Journal of Pathology and Translational Medicine

Original Articles

Immunohistochemical Evaluation of Cathepsin D, MMP-2, and TIMP in Prostate Carcinoma.: Jung Weon Shim, Soon Ran Kim, Yun Jung Kim, Hye Kyung Ahn, Young Euy Park, Sung Sook Kim, Min Young Kim; Korean J Pathol. 1997;31(4):342-350.

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Abstract PDF: Twenty six cases of primary adenocarcinoma of the prostate, ranging from 4 to 9 according to Gleason's summing score, were studied. Immunoreactivity was evaluated using the rabbit polyclonal anti-Cathepsin D antibody (CD), a mouse monoclonal MMP-2 antibody (MMP-2), and a tissue inhibitor metalloproteinase (TIMP) in formalin-fixed, paraffin-embedded prostatic tissue. Immunohistochemical staining was scored by summing the intensity of staining (0 to 3+) weighted by the percentage of tumor staining at each intensity (H score, theoretical range 0 to 300). For CD, the tumor cells showed diffuse cytoplasmic immunoreactivity in all 26 cases (100%). For MMP-2 the tumor cells showed cytoplasmic immunoreactivity in 17 of 26 cases (65.38%). As the Gleason grade increased the expression of CD increased (P=0.0027). The reactivity of CD was significantly correlated with the Gleason's score (R=0.65637), but, the reactivity of MMP-2 was not correlated. There were no significant correlations between each of the CD and the MMP-2 scores, and stage. TIMP expression was predominantly localized in the stroma rather than in the cancer cells themselves. We believe that 1) CD and MMP-2, both immunohistochemically detectable in a majority of prostate adenocarcinoma, may play a role in determination of the invasive or metastatic property, 2) the enhanced TIMP expression in the stroma may be associated with the response to cancer invasion.

Expression of Matrix Metalloproteinase-2 and -9 in Oral Squamous Cell Carcinomas in Relation to the Histologic Invasiveness and Cellular Differentiation.: Seong Doo Hong, San Pyo Hong, Yong Sik Kim, Jae Il Lee, Chang Yun Lim; Korean J Pathol. 1999;33(4):243-250.

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Abstract PDF: A poor prognosis of oral squamous cell carcinoma (SCC) is partly due to the invasiveness and metastasis of the tumor. A key element in tumor invasion and metastasis in the degradation of extracellular matrix is matrix metalloproteinases (MMPs). This study was performed to determine the expression of MMP-2 and MMP-9 of oral SCCs with regard to the histologic invasiveness and differentiation in 5 normal oral mucosa and 36 oral SCCs. The histologic invasiveness of oral SCCs were classified into 4 grades. The differentiation of oral SCCs was divided into 3 grades. The streptavidin-biotin immunohistochemical staining, using MMP-2 and MMP-9 monoclonal antibodies, was performed to determine the expression of MMP-2 and MMP-9. The expression of MMP-2 was positive in 6 of 17 oral SCCs with weak invasiveness and was positive in 7 of 19 oral SCCs with strong invasiveness. The MMP-2 expression did not increase significantly with respect to the invasiveness of oral SCCs (P>0.05). The expression of MMP-9 was strongly positive in 6 out of 17 SCCs with weak invasiveness and was strongly positive in 14 of 19 SCCs with strong invasiveness. The MMP-9 expression increased significantly with respect to the invasiveness of oral SCCs; the stronger the expression, the stronger the invasiveness (P<0.05). The expression of MMP-9 was in 57.9% of well differentiated SCCs, 57.1% of moderately differentiated ones, and 33.3% of poorly differentiated SCCs. The expression of MMP-2 and MMP-9 did not increase significantly with respect to the histologic differentiation. We conclude that with respect to the invasiveness, the MMP-9 expression increases significantly in oral SCCs but the MMP-2 expression does not; and that with respect to the histologic differentiation, their expressions do not increase significantly. These results suggeste that MMP-9 can be used as a tool to evaluate the invasiveness of oral SCCs.

Expression of Matrix Metalloproteinase and Tissue Inhibitors of Matrix Metalloproteinase in Malignant Lymphoma.: Ah Won Lee, An Hi Lee, Chang Suk Kang, Byung Kee Kim; Korean J Pathol. 2000;34(4):249-256.

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Abstract PDF: Matrix metalloproteinases (MMPs) and their inhibitors (tissue inhibitors of matrix metalloproteinases, TIMPs) play essential roles in the remodelling of the extracellular matrix. The balance between MMPs and TIMPs is altered in neoplasia, contributing to the invasive and metastatic properties of malignant tumors. Although MMP and TIMP are believed to play an important role in invasion and metastasis in malignant solid tumors, little is known about their involvement in malignant lymphoma. Immunohistochemical stains for MMP-1, MMP-2, MMP-9, TIMP-1 and TIMP-2 were performed using 56 paraffin blocks of the malignant lymphoma and the results were analyzed by using the tumor grade by Working Formulation. The expression of MMP-9 was noted in 45.5% of low grade, 86.1% of intermediate grade, and 100% of high grade malignant lymphoma. The incidence of MMP-9 expression in tumor cells was positively correlated with the grade of the malignant lymphoma (P<0.025). In nodal lymphomas, the incidence of the MMP-9 expression of the tumor cells was higher in malignant lymphoma with extracapsular invasion than those without extracapsular invasion (P=0.008). The incidence of TIMP-1 expression in the tumor cells and fibroblasts was positively correlated with the grade of the malignant lymphoma (P<0.025). In nodal lymphoma, the incidence of the TIMP-1 expression of the tumor cells was higher in malignant lymphoma with extracapsular invasion than those without extracapsular invasion (P=0.009). The incidences of the MMP-1, MMP-2, and TIMP-2 expression in malignant lymphoma were neither increased in the malignant lymphoma with extracapsular tumor invasion nor correlated with the grade by working formulation. There was no significant difference in the expression rate of MMP-1, MMP-2, MMP-9, TIMP-1, and TIMP-2 in nodal- and extra-nodal malignant lymphoma. The above results suggest that the expressions of MMP-9 and TIMP-1 are positively correlated with the grade and the presence of extranodal tumor invasion in malignant lymphomas.

Association between the Expresson of MMP-2 and TIMP-2, and Growth Pattern of Tumor Border, Lymph Node Metastasis, and Estrogen Receptor in the Invasive Ductal Carcinoma of the Breast.: Soo Kee Min, Joon Mee Kim, Young Chae Chu, Young Up Cho, Bom Woo Yeom; Korean J Pathol. 2000;34(5):366-373.

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Abstract PDF: The most important prognostic factor of breast cancer is the status of lymph node or distant metastasis, which is resisted by basement membrane and stromal matrix. MMP (matrix metalloproteinase)-2 is a 72-kilodalton type IV collagenase/ gelatinase and degrades the type IV collagen which is a main component of the basement membrane. Therefore, MMP-2 is believed to be one of the key molecule for cancer invasion and metastasis. Enzymatic activity of MMP is inhibited by TIMPs (tissue inhibitors of metalloproteinase). TIMP-2 forms a complex with latent pro-MMP-2 and inhibits the active forms of MMP-2. The balance of MMPs and TIMPs is suspected as the important factor of invasion and metastasis of the tumor cells. We studied the association between the expression of MMP-2/TIMP-2 and growth pattern of tumor border, lymph node metastasis, and estrogen receptor expression in the 57 cases of invasive ductal carcinoma of the breast using immunohistochemical staining methods. The results revealed increased expression of MMP-2 in the infiltrating tumor border and tumors with positive lymph node metastasis and negative estrogen receptor with no statistical significance (p>0.05). But the expression of TIMP-2 was increased in expanding tumor border and tumors with positive lymph node metastasis and negative estrogen receptor without statistical significance (p>0.05).

Expression of p53 and Matrix Metalloproteinase-2 Proteins in Colorectal Adenocarcinoma.: Seong Jin Cho, Hwa Eun Oh, Yang Seok Chae; Korean J Pathol. 2000;34(7):494-500.

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Abstract PDF: The p53 gene is believed to play an important role through the mutation and overexpression in the progression of various human malignant tumors. The type IV collagenase (matrix metalloproteinase: MMP-2) initiates the degradation of the extracellular matrix, and consequently may play a role in the tumor invasion and metastasis. To investigate the correlation between clinicopathologic features of the colorectal adenocarcinomas and benign tumors and expression of p53 and MMP-2 proteins, we performed an immunohistochemical study on 40 colorectal adenocarcinomas, 20 adenomas and 20 hyperplastic polyps by using the antibodies to p53 and MMP-2 proteins. The positive expression rate of the p53 protein in adenocarcinomas was 62.5% and significantly higher than in benign tumors. The positive expression rate of the MMP-2 protein was 47.5% in adenocarcinomas, but there was no expression of MMP-2 protein in benign tumors. The difference in p53 and MMP-2 expression rates between malignant and non-malignant tumors was statistically significant. The positive expression rate of p53 protein in the non-metastatic and metastatic adenocarcinomas was 59.1 and 66.7%, respectively. The positive expression rate of MMP-2 protein in the non-metastatic and metastatic adencarcinomas was 45.5 and 50.0%, respectively. The correlation between several clinicopathologic features and expression of p53 and MMP-2 protein was not statistically significant, but the rate of positive MMP-2 immunoreactivity showed a statistically significant difference between Astler-Coller stage B1 C1 group and B2 C2 group of adenocarcinoma (p=0.0431). We concluded that the expression of p53 and MMP-2 protein contributes to the cancer development and MMP-2 may play a certain role in the invasiveness of the colorectal tumor. p53 and MMP-2 protein expression is not correlated with lymph node metastasis.

Expression of Matrix Metalloproteinase and Tissue Inhibitor of Metallproteinase in Breast Carcinoma Related to Angiogenesis and Invasion.: Yoon Jung Choi, Woo Hee Jung, Hy De Lee, Kwang Gil Lee; Korean J Pathol. 2000;34(9):652-664.

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Abstract PDF: Among the enzymes which are responsible for basement membrane breakdown, matrix metalloproteinases (MMP) form a family of neutral proteases that are regulated at the levels of gene transcription, proenzyme activation by the cleavage of protein, and the inhibition of the active enzyme by tissue inhibitors of matrix metalloproteinases (TIMP). Recent reports have demonstrated that the expression of these proteolytic enzymes are elevated in several solid tumors and that it can be associated with invasiveness and poor prognosis. We examined the expression of MMP-2, MMP-9, TIMP-1 and TIMP-2 by immunohistochemistry in 160 cases of infiltrating ductal carcinoma. And we compared these data with the established prognostic parameters - tumor size, nodal status, clinical stage, hormonal receptor status, microvessel density, and TGF-beta1 expression in order to evaluate how MMP and TIMP expression are associated with breast cancer progression and prognosis. Microvessel density in invasive breast carcinoma was significantly correlated with tumor size and recurrence (p<0.05). The immunohistochemical expression of TGF-beta1 was significantly associated with tumor size, lymph node metastasis, and clinical stage (p<0.05). The microvessel density was significantly correlated with TGF-beta1 expression in more than 50% of tumor cells. The immunohistochemical expression of MMP-2 and MMP-9 were significantly correlated with nodal metastasis and absence of immunoreactivity for estrogen and progesterone receptors. The immunohistochemical expression of TIMP-1 was inversely correlated with clinical stage and microvessel density while that of TIMP-2 was inversely correlated with clinical stage (p<0.05). Small size of tumor, presence of progesterone receptor, highly differentiated histologic grade, and absence of immunoreactivity for MMP-9 were significantly associated with higher survival rate, but in multivariate analysis only tumor size and MMP-9 expression appeared to affect survival independently.

The Expression of Matrix Metalloproteinase-9 and Tumor Angiogenesis in Human Osteosarcoma.: Jinyoung Yoo, Ji Han Jung, Hyun Joo Choi, Seok Jin Kang, Anhi Lee, Eun Joo Seo, Sang In Shim, Chang Suk Kang; Korean J Pathol. 2005;39(6):418-423.

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Abstract PDF: BACKGROUND
Matrix metalloproteinase-9 (MMP-9) is a matrix-degrading enzyme that's believed to play a crucial role not only for tumor invasion and metastasis, but also for a variety of stromal reactions, including neovascularization. The aim of this study was to investigate the expression of MMP-9 and to compare its expression with the angiogenesis activity in human osteosarcoma.
METHODS
Archival tumor tissue samples from 20 patients with osteosarcoma were analyzed by performing immunohistochemistry for the expression of MMP-9 and CD34. The vascularity was measured as the average microvascular density (MVD) of the CD34-positive vessels. The clinical information was obtained through searching the computerized retrospective database from the tumor registry.
RESULTS
MMP-9 was expressed in 90% (18/20) of the tumors we examined. The MVD ranged from 10.5 to 179.7 with a mean of 64.9. There was no significant correlation between the MMP-9 expression and the MVD (p=.613). The MMP-9 expression was not associated with any of the clinicopathologic variables, whereas the MVD showed an increasing tendency according to the metastasis status (p=.073).
CONCLUSIONS
We demonstrated that MMP-9 activation is likely to occur in human osteosarcoma. However, there was no direct involvement of MMP-9 with tumor angiogenesis. It is noteworthy that MVD may aid physicians to predict the presence of distant metastasis in osteosarcoma patients.

Expression of Matrix Metalloproteinase-2 (MMP-2) and Tissue Inhibitor of Metalloproteinase-2 (TIMP-2) in Pancreatic Ductal Adenocarcinoma.: Mi Jin Gu, Young Kyung Bae, Joon Hyuk Choi; Korean J Pathol. 2004;38(2):73-78.

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Abstract PDF: BACKGROUND
Matrix metalloproteinase-2 (MMP-2) is known to be one of the key molecules for tumor invasion and metastasis. MMP-2 activity is modulated through interaction with the tissue inhibitor of metalloproteinase-2 (TIMP-2). The purpose of this study was to evaluate the expression of MMP-2 and TIMP-2 in pancreatic ductal adenocarcinoma.
METHODS
Using immunohistochemical staining, we investigated the expression of MMP-2 and TIMP-2 in 30 pancreatic ductal adenocarcinomas and 10 normal pancreas.
RESULTS
MMP-2 expression was present in tumor cells in 11 cases, and in stromal cells in 24 cases, out of 30 carcinomas. MMP-2 expression of tumor cells was significantly higher in poorly differentiated adenocarcinomas than in well/moderately differentiated adenocarcinomas, and in cases with vascular invasion than in cases without. MMP-2 expression was stronger in the marginal areas than in the central area of the tumor. TIMP-2 expression was detected in the tumor and stromal cells of all carcinomas. MMP-2 and TIMP-2 expression had no significant correlation with tumor size, lymph node metastasis, or TNM stage. MMP-2 expression was not correlated with TIMP-2 expression.
CONCLUSIONS
These results suggest that MMP-2 expression may play an important role in the invasive property of pancreatic ductal adenocarcinoma, whereas TIMP-2 expression increases as a reaction to invasion.

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