S.]
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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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Whereas the majority of the MMPs are secreted as soluble enzymes into the extracellular milieu, a subset of MMPs have been identified in recent years to contain additional sequences capable of anchoring on plasma membrane (10, 11, 12, 13, 14, 15) . Named after the putative transmembrane domains as MT-MMP-1 through -5, these enzymes have been proposed to be the master switches of ECM turnover based on the purported ability of MT-MMPs to activate other MMPs such as proMMP-2 and MMP-13. ProMMP-2 and MMP-13 are degradative enzymes widely implicated in tumor invasion and metastasis (10 , 16 , 17) .
As do other MMPs, MT1-MMP has also been proposed to play critical roles in both physiology and pathology by remodeling the ECM. MT1-MMP expression is particularly high in kidney during mouse embryogenesis and also in the adult human (12 , 18) . Recent data indicate that MT1-MMP may also function as a fibrinolytic enzyme in the absence of plasmin and mediate pericellular proteolysis in angiogenesis (19) . Recently it was reported that MT1-MMP-deficient mice develop dwarfism, osteopenia, arthritis, and connective tissue disease because of inadequate collagen turnover (20) . MT1-MMP is also overexpressed in various tumor tissues, including human colon, breast, and head and neck carcinoma (10 , 21, 22, 23, 24) . Although MT1-MMP expression has been proved in numerous tumors, the roles assigned to MT1-MMP in tumorigenesis and tumor progression are relatively poorly understood. In the present study, we generated MMTV/MT1-MMP transgenic mice and examined premalignant abnormalities and adenocarcinoma in mammary glands. The results suggest that overexpression of MT1-MMP may play a key role in development and tumorigenesis in mammary glands.
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MATERIALS AND METHODS |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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). The DNA-injected eggs were transferred to pseudopregnant ICR
female mice. Transgenic mice were identified by PCR analysis of the
genomic DNA using primers specific to mMT1-injection DNA. The
oligonucleotides used for the amplification were a forward primer
5'-ACA-AGA-GCG-CAA-CGG-ACT-CA-3' complementary to MMTV LTR
gene sequences and 5'-ACG-GTG-TAA-GCT-CCG-GTA-3' specific to the
MT1-MMP gene.
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Northern Blot Analysis.
Total RNA was isolated from tissues by the guanidium-thiocyanate
extraction method. RNA (20 µg) from each tissue sample was
fractionated on 1% agarose gels in the presence of 10% formamide and
transferred onto nylon membranes (Boehringer Mannheim, Mannheim,
Germany) to which it was fixed using an optimized UV
cross-linking procedure. As a probe for the MT1-MMP
transcript, 1.8 kb of MT1-MMP cDNA were used. The probe for
ß-casein was obtained by RT-PCR analysis with
total RNA from wild-type lactating mammary gland and specific
primers. The oligonucleotides for amplification were a forward
primer, 5'-GAG-ACT-TTG-ACA-CGA-GGC-GG-3', and a reverse primer,
5'-GAA-TGG-CCT-CGA-ATG-TG-3'. The probes were labeled with
[
-32P]dGTP by the random prime labeling
system (Amersham Pharmacia Biotech, Piscataway, NJ). Signals were
visualized by autoradiography.
RT-PCR Analysis.
For reverse transcription, the first strand of cDNA was synthesized
from total RNA using oligo-dT primer and AMV reverse transcriptase
according to the manufacturer’s instructions (Promega, Madison, WI).
The resulting cDNA served as a template for PCR reaction using MT1-MMP
primers. The primers for transgene and total (endogenous + transgene) MT1-MMP were designated from sequences of pmMT1.
Total MT1-MMP primers produced 320 bp in electrophoresis. The
oligonucleotides for amplification were the forward primer,
5'-AAC-TTC-AGC-CCC-GAA-GCC-TG-3', and the reverse primer,
5'-ACG-GTG-TAA-GCT-CCG-GTA-3'. For transgene detection, the 321-bp
fragments were detected as sequences from the SV40 polyadenylation site
in pmMT1, and the primers were a forward
5'-GGT-AGA-AGA-CCC-CAA-GGA-CT-3' and a reverse
5'-TCT-AGT-CAA-GGC-ACT-ATA-CAT-CAA-3'. The primers for 451 bp of mouse
GAPDH for internal control were a forward
5'-ACC-ACA-GTC-CAT-GCC-ATC-AC-3' and a reverse
5'-TAC-AGC-AAC-AGG-GTG-GTG-GA-3'.
Western Blot Analysis.
The mammary gland tissues were homogenized, total protein
concentrations were determined using a Bio-Rad protein assay kit
(Hercules, CA), and BSA was used as a standard. Equal amounts of
protein from each tissue homogenate were subjected to 12% SDS-PAGE and
then transferred to nitrocellulose membrane. The filters were blocked
with 5% BSA in Tris-buffered saline [50 mM Tris-HCl (pH
7.5) and 0.15 M NaCl] containing 0.1% Tween 20
(TBST) for 3 h at room temperature, then washed with TBST,
and blotted with a monoclonal antibody, 113-15E1 against MT1-MMP
(10)
. Bands were localized with the enhanced
chemiluminescence system (Amersham Pharmacia Biotech, Piscataway, NJ).
Gelatin Zymography.
Samples were applied without heating or reduction to 10%
polyacrylamide gel containing 1 mg/ml gelatin. After electrophoresis,
the gels were washed twice for 20 min with 2.5% Triton X-100, then
with brief water washes, and incubated overnight in 50 mM
Tris-HCl (pH 7.5) containing 10 mM
CaCl2, 0.5 M NaCl, and 0.02%
NaN3 at 37°C. After incubation, the gel was
stained with 0.25% Coomassie Blue R-250 and destained with 10%
methanol and 10% acetic acid. Proteolytic bands appeared clear on
blue-stained background.
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RESULTS |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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. Transgenic mouse
lines were established by mating transgenic founder mice to C57BL/6
mice. All of the founders were fertile and capable of transmitting the
transgene to progeny. Expression of the MMTV/MT1-MMP
transgene in various stages of mammary gland development was examined
by RT-PCR. The expression of transgene mRNA was readily detectable
throughout all of the stages (data not shown). Two lines, designated
nos. 4 and 11, were selected for the additional experiments because the
female founder showed poor lactation after the second and sixth
parturitions, respectively.
MT1-MMP Overexpression Induces Abnormalities in
Transgenic Mammary Glands.
To determine whether the expression of the MT1-MMP transgene
affected morphology of the transgenic mammary gland, we performed
macroscopic and histological examination using the female mice from 7
weeks to 18 months of age. The mammary glands were divided into groups
of virgin, pregnancy and lactation, after 1 or 2 times of parturition
(1–2 parous), and after 
3 times of parturition (multiparous).
There were several kinds of histological abnormalities in the mammary
glands of the MMTV/MT1-MMP transgenic mice, including
lymphocytic infiltration in the stroma, periductal fibrosis, epithelial
hyperplasia in the mammary ducts, alveolar structure disruption in the
lactating glands, dysplastic change in the ductal epithelium, and
adenocarcinoma (Fig. 2)
. Periductal fibrosis and ductal hyperplasia were most common, and
ectactic ducts containing proteinous materials with lipid droplets were
occasionally found in the mice with periductal fibrosis (Fig. 2C)
. Hyperplasias of the alveolar type were also seen in the
transgenic mammary glands (Fig. 2D)
. One of the lactating
glands showed numerous disclosed collapsed alveolar structures and
large dilated ducts containing secretory materials (Fig. 2E)
. In contrast, wild-type lactating glands
displayed disclosed-cell rounded alveolar structures with proliferation
of the epithelial cells (Fig. 2B)
.
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. The major histological patterns of the adenocarcinomas were acinar
carcinoma, which shows in typical MMTV-infected mice (27)
,
and papillary carcinoma in ductal epithelium adjacent to the major
tumor lesions (Fig. 3)
. Additionally, hyperplastic or dysplastic lesions and fibrotic stromas
were found consistently adjacent to the malignant tumor. Many mitotic
figures and necrosis were observed frequently in the tumor (Fig. 3B)
. The tumors were divided by thick fibrous tissue and
grew in a diffuse or nest formation. Pulmonary metastasis was
found in one of three mice with mammary carcinoma, confirming the
malignant nature of the tumors (Fig. 3E)
. Tumor cell emboli
were found in the lumen of the blood vessels in the mammary gland (Fig. 3D)
.
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, 70% of the transgenic mice investigated showed lymphocytic
infiltrations, 55% showed moderate and severe fibrosis (collagen and
fibroblast accumulation with the loss of adipocytes), 52% showed
moderate and severe hyperplasia (proliferation of epithelial cell),
15% showed dysplasia (proliferation of atypical cells), and 9% showed
mammary adenocarcinoma. Only 18% of all of the transgenic mice were
histologically normal in mammary glands. By comparison, 75% of the
wild-type control mice showed entirely normal mammary glands, and the
remaining 25% showed only mild hyperplasia or lymphocytic infiltration
(Table 2)
.
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Lesions in the mammary glands of multiparous transgenic mice were more
severe than in the other groups (Table 2)
. The hyperplastic and
fibrotic lesions tended to be much more severe in the multiparous
subset of transgenic mice. Moreover, mammary-gland tumors were
developed in three of six multiparous transgenic mice (Table 1)
.
Expression of MT1-MMP in Mammary Glands of Transgenic Mice.
MT1-MMP expression was investigated in mammary glands from transgenic
mice by immunohistochemical analysis (Fig. 4)
. MT1-MMP was expressed in the fibrous stroma cells of the mammary
glands from wild-type control mice (Fig. 4A)
. It was
expressed in the epithelial cells as well as in the fibrous stroma
cells of the mammary gland in lactating transgenic mice (Fig. 4B)
. Particularly, the expression of MT1-MMP was apparent in
the epithelial cells of the transgenic mammary gland, which showed
disrupted alveolar structures (Fig. 4C)
. Additionally,
MT1-MMP was markedly expressed in tumors surrounding the fibrous
stroma, but weakly expressed in the tumor cells of the transgenic mice
(Fig. 4D)
.
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. In addition, MT1-MMP transcripts were detected in the
tumor mammary glands, whereas negligible or no hybridization was
observed by Northern blot analysis in the wild-type control or in
normal lesions of the transgenic mammary gland (Fig. 5B)
.
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. The results demonstrated that the expression of MT1-MMP was elevated
not only at the transcriptional level, but also at the translational
level in mammary gland tumors.
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, Lane 1) and 3 days after weaning (Fig. 7
, Lane
3) showed high-level expression of ß-casein mRNA. By comparison,
in the same development stage and at the same ages of transgenic mice,
ß-casein was not expressed in disrupted
alveolar structure and tumors (Fig. 7
, Lanes 4,
5, and 6) and showed very low-level expression in
the normal residual glands of the transgenic mammary gland (Fig. 7
,
Lanes 7 and 8). The results demonstrate
that morphological changes, which were induced by ectopic expression of
MT1-MMP, resulted in the complete abolition of expression of
ß-casein mRNA in tumor-bearing mammary-gland tissues.
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, Lanes 1 and 2). In tumor tissues, a
representative zymogram revealed a significant increase in the
activation of progelatinase A (Fig. 8)
.
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DISCUSSION |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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and 2
. These results suggest that MT1-MMP may be involved in early
tumor promotion in transgenic mammary glands. Therefore, we have tried
to understand the mechanism that generates premalignant abnormalities
and tumorigenesis in the mammary glands of MMTV/MT1-MMP transgenic
mice.
Aberrant Expression of MT1-MMP in Epithelial Cells May Be a Direct
or Indirect Consequence of Genetic Changes in the Transformed Cells.
During all of the development stages of mammary gland at virgin,
pregnancy, lactation, and involution, MT1-MMP protein was localized in
the stromal fibrous tissue of wild-type control mice (Fig. 4A)
. In contrast, ectopic expression of MT1-MMP was detected
in ductal epithelial cells and was apparent in the disrupted alveolar
of the lactation glands of transgenic mice (Fig. 4, B and C)
. Other investigators have supported the idea that
expression of MT1-MMP could not be detected in normal
epithelial cells, even during wound healing, but that it can be seen in
transformed epithelial carcinoma cells (28
, 29)
. There are
some examples that the transcriptional activation of the
MT1-MMP gene is associated with the transformation of
carcinoma cells. Human breast carcinoma cell lines with weak
tumorigenicity do not express MT1-MMP, but cell lines with invasive and
metastatic properties express do MT1-MMP (30)
. These
findings suggest that expression of MT1-MMP in the cells correlates
with the loss of epithelial phenotype and the acquisition of
mesenchymal characteristics such as the expression of vimentin
(30)
. In association with the overexpression of
MT1-MMP in the mammary glands of abnormality-exhibiting
transgenic mice, we noted a significant reduction of
ß-casein gene expression (Fig. 7)
. Because
ß-casein is expressed in the ductal
epithelial cell of the mammary gland, we inferred that the reduction of
the gene expression resulted from the loss of cellular specificity in
the MMTV/MT1-MMP transgenic mice.
Mammary Gland Abnormalities Seen in MMTV/MT1-MMP Transgenic Mice
Characterize the Reactive Stroma.
In MMTV/MT1-MMP transgenic mammary glands, stromal changes, such as
lymphocytic infiltration and fibrosis, appeared to presage malignant
epithelial changes including hyperplasia, alveolar structure
disruption, dysplasia, and adenocarcinoma. In the stromal cells of
these mammary glands, these abnormalities were indicated throughout all
of the developmental stages of the mammary gland, even in virgin (Table 2)
mice. In addition, MT1-MMP expression was elevated in tumor tissue
surrounding the stromal cells of the MT1-MMP transgenic mammary glands
(Fig. 4D)
.
The reactive stroma defined as an accumulation of collagen fiber, recruitment of inflammatory cells, increased vascularization, and an up-regulation of MMPs (2 , 31, 32, 33) . There was evidence suggesting that the formation of the tumor mass in epithelial cancers was profoundly reliant on the stromal cells (34) . An altered stromal environment may actually promote neoplastic transformation and alterations in the stromal-epithelial interactions transduced via changes in the integrity of the ECM can promote neoplastic transformation (5 , 33, 34, 35, 36, 37, 38) . The dramatic alteration of stromal phenotype by overexpressed MMPs such as MMP-3 leads to tumor development (39) .
MT1-MMP Expression Level Relates to Activation of Substrates Such
as MMP-2.
Gelatin zymography results indicate the activation of MMP-2 was
associated with overexpression of MT1-MMP in the transgenic mammary
glands exhibiting abnormalities (Fig. 8)
. Elevated expression and
activation of MMP-2 have correlated to the tumor grade, promotion, and
malignancy of many tumors (3
, 40
, 41)
. MT1-MMP
has been implicated as a possible activator of MMP-2 and MMP-13
(12
, 42, 43, 44, 45, 46, 47)
. In addition, MT-MMPs can also degrade a
number of ECM proteins, such as gelatin, fibronectin, vitronectin,
fibrillar collagens, or aggrecan (48)
. Therefore, it is
suggested that the MT1-MMP expression level relates to
activation of the substrates including MMP-2 and results in increased
aberrant degradation of ECM, which might lead to tumor formation and
metastasis.
In conclusion, we hypothesize the ectopic expression of MT1-MMP in epithelial cells might be a direct or indirect consequence of cell environments, including ECM remodeling and the genetic change to transformation. We suggest that overexpression of MT1-MMP can alter its extracellular environment as a stromal product. Therefore, it may be partly responsible for the tumorigenic effects of an altered stroma.
It remains to be determined whether MT1-MMP is critical for early tumor promotion in mammary gland. Until recently, evidence for the activity of MMPs in early tumor promotion was limited. However, it was reported that MMP-3 induced mammary gland changes as a natural promoter in early tumor formation in the absence of exogenous mutagens or endogenous oncogenes or suppressor gene defects (49 , 50) . Therefore, the availability of MMTV/MT1-MMP transgenic mice as a mammary tumor model should lead to elucidation of the malignant process and to an understanding of how an abnormal microenvironment in mammary glands could lead to cancer induction and progression.
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FOOTNOTES |
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1 This work was supported by grants NB0540 and
NB0870 from the Ministry of Science and Technology of Korea. 
2 To whom requests for reprints should be
addressed, at Laboratory of Animal Developmental Biotechnology, Korea
Research Institute of Bioscience and Biotechnology, Taejon 305-333,
Korea. Phone: 82-42-860-4422; Fax: 82-42-860-4608; E-mail: dyyu10{at}kribb4680.kribb.re.kr
3 The abbreviations used are: MMP, matrix
metalloproteinase; MT, membrane-type; ECM, extracellular matrix;
RT-PCR, reverse transcription-PCR; MMTV LTR, mouse mammary
tumor virus long terminal repeat; GAPDH, glyceraldehyde-3-phosphate
dehydrogenase.
Received 11/17/99. Accepted 11/20/00.
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REFERENCES |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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