Expression of collagenase-3 (matrix metalloproteinase-13) in squamous cell carcinomas of the head and neck.
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Epidermoid carcinoma
Interstitial collagenase
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The gene expression of two type IV collagenases (matrix metalloproteinase [MMP]-2, a 72 kd type IV collagenase, and MMP-9, a 92 kd type IV collagenase) was investigated in carcinomas of the hypopharynx. We examined 27 cases operated on in our hospital by an in situ hybridization technique to detect their messenger RNA signals in cancer cells and surrounding stroma. Both signals were detected in all cancer nests and in stromal cells in the same specimens. Clinicopathologic studies showed a significant relationship between MMP-2 expression in the primary cancer and the outcome of treatment. Our present study suggests that hypopharyngeal squamous cell carcinoma producing MMP-2 has a high potential for invasion and metastasis and a poor outcome. The analysis of MMPs will be useful for treatment planning in hypopharyngeal carcinoma and for prognosis.
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Interstitial collagenase
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The expression of matrix metalloproteinase‐1 (MMP‐1) gene and the presence of MMP‐1 protein in gastric cancer were examined by in situ hybridization and immunohistochemistry. Expression of the interstitial Collagenase (MMP‐1) gene was detected within the stroma of the neoplastic glands, and infiltration of eosinopilic was observed to be associated with regions of MMP‐1 gene expression. The degree of eosinophils infiltration correlated with the level of MMP‐1 mRNA expression. Immunostaining showed localization of MMP‐1 protein in the stromal cells, and additionally in the neoplastic glands. These findings indicate that the stromal cells may play an important role in the expression of MMP‐1, and suggest a pathophysiological role for MMP‐1 in the invasion and metastasis of gastric cancer.
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Increased production of matrix metalloproteinases (MMPs) has been associated with increases in invasive and metastatic potential in many types of human carcinoma. Tissue inhibitors of metalloproteinase (TIMP)-1 inhibits most interstitial collagenases and MMP-9. TIMP-2 binds specifically and noncovalently to the pro-form of MMP-2 and inhibits its enzyme activity. In this study, we examined TIMP-1 and TIMP-2 expressions in relation to clinicopathological variables in colorectal carcinoma with in situ hybridization and immunohistochemistry. TIMP-1 and TIMP-2 expressions were localized overwhelmingly to pericancer stromal cells, while malignant and normal mucosal cells were weak or negative. Strong stromal TIMP-1 immunoreactivity correlated with Dukes' stage (p=0.022), status of lymph node metastasis (p=0.044) and poor survival (p= 0.005). The degree of immunohistochemical staining of TIMP-2 did not correlate with all clinicopathological variables. The correlation between enhanced TIMP-1 expression and advanced stage and poor survival suggest a growth promoting activity of TIMP-1 in colorectal carcinoma.
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Abstract Pancreatic cancer shows a strong desmoplastic reaction characterized by a remarkable proliferation of interstitial connective tissue (collagens type I and III, fibronectin). In this study we have analyzed the balance of expression of mRNAs encoding extracellular matrix components (collagens I, III and IV, laminin, fibronectin), extracellular matrix‐degrading metalloproteinases (MMP‐1,‐2,‐3 and‐9) and tissue inhibitors of metalloproteinases (TIMP‐1 and‐2) in pancreatic cancer and control pancreatic tissue by Northern‐blot analysis and mRNA in situ hybridization. Transcripts for MMP‐1 (interstitial collagenase) and MMP‐3 (stromelysin‐1) were not detectable in pancreatic cancer and control tissues. Steady‐state levels of transcripts encoding extracellular matrix proteins, MMP‐2 (72‐kDa collagenase IV), MMP‐9 (92‐kDa collagenase type IV), TIMP‐1 and TIMP‐2 were elevated in the majority of pancreatic‐cancer tissue samples as compared to control pancreatic tissue. A good correlation was seen between overexpression of these MMPs and TIMPs and the steady‐state levels of transcripts coding for extracellular matrix proteins, the amount of collagen protein and the severity of the desmoplastic reaction. In situ hybridization studies localized transcripts coding for collagens type I and III to spindle‐shaped stromal cells, whereas transcripts for MMP‐2, MMP‐9, TIMP‐1 and TIMP‐2 were found in both stromal and tumor cells. However, MMP‐2 transcripts appeared to be more abundant in stromal cells, TIMP‐1 and TIMP‐2 transcripts were evenly distributed over tumor and stromal cells and relatively more MMP‐9 transcripts were found in tumor cells. We conclude that, in human pancreatic cancer, MMP‐2, MMP‐9, TIMP‐1 and TIMP‐2 may be involved in processes leading to the strong desmoplastic reaction observed in these tumors. Both stromal and tumor cells appear to be the source of MMPs and TIMPs in human pancreatic cancer. © 1995 Wiley‐Liss, Inc.
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Interstitial collagenase
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Interstitial collagenase
Gelatinase A
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ABSTRACT Recent studies suggest that interstitial collagenase (MMP-1) is an essential enzyme in the early events leading to menstruation. This study analyses its cellular origin, regulation and relation to extracellular matrix breakdown in the human endometrium, both in cultured and non-cultured samples. The source of MMP-1 was identified by in situ hybridization and by immunohistochemistry on serial sections. This was compared with the immunolocalization of other MMPs, steroid receptors, macrophages, and laminin. In non-cultured endometrium, MMP-1 was only expressed during the perimenstrual period. It was either restricted to superficial foci of stromal cells or extended towards the entire functional layer. MMP-1 expression remarkably correlated with matrix breakdown, as assessed by silver staining, and was prominent at the periphery of shedding fragments and along some arterioles. In cultured non-menstrual explants, MMP-1 expression was induced within two days after deprivation of sex steroids. Both in cultured and non-cultured samples, progesterone receptors were not detectable in epithelial cells at foci of MMP-1 expression. The same stromal cells could synthesize MMP-1, MMP-2 (gelatinase A) and MMP-3 (stromelysin-1), as well as laminin, and did not correspond to macrophages. In conclusion, MMP-1 is focally expressed in stromal cells of the functional layer of the endometrium, when and where steroid receptors disappear, and especially where tissue breakdown is prominent. These observations point to an essential role for MMP-1 in the early stages of menstruation.
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Increased collagenase activity in colorectal carcinomas has recently been shown to be associated with increased malignant potential. To determine the tissue distribution of collagenase and its specific inhibitor, tissue inhibitor of metalloproteinases (TIMP), we carried out an immunohistochemical study on colorectal carcinomas (n = 20), adenomas (n = 7) and normal mucosa (n = 6). We found increased staining for collagenase in the connective tissue stroma of carcinomas, as compared with adenomas and normal mucosa. Little evidence of epithelial cell staining for collagenase was seen in any tissue. In carcinomas, both stromal fibroblasts and collagen fibres stained strongly and stromal staining was strongest close to neoplastic glands. Vascular staining was more prominent in neoplastic than normal tissues, perhaps reflecting the increased proteolytic activity during tumour angiogenesis. The pattern of TIMP immunostaining was similar to that of collagenase, although basement membrane staining for TIMP was generally more intense. Another difference was that, unlike TIMP, staining for collagenase was often increased at the invasive edge of carcinomas, perhaps reflecting increased collagenase activity at this location.
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