Zhong et al.

Expression of
amelo-blastoma

Int Chin J Dent 2004; 4: 19-26.

matrix

metalloproteinases

in

human

Ming Zhong, DDS, MS, Jie Wang, DDS, MD, and Yangli Yue, DDS
Department of Pathology, College of Stomatology, China Medical University, Shenyang, P. R.
China
Purpose: To investigate the expression of matrix metalloproteinase-2 (MMP-2), matrix
metalloproteinase-9 (MMP-9) and tissue inhibitor of metalloproteinase-1 (TIMP-1) in humanameloblastoma (AB), and to explore the relationship of the three factors with AB’s biological behavior in
combination with clinicopathological characteristics.
Materials and Methods: Specimens of 43 cases of AB, 10 cases of odontogenic keratocyst (OKC), and 16
cases of normal oral mucosa were examined immunohistochemically using the streptavidin-biotin method
to determine the expression of MMP-2, MMP-9 and TIMP-1.
Results: Of the 16 cases of normal oral epithelia, MMP-2 was positively expressed in six cases. In the 10
OKC cases, MMP-2 expression was strongly positive in stratum spinosum in two cases and weak or lost in
stratum basale. MMP-2 was strongly expressed in the central and peripheral cells of the tumor islands in
28 cases of AB. There was a significant difference among these three groups (p<0.01). MMP-9 expression
was negative in all cases of normal oral mucosa, and extensively positive in the entire strata of peritumor
epithelia in five cases of AB. MMP-9 was strongly expressed in two of nine cases of OKC. MMP-9 wasstrongly expressed in the central and peripheral cells of the tumor islands in 30 cases of AB. There was nodifference between normal epithelia and OKC (p>0.05). There was a great difference between AB andnormal oral mucosa (p<0.01). The positive rate and intensity increased as AB recurred and transformed
malignantly, but the increases were not associated with age, sex, pathological type, or disease location.
MMP-2 and MMP-9 were positively expressed in fibroblasts, endothelial cells, and inflammatory cells
including monocytes, neutrophils, plasmacytes and lymphocytes. TIMP-1 was weakly or not expressed innormal oral mucosa, OKC and AB.
Conclusion: The high expression of MMP-2 and MMP-9 is related to the biological behavior of AB.
Imbalance in the expression of MMP-2 and MMP-9 proteins is one mechanism for the invasiveness of AB.
The MMPs activation produced by stromal cells is also related to the invasiveness of AB.
(Int Chin J Dent 2004; 4: 19-26.)
Clinical Significance: The study provided that activity of MMP-2 and MMP-9 was closely related to theclinico-biological behavior of AB, which provided a new target to therapy for AB by gene.
Key Words: ameloblastoma, immunohistochemistry, matrix metalloproteinase, odontogenic keratocyst.

Introduction
Ameloblastoma (AB) and odontogenic keratocyst (OKC) of oral jaw are diseases that have a negative
impact on families and society in general. Currently, the most common treatment option for these diseases
is surgery, which does not improve quality of life and causes great mental anguish to, and places an
economic burden on, the patients. Furthermore, the prominent biological features of AB are aggressive
growth and have the possibility that cells will transform malignantly and metastasize with a relatively highpostoperative recurrence rate. However, the pathogenesis of AB and mechanisms for its aggressive growth
have not been fully clarified. Previous studies have demonstrated that the development and progression ofnumerous carcinomas are not only associated with epithelial adhesive molecules,1,2 but are also related tothe degradation and synthesis imbalance of extracellular matrix (ECM). Generally speaking, six types of
enzyme are involved in ECM degradation by tumor cells, including the important matrix metalloproteinase

19

Zhong et al.

(MMP).

Int Chin J Dent 2004; 4: 19-26.

In this study, we measured MMP-2, MMP-9 and TIMP-1 expressions in AB

immuno-histochemically by the standard streptavidin-biotin method, with the aim of exploring therelationship of the three factors to the biological behavior of AB.

Materials and Methods
Tissue Samples
All specimens were selected from archival paraffin blocks collected between 1987 and 2001 at the
Department of Pathology, College of Stomatology, China Medical University. Forty-three cases of AB
were studied, consisting of 16 primary, 21 recurrent and six malignant ABs. There were 19 males and 24
females, with a mean age of 36.5 years (range 11-65). Furthermore, mean ages in the primary, recurrent
and malignant AB cases were 31.8, 40.7 and 43.3 years, respectively. As for the disease sites, four cases of
AB were at the gum, three at the left maxillary bone, four at the right maxillary bone, 18 at the left inferior
maxilla, and 14 at the right inferior maxilla.

For pathological patterns, the AB cases included 21

follicle-type, seven cluster-type, four granular cell, three monocyst, and eight solid ABs. Complete clinicalrecords and follow-up data were available for all patients. The recurrent interval in the recurrent cases
ranged from two to 19 months with one to six relapses. The majority of relapses were connected withsurgical scaling and four cases relapsed after ilium transplantation. Of the malignant cases, two involved
pulmonary metastases and one had regional lymphatic involvement. Ten cases of OKC and 16 cases ofnormal oral mucosa (at gum or cheeks) were picked as controls. All specimens were reviewed anddiagnosed by two oral pathologists.
Reagents
Monoclonal antibodies against MMP-2 (MAB-0244), MMP-9 (MAB-0245) and TIMP-1 (MAB-0282),
an S-P ultrasensitive kit (kit-9703), and DAB (DAB-0031) were all purchased from Maxim
Biotechnological Inc., Ltd, Fuzhou, Fujian, P. R. China.
Immunohistochemistry
Further sections were cut from selected blocks at 4 µ m thickness. Sections from each specimen were
immunohistochemically examined separately by antibodies against MMP-2, MMP-9 and TIMP-1.
However, because of detachments during staining procedures, there was a slight difference between
numbers of cases stained by the three antibodies. Negative controls were set up by replacing the primary
antibodies with 0.01 mol/L phosphate-buffered saline (PBS), and positive controls were prepared according
to the manufacturer’s instructions.
Result Judgment
In general, the occurrence of yellow particles in cytoplasm was regarded as positive staining. Sections
were evaluated by two scoring systems, A and B. For system A, scores were determined according to thecolor shade of cytoplasmic particles: no yellow particles was scored at 0, light yellow at 1, yellow brown at
2, and brown at 3 points. The scores for system B were based on the ratio of the number of tumor cellswith positive particles to the total number of tumor cell in the sections. A ratio <25% was scored at 1,

20

Zhong et al.

Int Chin J Dent 2004; 4: 19-26.

25%-75% at 2, and >75% at 3 points. The final score of each case was expressed as AB, and stratified inaccordance with the magnitude of the scores, where 0 points was classified as negative (-), 1-4 points as
weakly positive (+), and >4 points as strongly positive (++). To perform a comparison between groups, wepooled the negative and weakly positive cases into one group, and the strongly positive cases were treatedas one group.3
Statistical Analysis
Comparisons between groups were made by a X2 test using SPSS 10.0 for Windows.

Results
Expressions of MMP-2, MMP-9 and TIMP-1 in Normal Oral Mucosa and Peritumor Epithelia
The expression of MMP-2 in normal oral mucosa was negative in 10 and positive in six cases, being
present mainly in stratum spinosum. There was no difference in expression between peritumor epithelia
and normal epithelia. All cases (n=8) of normal mucosa had negative MMP-9 expression, but strong
positive expression was found in the entire strata of peritumor epithelia (n=5) (Fig. 1). TIMP-1 was foundto be weakly expressed in normal epithelia, vascular endothelial cells, fibroblasts, mononuclear cells, andplasmacytes.
Expressions of MMP-2, MMP-9, and TIMP-1 in OKC and AB.
In stratum spinosum of OKC, MMP-2 was negatively or weakly expressed in eight cases and strongly
expressed in two weak cases, but in basal layer cells, there was weak or no expression (Fig. 2). MMP-2
was strongly expressed in stellate stratum and peripheral cells in 28 AB cases (Fig. 3), and weakly tomoderately expressed in granular cells in four AB cases. In interstitial fibroblasts, MMP-2 was expressed
positively in 33 and negatively in eight AB cases. Vascular endothelial and inflammatory cells including
monocytes, neutrophils and plasmacytes etc. had positive expression of MMP-2 (Fig. 4).

1

2

3

4

Fig. 1. MMP-9 was strongly expressed in the epithelium surrounding AB (S-P method, x400).
Fig. 2. MMP-2 expression was weakly positive in stratum spinosum, and lost in stratum basale
in OKC (S-P method, x200).
Fig. 3. MMP-2 was strongly expressed in stellate reticule stratum of AB (S-P method, x400).
Fig. 4. MMP-2 was strongly expressed in matrix fibroblasts and endothelial cells of AB (S-P
method, x200).

21

Zhong et al.

Int Chin J Dent 2004; 4: 19-26.

Table 1. The expression of MMP-2 in normal oral mucosa, OKC, and AB.
Groupsn-~+ (%)++ (%)
Normal mucosa
16
10 (62.5)
6 (37.5)OKC
10
8 (80.0)
2 (20.0)AB41
13 (31.7)
28 (68.3)
2

Note: Among the three groups, X =9.769, p<0.01; between normal mucosa and OKC, p>0.05 between normal mucosa andAB, p<0.05; between OKC and AB, p<0.05.

Table 2. The expression of MMP-2 in primary, recurrent, and malignant AB.
Groupsn-~+ (%)++ (%)
Primary AB
15
8 (53.3)
7 (46.7)
Recurrent AB
21
3 (14.3)
18 (85.7)
Malignant AB
5
2 (40.0)
3 (60.0)
Note: Between primary and recurrent AB, Fisher’s p<0.05; between primary and malignant AB, and between recurrent andmalignant AB, p<0.05.

Table 3. The expression of MMP-9 in normal oral mucosa, OKC, and AB.
Groupsn-~+ (%)++ (%)
Normal mucosa
8
8 (100.0)
0 (00.0)OKC
9
7 (77.8)
2 (22.2)
AB
43
13 (30.2)
30 (69.8)
Note: Between normal mucosa and OKC, p>0.05; between normal mucosa and AB, p<0.01; between OKC and AB,
p<0.05.

Table 4. The expression of MMP-9 in primary, recurrent, and malignant AB.
Groupsn-~+ (%)++ (%)
Primary AB
16
10 (62.5)
6 (37.5)
Recurrent AB
21
3 (14.3)
18 (85.7)
Malignant AB
60 (00.0)
6 (100.0)
Note: Between primary and recurrent AB, p<0.01; between primary and malignant AB, p<0.05; between primary andmalignant AB, p>0.05.

5

6

7

Fig. 5. MMP-9 expression was intensely positive in malignant ABs with metastatic nodes (S-P
method, x200).
Fig. 6. MMP-9 was strongly expressed in peripheral fibroblasts of AB (S-P method, x200).
Fig. 7. TIMP-1 expression was negative in AB, but positive in stroma, endothelia andinflammatory cells (S-P method, x200).
Table 1 shows the expression data of MMP-2 in normal oral mucosa, OKC and AB. As AB relapsed andtransformed malignantly, the number of cases with strong positive expression of MMP-2 increased.
Table 2 shows the expression data of MMP-2 in primary, recurrent and malignant AB groups. For the22

Zhong et al.

Int Chin J Dent 2004; 4: 19-26.

few malignant cases, no significant difference (p>0.05) was found between primary and malignant AB, andbetween recurrent and malignant AB. In OKC cases, only two had strong expression of MMP-9 and theother showed weak or negative expression. In AB cases, however, strong expression of MMP-9 was seenin 30 cases, being located in stellate and peripheral strata. The MMP-9 expression increased markedly as
AB replased and transformed malignantly (Fig. 5). Granular cells had negative or weak MMP-9 expression.
Monocyst AB displayed negative or weak MMP-9 expression. In addition, MMP-9 was strongly expressedin peritumor intertial fibroblasts (Fig. 6).
Table 3 shows the expression data of MMP-9 in normal oral mucosa, OKC and AB. As AB relapsed andbecome malignant, the intensity and positive ratio of MMP-9 expression rose significantly.
Table 4 shows the expression data of MMP-2 in primary, recurrent and malignant AB groups. TIMP-1
expression was negative or weak in four cases and strong in six cases of OKC, but the expression was
negative or weak in the majority of AB cases (29/38). The intensity of TIMP-1 expression in AB wasnoticeably lower than that of MMPs (Fig. 7). However, TIMP-1 was positively expressed in vascularendothelia and inflammatory cells. No significant difference was found between normal oral mucosa, OKC
and AB, or between primary, recurrent and malignant AB (p>0.05).
Relationshipbetweenthe

ExpressionofMMP-2,MMP-9

and

TIMP-1

Proteins

andClinico-pathological Characteristics of AB.
Expressions of the three proteins were correlated with patients’ age and sex, disease sites, X-ray
phenotype and pathological classification, but no significant correlation was found (p>0.05) (Table. 5).
Table 5.

The relationship of the expression MMP-2, MMP-9 and TIMP-1 proteins with clinicopathological characteristics of AB.
25
18
19
24
10
22

MMP-2
+
3
10
1
9
2
7
2
11
1
4
2
10

++
12
6
7
12
5
9

MMP-9
+
6
5
0
5
3
3
3
7
1
4
4
4

++
14
13
13
14
5
14

TIMP-1
+
7
10
6
6
6
9
7
7
3
6
13
7

++
4
5
4
5
1
2

7
4
6
27
21
7
4
3
8

0
1
1
2
1
1
1
0
1

2
2
2
12
7
5
2
1
4

0
1
1
4
4
0
1
1
0

6
2
3
18
12
5
2
2
6

2
1
3
9
6
1
2
2
2

2
1
1
8
6
3
0
0
0

Parameters

Classification

No.

Age

30 or more
<30
Male
FemaleAnterior region of lower jaw
Molars and ascending ramus
of mandible
MaxillaPeripheral
Mono-chamber
Multi-chambers
Follicle
Cluster
Granular cell
Monocyst
Solid

Sex
Site

X-ray
Pathologicalpatterns

4
1
3
13
11
1
1
2
3

1
1
2
5
5
2
1
0
2

0
0
2
10
7
3
1
1
4

Note: The expression of MMP-2 was measured in 41, MMP-9 in 43, and TIMP-1 in 38 cases of AB. X-ray results were notavailable for four of the 41 cases, six of the 43 cases with four peripheral ABs not included, and three of the 38 cases withtwo peripheral ABs not included.

Discussion
ECM is constituted of proteoglycan and glycoprotein gel, in which various types of collagen and elastic
fibers are embedded to form a tridimensional network structure. ECM plays an important role in the23

Zhong et al.

Int Chin J Dent 2004; 4: 19-26.

maintenance of normal structure and function of tissues and in cell growth and differentiation. It is nolonger thought to be static, but is believed to experience continuous metabolism and turnover, being in a
dynamic balance of degradation and remolding. A large amount of research has indicated that loss of thebalance is closely related to many pathological conditions, such as atherosclerosis, renal diseases and livercirrhosis, and to tumor invasiveness and recurrence in particular.

Since the discovery of specificproteolytic enzyme for collagen-collagenase, in 1962, many other enzymes acting on different componentsof ECM have been discovered.3
It is known that the acquisition of the ability to degrade ECM is necessary for in situ carcinomas to develop into
invasive ones. The degradation of ECM relies primarily on various enzymes, of which MMPs are the mostimportant. MMPs are capable of degrading almost all constituents of ECM. Therefore, MMPs have become thesubject of much attention in the field of research into tumor invasiveness and metastasis.
MMPs are a family of zinc-dependent endopeptidase, comprising 18 principal to tumor members. Closely related
aggression are MMP-2 (gelatinase A, 72 kDa) and MMP-9 (gelatinase B, 92 kDa), the principal action of which is
to degrade ECM and basement membrane, promote tumor angiogenesis, and regulate cell adhesion to facilitate
invasiveness and metastasis of carcinoma cells. Tissue inhibitor of metalloproteinases (TIMPs) are specificinhibitors of MMPs. TIMPs bind 1:1 with MMPs to inhibit the activity of MMPs,4 leading to the suppression oftumor invasiveness and metastasis. Besides, TIMPs can repress tumor angiogenesis to inhibit tumor growth.
Our results indicated that a great difference was produced between MMPs and TIMP-1 expressions in AB,
suggesting a loss of the balance between the two proteins. The expression of TIMP-1 in OKC was similar to that innormal mucosa, but was lost or weakened in 76.3% of AB cases (29/38). However, MMP-2 was strongly
expressed in peripheral and stellate strata cells in 28 of 41 AB cases (68.3%), which was significantly different fromthat in normal oral mucosa (X2=4.534, p=0.033<0.05) and OKC (X2=5.875, p=0.015<0.05). Moreover, there
was a significant difference in MMP-2 expression between primary and recurrent ABs (p=0.025<0.05), but nosignificant difference was found between primary and malignant, and between recurrent and malignant ABs, for asmall number of malignant cases. In addition, our data demonstrated a stronger intensity of MMP-9 expression thanthat of MMP-2 in AB. MMP-9 expression was negative in normal mucosa, but strong in peritumor epithelia and in
30 of 43 cases of AB (69.8%), showing a significant difference between the two groups (X2=10.827,
p=0.001<0.01). MMP-9 expression was negative or weak in seven out of nine cases of OKC, having a significant
difference from that in AB (X2=5.241, p=0.022<0.05). As AB relapsed and transformed malignantly, theexpression intensity and positive rate of MMP-9 increased. MMP-9 was intensely expressed in six out of 16(37.5%) primary AB cases, but the percentage rose to 85.7% (18/21) in recurrent cases (p=0.005<0.01), and to
100% (6/6) in malignant cases (p=0.015<0.05). These results indicated a correlation between the strong expressionof MMP-2 and -9 and AB’s biological behavior, and in addition, that the imbalance of MMPs and TIMP-1 was also
one of the principal mechanisms for the aggressive growth and high recurrence rate of AB. This has been
documented in human carcinomas of breast, colon, stomach and bladder, and squamous carcinoma of head andneck.3, 5
The development of oral cavity and maxillofacial region and dental germs involves the induction of epithelia by24

Zhong et al.

Int Chin J Dent 2004; 4: 19-26.

ECM. This induction is also seen in odontogenic tumors and cysts. ECM acts strongly on epithelia and can join theepithelia in invasive growth. Previous research found that interstitial tissues actively proliferated and telomerase hada high activity in AB.6 Results in this study found MMP-2 to be positively expressed in matrix fibroblasts in 33 of
41 AB cases. Similarly, matrix fibroblasts had relatively strong expression of MMP-9 in 34 of 43 AB cases, but theexpression of TIMP-1 was weak. It is now clear that tumor invasiveness depends on there being enough enzymes
to degrade ECM, which enzymes are not only produced by tumor cells themselves, but also by tumor matrix andinflammatory cells. There is also evidence from previous studies that the large quantities of MMPs in tumor tissues
can be produced by matrix cells.7, 8 This demonstrates that tumor cells can avail themselves of MMPs generated bymatrix cells in tumor invasive growth.9 However, the action of the matrix did not receive sufficient attention in paststudies. Kubota et al.10 measured the levels of IL-1α and -1β, IL-6 and TNF-α, and gelatinase species in intracystic
fluids of ABs and OKCs, and demonstrated significant differences in IL-1α and IL-6 between the two diseases.
Our data indicated that only two cases of OKC had strong expression of MMP-2 and -9 in the epithelial cells.
Therefore, OKC might depend to some degree upon the MMPs derived from the fluids or matrix to spreadinvasively. It is generally believed that MMPs levels are upregulated and TIMPs levels decreased in carcinomas,
which is supported by our results. However, other research found that with the enhancement of MMPs levels, theexpression of TIMPs also increased.11 These results suggest that TIMPs are bifunctional cytokines that are
differentially expressed in different tumors. Research by Kumamoto12 showed that both MMP-2 and -9 and
TIMP-1 were weakly expressed in AB, but that TIMP-2 was strongly expressed in matrix.
Like other carcinomas, AB is a typical disorder of vascular dependence.13 In certain conditions, the impact of
TIMPs upon tumor growth might be related to their action on tumor angiogenesis, because research has
demonstrated that TIMPs can block angiogenesis.14 The mechanisms of tumor inhibition by TIMPs might indicate
an indirect effect of their influence on angiogenesis and a direct action on tumor cell growth. Therefore, the strong
expression of MMPs and loss or weakness of TIMPs expression in AB promote tumor angiogenesis, allowing AB
to proliferate and differentiate, which reflects the biological features of AB, i.e., aggressive growth and highpotential to recur. Currently, some researchers believe that MMPs are a kind of angiogenesis associated protein.15
Basic fibroblast growth factor (bFGF) can stimulate the production of MMPs by endothelial cells. MMPs degrade
the collagen in ECM surrounding vessels, unmasking the hidden RGD-binding sites in the helical structure ofcollagens. Integrin αVβ3 binds to these sites, causing the invasion of vascular endothelial cells into ECM.16
Other researchers believe that MMPs may produce bioavailable VEGF, which is an important
pro-angiogenic factor and prognostic indicator of tumors with great promise.17

Our results revealed

positive expressions of MMPs and VEGF in endothelial cells.
In general, in-depth research into MMPs will deepen our understanding of the biological behavior of AB
and OKC. Meanwhile, further studies of TIMPs will give rise to advances in the field of tumor biology andtreatment.

References
1. Tian Z, Guo, W, Zhang WG. The expression of E-cadherin in oral carcinomas with different biological behaviors.
Shanghai Oral Med 2002; 11: 350-2.

25

Zhong et al.

Int Chin J Dent 2004; 4: 19-26.

2. Zhong M, Wang Y, Yue YL et al. Expressions of E-cadherin and b-catinin in human ameloblastoma. Oral Med Res
2003; 19: 176-9.
3. Hong SD, Hong SP, Lee JI, Lim CY. Expression of matrix metalloproteinase-2 and -9 in oral squamous cell carcinomas
with regard to the metastatic potential. Oral Oncol 2000; 36: 207-13.
4. Kim I, Kim HG, Moon SO, et al. Angiopoietin-1 induces endothelial cell sprouting through the activation of focal
adhesion kinase and plasmin secretion. Circ Res 2000; 86: 952-9.
5. Hoyhtya M, Fridman R, Komarek D, et al. Immunohistochemical localization of matrix metalloproteinase-2 and its
specific inhibitor TIMP-2 in neoplastic tissues with monoclonal antibodies. Int J Cancer 1994; 56: 500-5.
6. Zhong M, Wang J, Jiang L, et al. Expression of hTERT mRNA in human odontogenic lesions. CJDR, 2002; 5: 47-52.
7. Heppner KJ, Matrisian LM, Jensen RA, Rodgers WH. Expression of most matrix metalloproteinase family members inbreast cancer represents a tumor-induced host response. Am J Pathol 1996; 149: 273-82.
8. Poulsom R, Pignatelli M, Stetler-stevenson WG, et al. Stromal expression of 72KDa type IV collagenase (MMP-2) and
TIMP-2 mRNA in colorectal neoplasia. Am J Pathol 1992; 41: 389-96.
9. Thomas GT, Lewis MP, Speight PM. Matrix metalloproteinases and oral cancer. Oral Oncol 1999; 35: 227-33.
10. Kubota Y, Nitta S, Oka S, Nakagawa S Ninomiya T, Shirasuna K. Discrimination of ameloblastomas from odontogenic
keratocysts by cytokine levels and gelatinase species of the intracystic fluids. J Oral Pathol Med 2001; 30: 421-7.
11. Grignon DJ, Sakr W, Toth M, et al. High levels of tissue inhibitor of metalloproteinase-2 (TIMP-2) expression areassociated with poor outcome in invasive bladder cancer. Cancer Res 1996; 56: 1654-9.
12. Kumamoto H, Yamauchi K, Yoshida M, Ooya K. Immunohistochemical detection of matrix metalloproteinases (MMPs)
and tissue inhibitors of matrix metalloproteinases (TIMPs) in ameloblastoma. J Oral Pathol Med 2003; 32: 114-20.
13. Zhong M, Wang J, Wang ZY et al. The expression of CD34 and VEGF in human odontogenic lesions. Chin J Oral Med
2002; 37: 455.
14. Nelson AR, Fingleton B, Rothenberg ML, Matrisian LM. Matrix metalloproteinases: biologic activity and clinicalimplications. J Clin Oncol 2000; 18: 1135-49.
15. Hiraoka N, Allen E, Apel IJ, Gyetko MR, Weiss SJ. Matrix metalloproteinases regulate neovascularization by acting as
pericellulay fibrinolysins. Cell 1998; 95: 365-77.
16. Deryugina EI, Bourdon MA, Jungwirth K, Smith JW, Strongin AY. Functional activation of integrin alpha V beta 3 intumor cells expressing membrane type I matrix metalloproteinase. Int J Cancer 2000; 86: 15-23.
17. Shou Y, Hirano T, Gong Y, et al. Influence of angiogenetic factors and matrix metalloproteinases upon tumor
progression in non-small-cell lung cancer. Br J Cancer 2001; 85: 1706-12.

Reprint request to:
Dr. Ming Zhong
Department of Pathology, College of Stomatology, China Medical University
117 Nan Jing North Street, Heping District, Shenyang, 110002, P. R. China
Fax:+86-24-23410142 E-mail: zhongming1234@163.net
Received January 15, 2004. Revised February 24, 2004. Accepted February 28, 2004.
Copyright ©2004 by the Editorial Council of the International Chinese Journal of Dentistry.

26