Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0027627 (metastases)
 103,950 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The 72-kd type IV collagenase (matrix metalloproteinase-2 [MMP-2]) is a neutral metalloproteinase that initiates the degradation of type IV collagen in basement membranes. Its production by tumor cells has been correlated with the invasive and metastatic potential of neoplasms. Two recently developed affinity-purified antibodies against synthetic peptides from the amino terminus (H1) and an internal domain (Ab48) of the molecule were used to investigate immunohistochemically the distribution of this enzyme in a variety of thyroid tissues. All primary carcinomas (20 papillary, seven follicular, and three medullary) as well as nine of 11 metastases were positive, with the more aggressive tumors (tall cell variant of papillary carcinomas and invasive follicular carcinomas) tending to be more reactive than the low-grade tumors (classic and microinvasive papillary carcinomas and minimally invasive follicular tumors). Negative or minimal positivity was found in six cases of normal thyroid, one goiter, and two cases of Graves' disease. Immunoreactive follicular cells were seen focally in areas of inflammation, fibrosis, and distortion of normal follicles, and in Hashimoto's thyroiditis (four cases). Five of nine adenomas showed positive cells, but this could be related to previous trauma to the area. We conclude that there is increased production of the 72-kd type IV collagenase (MMP-2) in thyroid cancer; however, this enzyme also is elevated in benign conditions that are undergoing remodeling and repair.
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PMID:Distribution of the 72-kd type IV collagenase in nonneoplastic and neoplastic thyroid tissue. 146 77

The invasion and metastasis of cancer cells is a complex multistep process involving destruction of basement membranes as an early event in the metastatic cascade. Recent evidence implicates secreted matrix metalloproteinase enzymes, such as type IV collagenases, as playing a central role in this tumor cell mediated extracellular matrix proteolysis. Two distinct type IV collagenase enzymes are now recognized. Immunohistochemical and biochemical studies of several human tumors show correlations between invasive potential and the 72 kDa type IV collagenase enzyme. Studies in rodent tumor models suggest that the 92 kDa type IV collagenase may play an important role in these models, but data on human tumors and human tumor tissue is lacking. Evidence suggest that the regulation of the 72 kDa type IV collagenase enzyme activity may occur at many levels, including transcriptional mechanisms, extracellular activation of latent enzyme and specific inhibitors of active enzyme. Thus the invasion of human tumor cells through basement membranes may be the result of net type IV collagenolytic activity that is the result of a balance of activated enzyme species and inhibitors.
Cancer Metastasis Rev 1990 Dec
PMID:Type IV collagenases in tumor invasion and metastasis. 196 94

A conditional expression system was established whereby the human K-ras, v-src, and v-mos genes were cloned into a conditional expression vector downstream of the dexamethasone-inducible mouse mammary tumor virus long terminal repeat. Rat-1 fibroblasts were transfected with these constructs and selected in medium containing G418. Cloned transfectants were isolated and characterized for absolute dependence on dexamethasone for expression of oncogene products and anchorage-independent growth in soft agar. Expression of activated p21K-ras(val12) enabled the fibroblasts to degrade extracellular matrix collagen secreted by murine microvessel endothelial cells. Concurrent with p21K-ras(val12) induction a proteinase with the characteristic size and substrate specificity of transin, the murine homologue of the human matrix metalloproteinase stromelysin, was expressed and secreted. Induction of v-mos and v-src oncogenes resulted in little or no detectable transin expression respectively coinciding with a relative or absolute failure to increase degradation of extracellular matrix collagen. This study suggests that in this system the expression of the ras oncogene can contribute to the in vitro invasive behavior of tumor cells by upregulating the production of a metalloproteinase capable of degrading collagen synthesized by vascular endothelial cells.
Clin Exp Metastasis 1995 Jul
PMID:Degradation of endothelial cell matrix collagen is correlated with induction of stromelysin by an activated ras oncogene. 760 86

The matrix metalloproteinases (MMPs) have been associated with tissue remodeling in many normal and pathological processes, and in particular are thought to be critical for tumor invasion and metastasis. MMP overexpression has been correlated with the stage of progression in several tumor types. Because of the aberrant nature of tumor cells, it has been assumed that the tumor cells themselves are responsible for this abnormal MMP production. However, recent in situ hybridization experiments have determined that, while some members of the MMP family are expressed within neoplastic cells, many are found in normal stromal components immediately adjacent to the tumor tissue. In this review, we address the potential roles of both tumor and stromal MMPs in tumor progression. Also, using MMP expression as a point of reference, we discuss some of the potential mechanisms involved in tumor/host interactions.
Invasion Metastasis
PMID:Tumor and stromal expression of matrix metalloproteinases and their role in tumor progression. 765 16

The 72-kDa Type IV collagenase (T4C) is a matrix metalloproteinase, the expression of which may be important in normal basement membrane metabolism. The production of T4C by malignant cells has been linked to their invasive and metastatic potential in several tumor systems. The pattern of T4C immunoreactivity was assessed in formalin-fixed, paraffin-embedded prostatic tissue using polyclonal, monospecific antibodies. Basal cells in normal and hyperplastic epithelium demonstrated slight to moderate cytoplasmic immunoreactivity, while secretory epithelial cells showed generally weaker immunostaining. In 35 of 35 cases of primary adenocarcinoma and five of five cases of metastatic adenocarcinoma in lymph nodes, the majority of malignant cells showed strong immunoreactivity. Similar strong immunostaining was also seen in foci of prostatic intraepithelial neoplasia. The high level of expression of T4C in prostatic adenocarcinoma and its metastases suggests this metalloproteinase may play a role in determining the invasive and metastatic properties of this tumor. The enhanced immunoreactivity in prostatic intraepithelial neoplasia suggests the induction of T4C may be an early event in the development of the invasive phenotype. The expression of T4C in benign epithelial cells may be a manifestation of its putative physiological role in basement membrane metabolism.
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PMID:Immunohistochemical analysis of type IV collagenase expression in prostatic hyperplasia and adenocarcinoma. 767 36

Matrix degrading metalloproteinases are enzymes that degrade proteins in tissue extracellular matrices. These proteinases exhibit specific, well defined properties that allow them to be classified into a family of enzymes. They are secreted by various cell types as the cells effect their surrounding extracellular matrix. Such effects occur during normal physiologic tissue remodeling but also during pathologic processes such as tumor cell invasion and metastases. Currently there are seven proteases classified as members of the matrix metalloproteinase family and there are two putative members. Direct correlations can be made between the matrix metalloproteinases and normal tissue functions such as bone remodeling, uterine and mammary gland function and ovulation. The matrix metalloproteinases are also strongly associated with cancer progression in that they function to degrade epithelial basement membrane and stromal matrices in many different malignancies including brain tumors.
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PMID:Matrix degrading metalloproteinases. 796 73

The synthetic matrix metalloproteinase inhibitor batimastat was tested for its ability to inhibit growth and metastatic spread of the B16-BL6 murine melanoma in syngeneic C57BL/6N mice. Intraperitoneal administration of batimastat resulted in a significant inhibition in the number of lung colonies produced by B16-BL6 cells injected i.v. The effect of batimastat on spontaneous metastases was examined in mice inoculated in the hind footpad with B16-BL6 melanoma. The primary tumor was removed surgically after 26-28 days. Batimastat was administered twice a day from day 14 to day 28 (pre-surgery) or from day 26 to day 44 (post-surgery). With both protocols, the median number of lung metastases was not significantly affected, but there was a significant reduction in the weight of the metastases. Finally, the effect of batimastat was examined on s.c. growth of B16-BL6 melanoma. Batimastat administered daily, starting at day of tumor transplantation, resulted in a significant growth delay, whereas treatment starting at advanced stage tumor only reduced tumor growth marginally. Our results indicate that a matrix metalloproteinase inhibitor can not only prevent the colonization of secondary organs by B16-BL6 cells but also limit the growth of solid tumors.
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PMID:Inhibition of the metastatic spread and growth of B16-BL6 murine melanoma by a synthetic matrix metalloproteinase inhibitor. 805 Aug 28

Matrix metalloproteinases have been implicated in the growth and spread of metastatic tumors. This role was investigated in an orthotopic transplant model of human colon cancer in nude mice using the matrix metalloproteinase inhibitor BB-94 (batimastat). Fragments of human colon carcinoma (1-1.5 mm) were surgically implanted orthotopically on the colon in 40 athymic nu/nu mice. Administration of BB-94 or vehicle (phosphate buffered saline, pH 7.4, containing 0.01% Tween 80) commenced 7 days after tumor implantation (20 animals/group). Animals received 30 mg/kg BB-94 i.p. once daily for the first 60 days and then 3 times weekly. Treatment with BB-94 caused a reduction in the median weight of the primary tumor from 293 mg in the control group to 144 mg in the BB-94 treated group (P < 0.001). BB-94 treatment also reduced the incidence of local and regional invasion, from 12 of 18 mice in the control group (67%) to 7 of 20 mice in the treated group (35%). Six mice in the control group were also found to have metastases in the liver, lung, peritoneum, abdominal wall, or local lymph nodes. Only two mice in the BB-94 group had evidence of metastatic disease, in both cases confined to the abdominal wall. The reduction in tumor progression observed in the BB-94-treated group translated into an improvement in the survival of this group, from a median survival time of 110 days in the control group to a median survival time of 140 days in the treated group (P < 0.01). Treatment with BB-94 was not associated with any obvious toxic effect, and these results suggest that such agents may be effective as adjunctive cancer therapies.
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PMID:Matrix metalloproteinase inhibitor BB-94 (batimastat) inhibits human colon tumor growth and spread in a patient-like orthotopic model in nude mice. 806 71

Members of the matrix metalloproteinase (MMP) family have been implicated in the metastasis of tumor cells, but no direct evidence linking any given member of the MMP family to metastatic behavior has been presented. Rat embryo cells transformed by the Ha-ras and v-myc oncogenes or by Ha-ras alone are metastatic in nude mice and release the 92-kDa gelatinase/collagenase (MMP-9), whereas those transformed by Ha-ras plus the adenovirus E1A gene are not metastatic and do not release MMP-9. Here we demonstrate that MMP-9 expression can be induced in these tumorigenic but nonmetastatic rat cells by transfection with an MMP-9 expression vector. Transfection of a MMP-9 expression vector, but not control DNAs, conferred metastatic capacity on the nonmetastatic cells. The majority of colonies isolated after continued passage either in vivo or in vitro had lost the MMP-9 expression vector. However, occasional cells were isolated from metastases which retained MMP-9 expression after passage. These cells retained metastatic capacity. In contrast, cells isolated after losing MMP-9 expression also lost the ability to metastasize. These results provide direct evidence that MMP-9 has a role in tumor metastasis.
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PMID:Direct evidence linking expression of matrix metalloproteinase 9 (92-kDa gelatinase/collagenase) to the metastatic phenotype in transformed rat embryo cells. 818 3

To investigate the effect of matrix-degrading enzymes on the malignant potential of oral squamous cell carcinoma, the expression of matrix metalloproteinase-2 (MMP-2/72-kD gelatinase/type IV collagenase) in 46 patients who had neck surgery for oral cancer was studied immunohistochemically. In 20 of 26 patients (76.9%) with lymph node metastases, proMMP-2 was strongly expressed, whereas the production of proMMP-2 in tissue was detected only in 5 of 20 patients (25%) who had no lymph node metastases. In tissue specimens, proMMP-2 was expressed in a diffuse invasive mode and in the advancing front of cancer. Because MMP-2 can degrade type IV collagen composed of basement membrane, these results suggest that the in vivo production of the enzyme by cancer is an indicator of the degree of malignancy, and that the analysis of proMMP-2 expression is useful to evaluate the malignant potential in individual oral squamous cell carcinoma.
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PMID:Expression of matrix metalloproteinase-2 related to lymph node metastasis of oral squamous cell carcinoma. A clinicopathologic study. 842 10


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