ARTICLE
Auteur(s) : Ming-Fang Cheng1, Jong-Shiaw
Jin1, Huang-Wei Wu2, Pei-Chun
Chiang3, Lai-Fa Sheu1, Herng-Sheng
Lee1
1Department of Pathology, Tri-Service General
Hospital and National Defense Medical Center, Sec. 2, Cheng-Kung
Road, Neihu 114, Taipei, Taiwan, Republic of China
2Department of Pediatrics, Kaohsiung Armed Forced
General Hospital, Taiwan, Republic of China
3Taipei City Hospital, Taiwan, Republic of China
accepté le 30 Mars 2007
Matriptase, also known as membrane-type serine protease-1 (MT-SP1)
or tumor-associated differentially expressed gene-15 (TADG-15), has
been revealed by cDNA cloning to be a member of the type II
transmembrane serine protease family [1-3]. Biologically,
matriptase can be expressed in some major vertebral genomes,
including human, chimpanzee, dog, mouse, rat, chicken, zebrafish,
and spotted green and tiger pufferfish, which suggests a conserved
evolutionary function. In addition, matriptase has physiologically
been shown to play an important role in hair follicle growth, in
corneocyte maturation, profilaggrin processing, and lipid matrix
formation, associated with terminal differentiation of the oral
epithelium and the epidermis [4].This protease was initially
isolated as a trypsin-like serine proteinase from breast carcinoma
[5] and subsequently purified as a complex with hepatocyte growth
factor activator inhibitor-1 (HAI-1) from human milk [6].
Matriptase is a multiple-domain protease composed of a short
cytoplasmic domain at the N-terminus followed by: a putative
transmembrane domain; a sperm protein, enterokinase and agrin
domain; two tandem C1r/C1s, urchin embryonic growth factor and bone
morphogenetic protein-1 (CUB) domains; four tandem low-density
lipoprotein (LDL) receptor class A domains; and a trypsin-like
serine protease domain at its C-terminus [6, 7]. Matriptase could
proteolytically cleave various synthetic substrates containing
arginine or lysine at their P1 sites [6, 8, 9], known as the latent
forms of hepatocyte growth factor (HGF), urokinase-type plasminogen
activator (uPA), and protease-activated receptor-2 (PAR-2) in vitro
[8, 9]. Both HGF and uPA, apparently produced by the stromal cells
located outside the vessel wall [10-12], have been implicated in
regulating extracellular matrix degradation, cell proliferation,
cell survival and cell motility [13-15]. There is also evidence
that activation of HGF and uPA could play an important role in
tumor cell progression, growth, invasion and metastasis in vitro
and in vivo [16-19].Mast cells, originating from pluripotent
hematopoietic cells in the bone marrow, can be found in all
supporting tissues. Mast cells can produce and store almost
cellular-specific neutral serine proteases, such as tryptase and
chymase [20, 21], which may functionally control blood flow,
angiogenesis, inflammation, or fibrosis [22]. Chymase secreted by
mast cells may activate pro-matrix metalloproteinase (MMP) -2 and
MMP-9 [23]. Gingival mast cells have been shown to strongly express
MMP including MMP-1, MMP-2 and MMP-8, and to a lesser degree the
tissue inhibitors metalloproteinases (TIMPs) including TIMP-1/-2
[24]. Trypsin secreted by mast cells could regulate, via cleavage,
PAR-2, extracellular matrix-active enzymes (e.g.,
metalloproteinases), and extracellular matrix components (e.g.,
fibrinogen) [25-27].It is well known that mast cells play a key
role in type 1 hypersensitivity and in some non-allergic diseases
as well [27]. In addition, mast cells are significantly increased
in several neoplasms including oral, skin, breast, cervical and lip
cancers [28-31]. Such activity indicates that mast cells are likely
to play an important role in the degrading of tissue matrix.In the
present study, the expression of matriptase by mast cells was
investigated. Our findings demonstrate that matriptase is not only
present in human epithelia, but immunohistochemically active in
mast cells. Such knowledge suggests that matriptase may be useful
as an additional marker for mast cells and may itself be involved
in the physiopathological function of mast cells.
Materials and methods
Tissues
Paraffin-embedded tissue specimens were obtained from the archives
of the Department of Pathology of Tri-Service General Hospital and
National Defense Medical Center including 6 samples of mast cell
diseases (n = 6; 2 females and 4 males; age: 3 to 70, mean: 25.3
years), 10 samples of uterine leiomyomas with surrounding
relatively normal myometrial tissue (n = 10; all females; age: 29
to 56, mean: 47.2 years), 10 samples of dilated cardiomyopathy (n =
10; 5 females and 5 males; age: 38 to 54, mean: 46.4 years) and 10
samples of chronic allergic rhinitis (n = 10; 5 female and 5 male;
age: 22 to 34, mean: 46.4 years) as well as 10 samples each of
relatively normal parenchymal tissues from patients with
osteoarthritis (synovium) (n = 10; 5 female and 5 male; age: 55 to
68, mean: 62.4 years), colon adenocarcinoma (n = 10; 5 female and 5
male; age: 51 to 79, mean: 65.4 years), hepatocellular carcinoma (n
= 10; 5 female and 5 male; age: 43 to 65, mean: 58.6 years),
pulmonary adenocarcinoma (n = 10; 5 female and 5 male; age: 39 to
59, mean: 43.8 years) and esophageal squamous cell carcinoma (n =
10; 5 female and 5 male, mean: 53.2 years).
Serial sections from the paraffin-embedded blocks were cut into
5 μm sections for hematoxylin and eosin (H & E) staining
and further immunohistochemical studies. Table
1 shows the general characteristics of patients with mast
cell diseases whose specimens were examined.
Table 1 General characteristic of selected patients
with mast cell disease
|
Case
|
Sex/age
|
Place of biopsy
|
Type
|
|
1
|
M/3
|
Back
|
Urticaria pigmentosa
|
|
2
|
F*/26
|
Back
|
Urticaria pigmentosa
|
|
3
|
F/13
|
Arm
|
Mastocytoma
|
|
4
|
M/34
|
Chest wall
|
Diffuse cutaneous mastocytosis
|
|
5
|
M/3
|
Thigh
|
Diffuse cutaneous mastocytosis
|
|
6
|
M/70
|
Liver
|
Chronic myelomonocytic leukemia with systemic mastocytosis
|
Immunohistochemistry
Standard immunohistochemical stainings were modified and performed
as our previous reports [32]. The primary antibodies and
concentrations used in this study including polyclonal rabbit
antihuman matriptase/ST14 antibody (used at 1: 500 dilution, Bethyl
Laboratories, Montgomery, TX, USA), monoclonal rabbit antihuman
CD117 (c-kit, used at 1:400 dilution, Dako North America, Inc.,
Carpinteria, CA , USA) and monoclonal mouse anti-human tryptase
(used at 1:100, clone AA1, DakoCytomation Denmark A/S, Glostrup,
Denmark). Immunostaining was performed with
avidin-biotin-peroxidase complex detection kit (DakoCytomation
Denmark A/S, Glostrup, Denmark). Sections were de-waxed in xylene,
dehydrated in alcohol, and retrieved by pressure cooking in 10 mM
citrate buffer, pH 6.0, for 30 min. Endogenous peroxidase
activity and non-specific-binding were blocked by incubation with
3% hydrogen peroxide and non-immune goat serum, respectively.
Slides were then incubated sequentially with primary antibody for
30 min, biotinylated secondary antibody for 10 min, and
peroxidase-conjugated streptavidin for 10 min at room
temperature. Then, the chromogen aminoethylcarbazole (AEC) test was
performed to localize positive staining by microscopy. Sections
were counterstained with hematoxylin and coverslipped. Control
sections were stained following the same procedure as the test
samples, except that the primary antibody was omitted.
Additionally, equivalent dilution of normal rabbit IgG (Santa Cruz
Biotechnology, Inc., CA, USA) to replace the primary antibody was
also tested for non-specific binding control. Some slides with
matriptase staining after photograph recording were de-stained.
Slides were put in a 60 °C water bath to remove coverslip and
then subjected to the same procedure to re-stain the tryptase and
CD117 (c-kit). After heat retrieval, the loss of original staining
signal was confirmed by microscopy.
Results
Matriptase expressed in normal epithelium
Analysis of matriptase expression by immunohistochemistry revealed
that membranous staining for matriptase was detected in the
covering epithelium components of all epithelial tissues examined,
including colon mucosa, nasal and bronchial respiratory mucosa, and
esophageal stratified squamous epithelium. No matriptase staining
was observed in the control sections, except for its primary
antibody. Figure
1A shows positive immunoreactivity for matiptase in
esophageal squamous epithelium, consistent with previous
observations from our and other publications [31, 32]. Staining was
not seen in chondrocytes within cartilage or in stromal
fibroblasts. Likewise, hepatocytes, pneumocytes, cardiac muscle and
smooth muscles of uterine myometrium were all negative.
Matriptase expressed in mast cells of normal tissue
examined
The expression of matriptase was immunohistochemically observed in
almost all mast cells present in all connective tissue examined.
Figure 1 shows
matriptase staining in mast cells from lung (figure 1B), liver (figure 1C) and heart
(figure 1D).
Predominant cytoplasmic granular staining pattern was recognized in
the almost populations of mast cells (figures 1B & 1C inset).
Some synchronous membranous stain was also present (figure 1D inset). Mast
cells in uterine myometrium (figure 2A) and leiomyomas
also showed positive immunoreactivity (figure 2C). In addition,
the presence of matriptase-positive mast cells in the uterine
muscle and leiomyomas was confirmed by repeated staining with
antibodies anti-tryptase and CD117 (c-kit) in the same slide with
de-staining. Figure
2D shows this confirmatory result. Positive staining was
found neither in the sections of uterine leiomyoma nor cutaneous
mastocytosis in either of the negative controls (figures 2E and 2F).
Matriptase expressed in neoplastic cells in mast cell
diseases
Predominant granular cytoplasmic expression of matriptase was also
found in neoplastic mast cells in all samples with mast cell
diseases, including two cases of urticaria pigmentosa, one case of
cutaneous mastocytoma, two cases of diffuse cutaneous mastocytosis
and one case of chronic myelomonocytic leukemia with systemic
mastocytosis. In the all mastocytosis lesions, as many as 75-100%
of mast cells were positive for matriptase. Additionally, almost
all mast cells from these lesions exhibited positive staining for
the other mast cell markers, typtase and CD117 (figures 3 and 4).
Discussion
In this study, we demonstrate that matriptase was expressed, not
only in a broad range of epithelium-containing tissue, but also in
mast cells of all mesenchyme tissue examined. By
immunohistochemistry, matriptase expression was found in the
surface epithelium of selected tissues including stratified
squamous, pseudo-stratified columnar, simple columnar and cuboid
epithelium, consistent with the pattern previously reported by
Michael et al. [33]. In our current observation, matriptase could
be also expressed by mast cells in all connective tissue examined,
including heart, lung, liver and uterus. Matriptase was also
expressed in neoplastic mast cells.
By using enzymatic gene trapping with immunohistochemical and
ultrastructural analysis for localization studies, matriptase has
been shown to colocalize with profilaggrin [34] and expressed in
postmitotic transitional-layer keratinocytes in the process of
undergoing terminal differentiation. The expression of the
matriptase is also revealed in the growth phase of hair follicles
and located in undifferentiated and rapidly proliferating hair
matrix cells [34]. The specific regulation mechanisms of matriptase
are not completely understood [35]. However, some evidence has
shown that matriptase translocates to the cell surface and is
activated within minutes after exposure of breast cancer cells to
sphingosine-1-phosphate, a serum-derived lipid that signals through
specific G-protein-coupled receptors, and the regulation process
required the remodeling of actin cytoskeleton [35, 36]. Other
molecular evidence revealed that spatial redistribution including
suramin and androgens could activate the matriptase in prostate
cancer cells [37]. In peripheral blood monocytes, matriptase has
been demonstrated to play a role in rapid initiation and regulation
of plasminigen activation [38], and induces interleukin-6 and -8
releasing from the endothelial cells by activation of PAR-2 which
may contribute to atherosclerosis [39].
Matriptase could cleave proteolytically to the latent forms of
hepatocyte growth factor (HGF), urokinase-type plasminogen
activator (uPA), and protease-activated receptor-2 (PAR-2) in vitro
[8, 9]. HGF and uPA play an important role in tumor cell invasion
by regulating extracellular matrix degradation, cell proliferation,
cell survival and cell motility [13-15]. Matriptase potentially
acts as an upstream activator of uPA and HGF [16, 17], thought to
play a role in tumor cell progression, growth, invasion and
metastasis by its proteolytic degradation of extracellular matrix
components such as laminin, fibronectin and MMP-3 [19, 40].
Mast cells originate from CD34+ pluripotent hematopoietic cells
in the bone marrow [41]. The cells are found in connective tissues
and reside in abundance at the interface with the environment as a
barrier of the human body. They are particularly prevalent in the
skin, gastrointestinal mucosa, peritoneal mesothelia and around
blood vessels. These locations expose mast cells to inhaled or
ingested environmental challenges and thus mast cells play a
central role in inflammation, immediate allergic reactions and even
as the first line of defense against infection [42].
Beside producing tryptase, mast cells can also produce and store
cellular-specific neutral serine proteases, including chymase and
carboxypeptidase A [20, 21], as well as inflammatory mediators
including histamine and proteoglycans (e.g., heparin, chondroitin
sulphates) which have been shown to function pathophysiologically
in the control of blood flow, angiogenesis, inflammation and
fibrosis [22]. Mast cells could exert an angiogenic effect by
releasing vasoactive or thromboactive chemical mediators including
proteolytic enzymes, tryptase, histamine, tumor necrosis
factor-alpha and heparin [42, 43]. Here, we first identify that
mast cells express both typtase and matriptase simultaneously. It
is known that mast cells are the only cells which can produce
heparin in living animals [44]. By thrombin stimulation, activated
mast cells undergo degranulation and are confirmed to induce a
rapid increase in plasma HGF [43, 45]. HGF has been shown to play a
paracrine signaling role in regenerating capillary endothelial
cells in ischemic myocardium [46, 47]. Additionally, increased
circulating HGF can be detected very early in acute myocardial
infarction and has recently been suggested as a maker of arterial
thrombosis [43].
Mast cells could be involved in several human diseases. During
IgE-mediated activation, mast cells can produce newly generated
mediators including arachidonic acid metabolites such as
leukotrienes, prostaglandins, cytokines, tumor necrosis factor and
interleukins (IL)-4, IL-5 and IL-6, which are involved in the
allergic-asthmatic response [42]. Via IgE-independent mechanisms,
it is suggested that mast cell degranulation is involved in Sudden
Infant Death Syndrome [48]. Furthermore, mast cell-mediated
fibrosis of the bone marrow, spleen and liver may give rise to
portal hypertension and ascites [42]. Additionally, elevated serum
tryptase levels are also found associated with some hematological
conditions including hypereosinophilic syndrome (HES) and
myelodysplastic syndrome (MDS) [49]. Recently, mast cell chymase
has shown to play a key role in activation of pro-matrix
metalloproteases-2 and -9 which share the ability to degrade
denatured collagen (gelatin) and are implicated in angiogenesis and
tumor metastasis [23].
Systemic mastocytosis is characterized by hyperplasia of mast
cells in skin, liver, spleen, gastrointestinal mucosa and bone
marrow [50, 51]. By releasing bioactive substances, these neoplatic
mast cells can induce multiple clinical manifestations including
pruritus, flushing, palpations and urticaria pigmentosa, as well as
heparin-mediated gastritis, diarrhea and peptic ulceration [51,
52]. Mast cell degranulation modulates intestinal chloride ion
transport under normal conditions and in inflammatory bowel
diseases, which causes motility disturbances [52]. Despite the
small number of cases with mast cell diseases included in this
study, we believe our findings might be useful in characterizing
neoplastic mast cells.
In our study, we found that matriptase is immunohistochemically
expressed in the mast cells distributed in selected
epithelium-containing normal human tissues, parenchyma of lung,
liver, kidney, and uterine myometrium as well as in mast cell
diseases. This finding suggests that mast cells may produce a
serine proteinase, such as matriptase, that cooperatively
contributes to cell degranulation, migration, wound healing, airway
remolding, inflammatory diseases, or even in tumor progression.
This matriptase expression may not only be useful as an additional
marker for mast cells but also be involved in their
pathophysiological function. Such an intriguing connection is
worthy of further investigation [53].
Acknowledgements
This study was supported by grants from National Science Counsel,
NSC94-2320-B-016-017, and Tri-Service General Hospital, TSGH-C95-78
and TSGH-C95-16-S04, Taiwan, R.O.C.
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