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)

We have previously shown that alendronate can prevent human PC-3 ML tumor cell metastasis to the bone (Wang and Stearns, 1991, Differentiation, 48, 115-25). In this paper, ELISAs and Western blots showed that TGF-beta1 stimulated the secretion of a 72 kDa matrix metalloproteinase 2 (MMP-2) to enhance the solubilization of radiolabeled collagen 1 by metastatic human prostate PC-3 ML cells. A potent bisphosphonate compound, alendronate, inhibited MMP-2 secretion to block solubilization of collagen 1. Alendronate failed to inhibit MMP-2 activity directly, but instead appeared to block cellular secretion of MMP-2. Alendronate failed to inhibit secretion of tissue inhibitor of metalloproteinase-2 (TIMP-2; the inhibitor of MMP-2) and the decrease in collagen 1 solubilization observed may occur, in part, from changes in the molar stoichiometry of TIMP-2 to MMP-2. We conclude that alendronate may be a potent inhibitor of bone resorption based on its ability to block MMP-2 secretion by tumor cells.
Clin Exp Metastasis 1998 May
PMID:Alendronate blocks TGF-beta1 stimulated collagen 1 degradation by human prostate PC-3 ML cells. 962 12

We have investigated the effect of calcium spirulan (Ca-SP) isolated from a blue-green alga, Spirulina platensis, which is a sulfated polysaccharide chelating calcium and mainly composed of rhamnose, on invasion of B16-BL6 melanoma, Colon 26 M3.1 carcinoma and HT-1080 fibrosarcoma cells through reconstituted basement membrane (Matrigel). Ca-SP significantly inhibited the invasion of these tumor cells through Matrigel/fibronectin-coated filters. Ca-SP also inhibited the haptotactic migration of tumor cells to laminin, but it had no effect on that to fibronectin. Ca-SP prevented the adhesion of B16-BL6 cells to Matrigel and laminin substrates but did not affect the adhesion to fibronectin. The pretreatment of tumor cells with Ca-SP inhibited the adhesion to laminin, while the pretreatment of laminin substrates did not. Ca-SP had no effect on the production and activation of type IV collagenase in gelatin zymography. In contrast, Ca-SP significantly inhibited degradation of heparan sulfate by purified heparanase. The experimental lung metastasis was significantly reduced by co-injection of B16-BL6 cells with Ca-SP. Seven intermittent i.v. injections of 100 microg of Ca-SP caused a marked decrease of lung tumor colonization of B16-BL6 cells in a spontaneous lung metastasis model. These results suggest that Ca-SP, a novel sulfated polysaccharide, could reduce the lung metastasis of B16-BL6 melanoma cells, by inhibiting the tumor invasion of basement membrane probably through the prevention of the adhesion and migration of tumor cells to laminin substrate and of the heparanase activity.
Clin Exp Metastasis 1998 Aug
PMID:Inhibition of tumor invasion and metastasis by calcium spirulan (Ca-SP), a novel sulfated polysaccharide derived from a blue-green alga, Spirulina platensis. 987 1

The penetration of the subepithelial basement membrane is the first critical step in the dissemination of melanoma. In vitro studies have suggested that the 72 kD type IV collagenase (MMP-2) may be important in melanoma invasion. It has recently been demonstrated that the expression of MMP-2 immunoreactive protein increased with increasing atypia in melanocytic tumours and was associated with later haematogenous metastases in melanoma. This paper investigates the value of MMP-2 as a possible prognostic marker in melanoma. The expression of MMP-2 immunoreactive protein was studied with immunoperoxidase staining in paraffin-embedded sections of 50 cases of primary skin melanoma by using specific, affinity purified antibodies. Positive immunostaining was quantified by counting the percentage of positive cancer cells and was compared with clinical patient characteristics and survival. Sixty-four per cent of the primary melanoma cases displayed positive cytoplasmic immunostaining for MMP-2 in tumour cells. Marked overexpression of MMP-2 protein (> or = 34 per cent of melanoma cells positive) correlated with the 5-year survival of the patients when compared with patients with lower MMP-2 positivity, 55 per cent vs. 85 per cent, respectively (P < 0.05). Male patients displayed positive staining more often than females (75 per cent vs. 54 per cent, respectively). There was no correlation between MMP-2 positivity and Clark level or Breslow classification. A distinct group with unfavourable prognosis was identified. The 10-year survival for MMP-2-positive male melanoma patients was 39 per cent as opposed to 79 per cent with the other melanoma patients (P < 0.05). In the hierarchic Cox regression model for survival, MMP-2 immunoreactive protein was found to be independent of Clark level and Breslow classification. Overexpression of MMP-2 protein indicated a 4.5-fold relative risk of dying from melanoma. It is concluded that MMP-2 immunoreactive protein in melanoma cells is an independent prognostic factor for survival. High MMP-2 expression in male melanoma patients indicates an unfavourable prognosis.
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PMID:Prognostic value of MMP-2 immunoreactive protein (72 kD type IV collagenase) in primary skin melanoma. 987 40

The purpose of this study was to investigate the association among matrix metalloproteinases (gelatinases A and B, stromelysin-3 (ST3) and matrilysin) mRNAs expressed in primary breast carcinomas and standard prognostic parameters and clinical outcome. mRNA levels were determined by Northern analysis in samples of 81 breast cancer patients (median follow-up, 40 months) and 27 samples of uninvolved adjacent breast tissue. Proteases were expressed by the majority of the tumors and normal breast tissues examined. ST3, gelatinase A and matrilysin mRNAs were more often expressed at high levels in carcinomatous than in normal breast tissues. Differences in the distribution of gelatinase B mRNA were not found. However, paired normal tissues generally produced weaker signals when compared to matched tumor samples. Univariate analysis showed no significant association of gelatinase A and matrilysin mRNAs with the classical prognostic markers (age, menopausal status, stage, size, nodal status, vascular infiltrate, necrosis, steroid receptors, metastasis and survival). Overexpression of ST3 was more frequently found in tumors of post-menopausal women (P < 0.022). Elevated expression of gel B mRNA was associated with the presence of vascular infiltrate (P < 0.026), necrosis (P < 0.039), PR negative tumors (P < 0.014) and inversely correlated to the number of survivors (P < 0.021). Multivariate analysis including 68 patients for whom all information was available indicated that neither stromelysin correlated significantly with pathological, clinical or biochemical features. High levels of gelatinase A and B mRNAs were inversely associated with the number of survivors. Our findings suggest that measurements of gelatinase A and B mRNAs expression in breast carcinoma may help to identify patients with an aggressive form of the disease.
Clin Exp Metastasis 1998 Oct
PMID:Expression of gelatinases A and B, stromelysin-3 and matrilysin genes in breast carcinomas: clinico-pathological correlations. 993 4

Metastatic dissemination of epithelial ovarian carcinoma is thought to be mediated via tumor cell exfoliation into the peritoneal cavity, followed by adhesion to and invasion through the mesothelium which overlies the contents of the peritoneal cavity. In this study, we have utilized short-term primary cultures to analyze the effect of specific extracellular matrix proteins on properties of human ovarian epithelial carcinoma cells which contribute to the invasive phenotype. Analysis of cell:matrix adhesive profiles indicated that ovarian carcinoma cells adhere preferentially to type I collagen. Immunoprecipitation analyses demonstrated the presence of the collagen-binding alpha2beta1 integrin in biotin-labeled ovarian carcinoma cell membranes, and cellular adhesion was inhibited by blocking antibodies directed against the alpha2 and beta1 integrin subunits. The alpha2beta1-binding peptide Asp-Gly-Glu-Ala (DGEA) was also moderately effective at blocking adhesion to collagen relative to the control peptide Ala-Gly-Glu-Ala (AGEA). Analysis of cell motility on protein-coated colloidal gold coverslips demonstrated that ovarian carcinoma cells migrate preferentially on type I collagen coated surfaces. Type I collagen promoted migration in a concentration-dependent, saturable manner, with maximal migration observed at a collagen-coating concentration of 50 microg/ml. Migration on collagen was inhibited by antibodies directed against the alpha2 and beta1 integrin subunits and by DGEA peptide, providing evidence for the role of the alpha2beta1 integrin in ovarian carcinoma cell motility. Culturing ovarian carcinoma cells on type I collagen gels led to a significant increase in conversion of the matrix metalloproteinase 2 zymogen to the 66-kD form, suggesting that adhesion to collagen also influences matrix-degrading proteinases. These data suggest that alpha2beta1-integrin-mediated interaction of ovarian carcinoma cells with type I collagen, a protein prevalent both in the mesothelial extracellular matrix and in the peritoneal cavity of ovarian carcinoma patients, may function on multiple levels to promote metastatic dissemination of ovarian carcinoma cells.
Invasion Metastasis 1998
PMID:Metastatic dissemination of human ovarian epithelial carcinoma is promoted by alpha2beta1-integrin-mediated interaction with type I collagen. 1020 47

Breakdown of basement membrane (BM) is believed to be an essential step for tumor invasion and metastases. We have previously demonstrated that matrix metalloproteinase-9 (MMP-9), the 92 kDa collagenase expression correlates with metastases in human colorectal cancer (CRC). This study explores the relationship between the 72 and 92 kDa type IV collagenase (MMP-2 and MMP-9) activities and pattern of type IV collagen expression during human colorectal tumorigenesis. Thirty-four CRC patients, including four synchronous adenomas and one synchronous liver metastases, were involved in this study. By immunohistochemical staining, type IV collagen expression was noted to be continuous in the BM of normal mucosa, adenoma and in two cases of carcinoma in situ. Limited or absent type IV collagen staining pattern was seen in 100 (19/19) and 23% (3/13) of CRC with and without metastases, respectively. By double immunostaining, MMP-9 protein expression was noted to localize within areas of limited type IV collagen staining. Similarly, type IV collagen staining was noted to be greatest in areas devoid of MMP-9 expression. Gelatin zymography detected both 92 and 72 kDa proenzyme forms in all CRC and normal mucosa extracts examined. The mean tumor/normal fold increases of the proMMP-2 and proMMP-9 enzyme forms were 1.6+/-0.1 (mean +/- SE) and 2.4+/-0.5 in adenomas, and 2.1+/-0.2 and 4.1+/-0.7 in CRC, respectively. The 62 and 82 kDa bands were present in 63 (12/19) and 74% (14/19) of CRC with metastases, compared with only 20 (3/15) and 33% (5/15) of CRC without metastases, respectively. These differences were significant (P = 0.045 and P = 0.030, respectively). Our results demonstrate that loss of BM type IV collagen along with elevations in MMP-2 and MMP-9 expression, especially the activated forms, occur during colorectal tumorigenesis. Our data suggest that control of type IV collagenase activation may be beneficial in preventing human colorectal tumor progression.
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PMID:Loss of basement membrane type IV collagen is associated with increased expression of metalloproteinases 2 and 9 (MMP-2 and MMP-9) during human colorectal tumorigenesis. 1033 90

The protein MMP-2 (type IV collagenase) belongs to the family of metalloproteinases. Its function is related to cellular matrix degradation including basement membrane type IV collagen. Its presence in the neoplastic cells might enhance its capacity for dissemination. To find out some of its clinico-pathological and immunohistochemical behavior, 98 adenocarcinomas of the stomach were immunohistochemically studied, in search for MMP-2 in neoplastic cells. The results showed a correlation between MMP-2 with parietal depth of infiltration (p = 0.03) and with metastases in regional lymph nodes (p = 0.05). On the other hand, no correlation was found with sex, gastric localization, size of the tumor, histological type or grade neither with expression of MIB-1, c-erbB-2 nor p53 proteins, recurrence nor 5 year survival or no recurrency.
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PMID:[MMP-2 expression (type IV collagenase) in gastric cancer]. 1034 87

The in vitro release of matrix-degrading proteinases from breast cancer cells is associated in part with shed membrane vesicles. To determine whether shed vesicles might play a similar role in ovarian cancer cells, we analyzed the shedding phenomenon in vivo and in vitro as well as the enzymatic content of their vesicles. This is the first time that an immunoelectron microscopical analysis revealed membrane vesicles carrying tumor-associated antigen alpha-Folate Receptor (alpha-FR), circulating in biological fluids (ascites and serum) of an ovarian carcinoma patient. These vesicles were trapped in a fiber network with characteristic fibrin periodicity. An ovarian cancer cell line (CABA I) established from ascitic fluid cells of this patient, grew in Matrigel and formed tubular structures suggesting invasive capability. Immunofluorescence analysis demonstrated strong cytoplasmic staining of CABA I cells with anti-matrix metalloproteinase-9 (MMP-9) and anti-urokinase-type plasminogen activator (uPA) antibodies. CABA I cells shed membrane vesicles, which were morphologically similar to those identified in vivo, as determined by electron microscopy. Gelatin zymography of vesicles isolated both in vivo and in vitro revealed major gelatinolytic bands of the MMP family, identified as the zymogen and active forms of gelatinase B (MMP-9) and gelatinase A (MMP-2). By casein-plasminogen zymography we observed high-molecular weight (HMW)-uPA and plasmin bands. Incubation of purified vesicles from CABA I cells with Matrigel led to cleavage of Matrigel components. Taken together, our results point to a possible role of shed vesicles, both in vivo and in vitro, in proteolysis that mediates invasion and spread of ovarian epithelial carcinoma cells.
Clin Exp Metastasis 1999 Mar
PMID:Matrix-degrading proteinases are shed in membrane vesicles by ovarian cancer cells in vivo and in vitro. 1041 Nov 5

We have previously reported the identification of the endogenous angiogenesis inhibitor angiostatin, a specific inhibitor of endothelial cell proliferation in vitro and angiogenesis in vivo. In our original studies, we demonstrated that a Lewis lung carcinoma (LLC-LM) primary tumor could suppress the growth of its metastases by generating angiostatin. Angiostatin, a 38-kDa internal fragment of plasminogen, was purified from the serum and urine of mice bearing LLC-LM, and its discovery provides the first proven mechanism for concomitant resistance (O'Reilly, M. S., Holmgren, L., Shing, Y., Chen, C., Rosenthal, R. A., Moses, M. A., Lane, W. S., Cao, Y., Sage, E. H., and Folkman, J. (1994) Cell 79, 315-328). Subsequently, we have shown that systemic administration of angiostatin can regress a wide variety of malignant tumors in vivo. However, at the time of our initial discovery of angiostatin, the source of the protein was unclear. We hypothesized that the tumor or stromal cells might produce an enzyme that could cleave plasminogen sequestered by the primary tumor into angiostatin. Alternatively, we speculated that the tumor cells might express angiostatin. By Northern analysis, however, we have found no evidence that the tumor cells express angiostatin or other fragments of plasminogen (data not shown). We now report that gelatinase A (matrix metalloproteinase-2), produced directly by the LLC-LM cells, is responsible for the production of angiostatin, which suppresses the growth of metastases in our original model.
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PMID:Regulation of angiostatin production by matrix metalloproteinase-2 in a model of concomitant resistance. 1050 24

Uterine cervical adenocarcinoma typically is an aggressive neoplasm with a propensity for early invasion and dissemination; however, the regulatory mechanism of invasive activity of cervical adenocarcinoma cells has not been fully understood. In this study, biological effects of epidermal growth factor (EGF) and transforming growth factor (TGF)-alpha on invasion and proteinase expression of human cervical adenocarcinoma OMC-4 cells were investigated. Tumor cell migration along a gradient of substratum-bound fibronectin and invasion into the reconstituted basement membrane were stimulated by 0.1-10 nM EGF and TGF-alpha in a concentration-dependent manner. Their effects on tumor cell migration were also confirmed by wound assay. The zymography of tumor-conditioned medium showed that the treatment of OMC-4 cells with EGF and TGF-alpha resulted in the increase of matrix metalloproteinase (MMP)-2 and urokinase-type plasminogen activator (uPA). Matrilysin (MMP-7), also secreted by OMC-4 cells, was not affected by these growth factors. These results suggest that EGF and TGF-alpha act as positive regulators on the invasion of cervical adenocarcinoma cells, which may be associated with their stimulatory effects on tumor cell motility and the induction of type IV collagenase and uPA secreted by tumor cells.
Invasion Metastasis
PMID:Effects of EGF and TGF-alpha on invasion and proteinase expression of uterine cervical adenocarcinoma OMC-4 cells. 1064 Sep 3


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