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)

Interaction of T and B lymphocytes, platelets, granulocytes, macrophages and mast cells with the subendothelial extracellular matrix (ECM) is associated with degradation of heparan sulfate (HS) by a specific endoglycosidase (heparanase) activity. The enzyme is released from intracellular compartments (i.e., lysosomes, specific granules) in response to various activation signals (i.e., thrombin, calcium ionophore, immune complexes, antigens, mitogens), suggesting its regulated involvement in inflammation and cellular immunity. In contrast, various tumor cells appear to express and secrete heparanase in a constitutive manner, in correlation with their metastatic potential. Heparanase enzymes produced by different cell types may exhibit different molecular properties and substrate cleavage specificities. The platelet enzyme appears also in a latent form. It can be activated by tumor cells and thereby facilitate their extravasation in the process of metastasis. Degradation of ECM-HS by all cell types was facilitated by a proteolytic activity residing in the ECM and/or expressed by the invading cells. This proteolytic activity produced a more accessible substrate for the heparanase enzymes. Heparanase-inhibiting, nonanticoagulant species of heparin markedly reduced the incidence of lung metastasis in experimental animals. These species of heparin also significantly impaired the traffic of T lymphocytes and suppressed cellular immune reactivity and experimental autoimmune diseases. Heparanase activity expressed by intact cells (i.e., platelets, mast cells, neutrophils, lymphoma cells) was found to release active HS-bound basic fibroblast growth factor from ECM and basement membranes. Heparanase may thus elicit an indirect neovascular response in processes such as wound repair, inflammation and tumor development. The significant anticancerous effect of heparanase-inhibiting molecules may therefore be attributed to their potential inhibition of both tumor invasion and angiogenesis. Both normal leukocytic cells and metastatic tumor cells can enter the bloodstream, travel to distant sites and extravasate to the parenchyma at these sites. We suggest that heparanase is utilized for this purpose by both types of cells. Other functions (i.e., enzyme activities, adhesive interactions, chemotactic and proliferative responses) of metastatic tumor cells seem to mimic the equivalent functions of leukocytes as they migrate across blood vessels to gain access to sites of inflammation.
Invasion Metastasis 1992
PMID:Expression of heparanase by platelets and circulating cells of the immune system: possible involvement in diapedesis and extravasation. 139

Neoplastic cells require an appropriate pericellular environment and new formation of stroma and blood vessels in order to constitute a solid tumor. Tumor progression also involves degradation of various extracellular matrix (ECM) constituents. In this review we have focused on the possible involvement of ECM-resident growth factors and enzymes in neovascularization and cell invasion. We demonstrate that the pluripotent angiogenic factor, basic fibroblast growth factor (bFGF) is an ECM component required for supporting cell proliferation and differentiation. Basic FGF has been identified in the subendothelial ECM produced in vitro and in basement membranes of the cornea and blood vessels in vivo. Despite the ubiquitous presence of bFGF in normal tissues, endothelial cell (EC) proliferation in these tissues is usually very low, suggesting that bFGF is somehow sequestered from its site of action. Our results indicate that bFGF is bound to heparan sulfate (HS) in the ECM and is released in an active form when the ECM-HS is degraded by cellular heparanase. We propose that restriction of bFGF bioavailability by binding to ECM and local regulation of its release, provides a novel mechanism for regulation of capillary blood vessel growth in normal and pathological situations. Heparanase activity correlates with the metastatic potential of various tumor cells and heparanase inhibiting molecules markedly reduce the incidence of lung metastasis in experimental animals. Heparanase may therefore participate in both tumor cell invasion and angiogenesis through degradation of the ECM-HS and mobilization of ECM-resident EC growth factors. The subendothelial ECM contains also tissue type- and urokinase type- plasminogen activators (PA), as well as PA inhibitor which may regulate cell invasion and tissue remodeling. Heparanase and the ECM-resident PA participate synergistically in sequential degradation of HS-proteoglycans in the ECM. These results together with similar observations on the properties of other ECM-immobilized enzymes and growth factors, suggest that the ECM provides a storage depot for biologically active molecules which are thereby stabilized and protected. This may allow a more localized, regulated and persistent mode of action, as compared to the same molecules in a fluid phase.
Cancer Metastasis Rev 1990 Nov
PMID:Extracellular matrix-resident growth factors and enzymes: possible involvement in tumor metastasis and angiogenesis. 170 86

Many cancers metastasize nonrandomly to particular distant sites, and their colonization properties cannot be explained by mechanical considerations, such as arrest of tumor cells in the first microcirculatory network encountered. Metastatic cells that show a high propensity to metastasize to certain organs adhere at higher rates to microvessel endothelial cells isolated from these target sites, invade into target tissue at higher rates and respond better to paracrine growth factors from the target site. These properties depend on multiple tumor cell, host cell, and stromal molecules that are differentially expressed by particular tumor and organ cells and by the extracellular matrix. For example, some of the adhesion molecules involved in tumor cell-endothelial cell adhesion have been identified on both tumor and host cells. Among them are: integrins, endogenous lectins, annexins, and other molecules. The invasive properties of particular tumor cells are dependent on the production of degradative enzymes, such as metalloproteinases, heparanase and cys and ser proteinases, and on responses to organ-derived paracrine and autocrine motility factors. The subsequent growth of particular tumor cells at certain organ sites is determined, in part, by their responses to organ paracrine growth factors and the organ extracellular matrix. Collectively these factors appear to determine the organ colonization properties of blood-borne metastatic cells.
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PMID:Tumor and host molecules important in the organ preference of metastasis. 191 24

The effects of gamma-irradiation on the properties of microvessel endothelial cells were studied in vitro. After incubating confluent endothelial cell monolayers in low serum-containing medium for 24 h, the monolayers were irradiated with 137Cs. Survival of rat lung microvessel endothelial (RLE) and mouse brain microvessel endothelial (MBE) cells were similar after irradiation (Do = 2.17 and 1.75 Gy, Dq = 4.44 and 5.67 Gy, and n = 7.8 and 25 for RLE and MBE cells, respectively). We examined the effects of gamma-irradiation on endothelial cell morphology, adhesion of syngeneic rat lung or mouse brain metastasizing tumor cells, release of the subendothelial matrix-degrading enzyme heparanase, and secretion of soluble mitogenic factors that stimulated the growth of syngeneic metastatic tumor cells. The effects of gamma-irradiation were not apparent until several hours after irradiation, and by 24 h doses of greater than or equal to 10 Gy caused limited endothelial cell retraction and reorganization of the endothelial monolayer. By 24 h after irradiation there was also increased adhesion of metastatic tumor cells to RLE but not MBE cells. We also examined the effects of gamma-irradiation on the release from endothelial cells of enzymes that solubilize the subendothelial matrix. Radiation resulted in a significant increase in the release of matrix-degrading enzyme (heparanase) that solubilized [35S]-labeled heparan sulfate from subendothelial matrix. This was most pronounced in the 24 h sample from gamma-irradiated endothelial cells. Finally, we examined the gamma-irradiation-induced release of mitogenic factors from endothelial cells that could stimulate the growth of metastatic cells in serum-limiting medium. The medium from RLE but not MBE cells stimulated the growth of a rat mammary carcinoma cell line. The results suggest that gamma-irradiation of microvessel endothelial cells can affect the interactions of tumor cells with endothelial cells and their subendothelial matrix; these processes could facilitate metastasis formation in irradiated tissues such as the lung.
Clin Exp Metastasis
PMID:Effects of gamma irradiation on cultured rat and mouse microvessel endothelial cells: metastatic tumor cell adhesion, subendothelial matrix degradation, and secretion of tumor cell growth factors. 191 80

Orthotopic implantation of human colon carcinoma cells is useful for studying the behavior of metastatic subpopulations. We observed that the parental line and variants of human colon carcinoma KM12 cells were all tumorigenic following implantation into the subcutis or cecal wall of BALB/c nude mice. Their ability to metastasize to distant organ sites varied, however, with the site of growth. Subcutaneous (SC) tumors did not produce visceral metastases, whereas cecal tumors metastasized to the regional mesenteric lymph nodes and to the liver. To examine the influence of organ environment on the extracellular matrix-degrading activity of the tumors, we inoculated human colon carcinoma cells into the subcutis or cecal wall and after 7 weeks isolated and cultured the tumors in serum-free medium. The conditioned media of SC tumors contained very low levels of type IV collagenase (gelatinase) and heparanase (heparan sulfate-specific endo-beta-D-glucuronidase), whereas the media of the cecal wall tumors contained high levels of both. Zymograms of the media revealed that the intracecal human colon carcinomas secreted more than three times the amount of latent and active forms of 92-kd type IV collagenase than did the SC tumors. Moreover, only the conditioned media of intracecal tumors contained latent and active forms of 64-kd type IV collagenase. Histochemical analysis using rabbit antiserum raised against the synthetic peptides of 72-kd procollagenase type IV showed type IV collagenase in the intracecal tumors; human colon carcinoma growing SC, however, were not stained significantly. These results suggest that factors in the organ environment may affect production and secretion of tumor extracellular matrix-degrading enzymes, and these factors may modify the metastatic behavior of human colon carcinoma cells in nude mice.
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PMID:Influence of organ environment on extracellular matrix degradative activity and metastasis of human colon carcinoma cells. 225 Mar 3

This manuscript reviews the molecular aspects of tumor cell invasion of extracellular matrix. The changes in cell:substrate and cell:cell receptors that characterize motile cells are discussed for their importance not only in mediating invasive cell behavior, but also as diagnostic markers for invasive potential. Autocrine motility and scatter factors probably have key roles in initiating migratory behavior, while specific and non-specific extracellular matrix alterations can facilitate cell locomotion. The manuscript reviews reported changes, such as induction of cell motility, matrix degrading enzymes, and invasive/metastatic potential, which can follow transfection with ras oncogenes, and details the key roles of metalloproteinases, heparanase, and plasminogen activator in matrix degradation. Enzymatic inhibitors of initial steps in extracellular matrix degradation, such as rTIMP, and synthetic blockers of adhesive steps in tumor cell invasion represent types of reagent with potential as anti-metastatic agents. Their potential usefulness may be increased if they can be incorporated into a novel, long-term, non-traditional delivery system.
Cancer Metastasis Rev 1990 Sep
PMID:Cell-matrix interactions during tumor invasion. 225 11

Circulating polymorphonuclear cell (PMN) levels rise in proportion to the metastatic potential of the tumor in 13762NF mammary adenocarcinoma tumor-bearing rats. These tumor-elicited PMNs (tcPMNs) secrete high levels of the basement-membrane-degrading enzymes, type IV collagenase and heparanase, suggesting that metastatic tumor cells stimulate neutrophilia so that the tcPMNs might assist tumor cell extravasation during metastasis. To test this hypothesis, purified proteose peptone-elicited PMNs from peritoneal exudate, circulating normal PMNs, and tcPMNs were evaluated for their effects on in vitro invasive and in vivo metastatic potentials of syngeneic 13762NF mammary adenocarcinoma tumor cells. tcPMNs caused a dose-dependent increase in invasion through a reconstituted basement membrane barrier in an in vitro invasion assay. At PMN:tumor cell ratios of 30:1, invasion potential significantly (P less than 0.05) rose to 26-fold, 40-fold, and 37-fold for poorly metastatic MTLn2 cells, highly metastatic MTLn3 cells, and moderately metastatic MTF7 cells, respectively. In contrast, purified proteose peptone-elicited PMNs and circulating normal PMNs did not significantly alter invasive potential. Intravenous coinjections of purified proteose peptone-elicited PMNs did not change the number of experimental lung metastases, but tcPMNs at ratios to 50:1 significantly raised the mean number of metastases 23-fold for MTLn2, 3- to 4-fold for MTLn3, and 1.6- to 1.8-fold for MTF7. These results demonstrate that tcPMNs contribute to the metastatic propensity of mammary adenocarcinoma clones by increasing efficiency of invasion through basement membrane.
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PMID:Tumor-elicited polymorphonuclear cells, in contrast to "normal" circulating polymorphonuclear cells, stimulate invasive and metastatic potentials of rat mammary adenocarcinoma cells. 276 1

Circulating neutrophil (PMN) levels can increase in rats bearing subcutaneously growing clones of the 13762NF mammary adenocarcinoma and the level of increase correlates with the metastatic potential of the clone. In rats with poorly metastatic MTC tumors, numbers of circulating PMN did not rise, whereas PMN levels rose 50-fold in rats bearing highly metastatic MTLn3, 12-fold in rats with weakly metastatic MTLn2, and 14-fold in those with moderately metastatic MTF7 tumors. Neutrophilia was caused partly by tumor size, but metastatic potential was a stronger determinant, suggesting that PMNs may play a role in the metastatic process. To determine whether circulating PMNs indeed contribute to cellular metastatic potential, we examined effects of PMN on various aspects of the metastatic process. Experimental metastasis assays involving i.v. co-injections of PMNs yielded a dose-dependent increase in extrapulmonary metastases for MTLn3, but no change in lung colonization potential for any of the clones examined. The change in the metastatic profile was not due to any modification in in vivo distribution of i.v. injected tumor cells or in adhesion to endothelial monolayers in vitro. PMNs also had no effect on in vitro DNA, RNA or protein synthesis and were not cytolytic (E:T 100:1). However, PMNs collected from high-passage MTLn3 tumor-bearing rats had a 50% increase in heparanase and type-IV collagenolytic activity as compared to unstimulated PMNs isolated from normal rats. These results indicate that polymorphonuclear cells may contribute to the metastatic potential of highly metastatic clones from the 13762NF mammary adenocarcinoma cells by assisting in the degradation of basement membrane during extravasation.
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PMID:The role of polymorphonuclear leukocytes (PMN) on the growth and metastatic potential of 13762NF mammary adenocarcinoma cells. 284 49

The successful penetration of endothelial basement membranes is an important process in the formation of hematogenous tumor metastases. Heparan sulfate (HS) proteoglycan is a major constituent of endothelial basement membranes, and we have found that HS-degradative activities of metastatic B16 melanoma sublines correlate with their lung-colonizing potentials. The melanoma HS-degrading enzyme is a unique endo-beta-D-glucuronidase (heparanase) that cleaves HS at specific intrachain sites and is detectable in a variety of cultured human malignant melanomas. The treatment of B16 melanoma cells with heparanase inhibitors that have few other biological activities, such as N-acetylated N-desulfated heparin, results in significant reductions in the numbers of experimental lung metastases in syngeneic mice, indicating that heparanase plays an important role in melanoma metastasis. HS-degrading endoglycosidases are not tumor-specific and have been found in several normal tissues and cells. There are at least three types of endo-beta-D-glucuronidases based on their substrate specificities. Melanoma heparanase, an Mr approximately 96,000 enzyme with specificity for beta-D-glucuronosyl-N-acetylglucosaminyl linkages in HS, is different from platelet and mastocytoma endoglucuronidases. Elevated levels of heparanase have been detected in sera from metastatic tumor-bearing animals and malignant melanoma patients, and a correlation exists between serum heparanase activity and extent of metastases. The results suggest that heparanase is potentially a useful marker for tumor metastasis.
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PMID:Heparanases and tumor metastasis. 328 60

Many enzymes capable of proteolytic degradation of extracellular matrix and basement membranes have been implicated in tumor progression, including the matrix metalloproteinases, cathepsins, plasminogen activators, and heparanase. Matrix metalloproteinases, a family of zinc-dependent proteases, participate in several steps in tumor progression, including invasion, metastasis, and angiogenesis. In this review, we will give a brief overview of this protease family, and we will review in vitro and in vivo evidence implicating a particular metalloproteinase, the 92-kD type IV collagenase/gelatinase (MMP-9 or gelatinase B), as well as other metalloproteinases, in cancer progression. Finally, using recent studies from our laboratory, we will demonstrate the importance of both tumor cell and host stromal cell production of MMP-9 in tumor progression.
Invasion Metastasis
PMID:Metalloproteinases in tumor progression: the contribution of MMP-9. 765 17


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