Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0027651 (tumor)
 685,946 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The effects of the antitumorigenic drug estramustine on tumor cell membrane penetration (invasion) were investigated in vitro by utilizing a synthetic basement membrane system (a modified Boyden chamber). Tumor cells were plated on a "partition barrier," consisting of a porous filter (8-micron pores) which was coated with a reconstituted basement membrane matrix (Matrigel), and induced to migrate across the barrier with conditioned medium obtained from 9DU 145 human prostatic tumor cells (passage 9). Quantitative radiolabeling studies demonstrated that specially isolated lines (isolated by several passages through the Matrigel) of DU 145 cells, A2058 melanoma, and B16-F10 melanoma cells were highly invasive such that 15 to 20% migrated across a 1-mm-thick Matrigel layer within 5 h at 37 degrees C. NIH-3T3 cells, mouse fibroblasts, and 20DU 145 cells (passage 20) exhibited little or no membrane invasive behavior. Micromolar concentrations of estramustine (30 to 120 microM) inhibited invasion by the invasive cell lines in a dosage-dependent fashion. Quantitative enzymatic assays and radioimmune assays demonstrated that estramustine inhibited membrane invasion by blocking type IV collagenase secretion. Sodium dodecyl sulfate-polyacrylamide gel electrophoresis and Western blots confirmed that 30 to 60 microM estramustine blocked secretion of a Mr 105,000 collagenase protein. Indirect studies showed that a collagenase antibody raised against the Mr 105,000 protein and inhibitors of proteinase activity, including a metalloproteinase inhibitor, and 1,10-phenanthroline, blocked invasion. Because the antibodies inhibited type IV collagenase digestion of 3H-mouse type IV collagen, and invasion simultaneously, it is proposed that collagenolytic activity is involved in invasion. These data demonstrate that estramustine blocks proteinase secretion, and suggest that estramustine may be a useful therapeutic drug for the prevention of metastasis.
 ...
PMID:Blocking of collagenase secretion by estramustine during in vitro tumor cell invasion. 284 50

We analyze here recent data from literature concerning the role of collagenases in cancer. The alteration of basement membrane (BM) and extracellular matrix components, in particular collagens, has been widely reported during tumor invasion. The collagenases degrade interstitial collagens (types I and III) and BM collagens (type IV). So, they break natural barriers and allow tumor cells to spread in surrounding tissues and metastasize. Classical collagenases are not able to degrade type IV collagen (the main component of BM) which, however, often appears to be very altered around tumor cells. Therefore, the existence of a specific type IV collagenase is necessary to explain this phenomenon. Most studies performed with the object of proving the role of collagenases in tumor invasion and metastasis have shown the presence of a type I collagenase, but type IV collagenase has been more difficult to evidence.
 ...
PMID:[Collagenases and cancers]. 285 69

Cancer invasion and metastases is a complex multistep process. In order for a tumor cell to successfully traverse all the steps of this process and initiate a metastatic colony, it must express the right combination of gene products. Such gene products may include proteins which regulate cell interaction with the basement membrane and cell motility. Tumor cells attach to the basement membrane glycoprotein laminin via the cell surface laminin receptor. The human laminin receptor was purified and molecularly cloned. The level of laminin receptor mRNA is a variety of human carcinoma cells correlated with the number of laminin receptors on the cell surface of these cells. Following attachment to the basement membrane, the tumor cell next secretes proteases which may degrade type IV collagen. A genetic linkage between type IV collagenase secretion and metastases was studied using our new genetic system for inducing metastases employing the ras oncogene. Following attachment and local proteolysis, the third step of invasion is tumor cell motility. We have isolated a tumor cell autocrine motility factor (AMF). This factor is secreted by the tumor cells and binds to a cell surface receptor resulting in a profound (greater than 100x) stimulation of cell locomotion. AMF may play a major role in the autonomous invasive behavior of tumor cells.
 ...
PMID:Biochemical mechanisms of tumor invasion and metastases. 285 25

Collagenase type IV degradation activity was examined in metastatic and nonmetastatic clones of the Lewis lung carcinoma (3LL) and of the T10 sarcoma. Conditioned media prepared from cells of both tumors grown in vitro contained low degradation activities, whereas conditioned media from organ cultures of the same clones grown as solid tumors in animals exhibited higher degradation activities. Analysis of subcellular fractions of tumor cells showed that collagenase type IV activity was localized mainly in the cytoplasmic fraction. Crude homogenates or detergent lysates manifested low degradation activities. Little activity was associated with purified plasma membrane preparations and endoplasmic reticular fractions. However, addition of plasma membrane to conditioned media and to cytoplasmic fractions reduced the degradation activities of the cytoplasmic fractions. Possibly a factor that inhibits collagenase type IV exists in the cells in a vesicular form. No correlation between degradation activity and metastatic capacity was demonstrated in the models used in this study. Both metastatic and nonmetastatic clones of the same tumor similarly could degrade basement membrane components.
 ...
PMID:Proteolytic enzymes in tumor metastasis. II. Collagenase type IV activity in subcellular fractions of cloned tumor cell populations. 298 56

Expression of a basement membrane collagen-degrading metalloprotease activity (collagenase IV) was studied in a series of murine cell hybrids derived from fusions between highly metastatic cells (B16-F10RR) or moderately metastatic cells (UV-2237RR) and tumorigenic cells (K-1735 clone 16) or normal cells [peritoneal macrophages (PEC) or C3H mouse embryo fibroblasts (C3H-F)]. The collagenase IV activity of the parent cells and the hybrids was assayed in vitro and compared to the metastatic propensity of the same cells evaluated in both syngeneic (C57BL/6 X C3H/HeN)F1 mice and BALB/c nude mice. The level of collagenase IV activity secreted by the parent lines correlated with their metastatic capacity. The highly metastatic B16-F10RR line secreted the highest enzyme activity, whereas the tumorigenic but nonmetastatic K-1735 clone 16 and the normal parents PEC and C3H-F secreted the lowest enzyme activity. The enzyme activity was completely inhibited with EDTA. The hybrid derived from fusion of cells from two metastatic cell lines as well as hybrids derived from a metastatic and a nonmetastatic tumor cell line expressed higher levels of collagenase IV activity than either parent, and this expression was associated with a high ability to produce metastases in both nude and syngeneic mice. Fusion of metastatic cells with normal cells produced hybrid cells that exhibited suppression of both collagenase IV activity and metastatic capacity. Collagenase IV activity and metastatic propensity can, therefore, be altered by somatic cell hybridization; in the series of hybrids examined in these experiments the expression of type IV collagen-degrading metalloprotease activity and the metastatic ability were closely correlated, which suggests that collagenase IV activity and other properties required for metastasis are genetically linked.
 ...
PMID:Expression of collagenase IV (basement membrane collagenase) activity in murine tumor cell hybrids that differ in metastatic potential. 298 6

We have studied the effect of laminin on type IV collagenolytic activity elaborated by malignant cells in culture. Laminin (at concentrations of 4-8 micrograms/ml) added to serum-free culture supernatants of subconfluent A2058 human melanoma cells significantly increased the release of the type IV collagenolytic activity (200-300%). The induction of type IV collagenase was more pronounced (580%) using a fragment of laminin which binds to the cell surface laminin receptor. A monoclonal antibody against the human laminin receptor blocked the effect of laminin on type IV collagenase, suggesting that occupation of the laminin receptor may be necessary for the effect. Increase in the type IV collagenolytic activity mediated by laminin was also demonstrated in two other malignant cell lines, HT fibrosarcoma (168%) and mouse melanoma (B16-F10) (271%). The increase in type IV collagenase was found to be specific for laminin because another cell-binding matrix protein, fibronectin, did not have any effect, and epidermal growth factor and transferrin actually decreased the type IV collagenase in human melanoma culture medium (epidermal growth factor, 50% at 20 ng/ml; and transferrin, 20% at 10 micrograms/ml). These studies suggest that tumor cell binding to laminin, which comprises the first step of basement membrane invasion, will induce the second step, namely the collagenolytic dissolution of the basement membrane.
 ...
PMID:Laminin increases the release of type IV collagenase from malignant cells. 300 87

A detailed understanding of the pathogenesis of colon cancer metastasis has been hindered by the lack of appropriate animal models which accurately reflect events in this complex process. An animal model for colon cancer metastasis is described in which spontaneously metastasizing colonic tumors are formed after injection of murine colon cancer cells into the cecal wall of BALB/c mice. Using this model, tumor cells with different liver-metastasizing potential were selected and shown to possess several properties known to be associated with other metastatic cell lines. The ability of tumor cells to invade a reconstituted basement membrane and to secrete type IV collagenase was directly proportional to their metastatic ability. In addition, liver-metastasizing cells preferentially migrated toward liver extracts in a Boyden chamber assay, as compared to extracts of brain or lung, and adhered rapidly to highly purified hepatic sinusoidal endothelial cells versus hepatic parenchymal cells in vitro. This model may thus be useful for studying many aspects of the pathogenesis of colon cancer metastasis.
 ...
PMID:An animal model for colon cancer metastasis: establishment and characterization of murine cell lines with enhanced liver-metastasizing ability. 302 9

Activated ras oncogene transfection into suitable recipient cells has been shown to induce the metastatic phenotype (Thorgeirsson, et al., Mol. Cell. Biol., 5: 259-262, 1985). We have used this model system to study the correlation of basement membrane collagenolysis with metastatic propensity. The c-Ha-ras oncogene alone, or combined with v-myc, transfected into early passage rat embryo fibroblasts, induce these cells to secrete high levels of type IV collagenolytic metalloproteinase and to concomitantly exhibit a high incidence of spontaneous metastases in nude mice. Cotransfection of c-Ha-ras plus the adenovirus type 2 E1a gene yields cells which are highly tumorigenic but nonmetastatic and fail to produce type IV collagenase. This effect is due to a suppression of collagenase elaboration, not increased production of a collagenase inhibitor, and not decreased production of a collagenase activator. The characteristics of the collagenase are identical to tumor type IV collagenase described previously. The nonmetastatic cells which failed to produce type IV collagenase retain the ability to secrete high levels of plasminogen activator. Transfection with the protooncogenic forms of Ha-ras or mos, or spontaneous transformation of NIH 3T3 cells or chemical transformation of BALB 3T3 cells yields cells which fail to produce collagenase, are tumorigenic, but totally nonmetastatic. These data support a biochemical linkage of type IV collagenase expression with the metastatic phenotype in this rodent system.
 ...
PMID:Secretion of type IV collagenolytic protease and metastatic phenotype: induction by transfection with c-Ha-ras but not c-Ha-ras plus Ad2-E1a. 302 10

Desmoplastic basal cell carcinomas (fibrosing or morphea types) were studied ultrastructurally, immunocytochemically, and biochemically for basement membrane-degrading activity and compared with the common varieties of basal cell (superficial and nodular-ulcerative types). Whereas the latter lesions demonstrated intact basement membranes as evidenced by extracellular laminin and type IV collagen immunoreactivity and the presence of an unusually thickened basal lamina, desmoplastic basal cell carcinomas showed large defects and absences in basal lamina and basement membrane immunoreactivity. Intense tumor cytoplasmic immunoreactivity for type IV collagenase was present in 13 of 15 cases of desmoplastic basal cell but absent in the superficial and nodular-ulcerative varieties. Whereas explant cultures of all the types of basal cell carcinoma studied gave rise to high levels of interstitial (type I) collagenase activity in conditioned media, only the desmoplastic variety exhibited high type IV collagenase activity. These findings suggest that the mechanisms by which the desmoplastic and the common varieties of basal cell carcinoma infiltrate host tissues may be fundamentally different.
 ...
PMID:Desmoplastic basal cell carcinomas possess unique basement membrane-degrading properties. 302 37

The expression of a basement membrane (BM) collagen-degrading metalloprotease (Type IV collagenase) was studied in a herpes simplex virus (HSV)-2 transformed hamster fibrosarcoma and its in vivo derived sublines and in vitro derived clones of varying metastatic potential. The primary parent tumor was shown to release more or less Type IV collagenolytic activity compared with its sublines (derived from lung nodules that developed after resection of the primary tumor). Normal baby hamster kidney and hamster embryo fibroblasts did not secrete detectable amounts of BM collagenase, whereas normal hamster lung fibroblast secreted intermediate levels of Type IV collagenase activity. The collagenase IV activity of the parent tumor and its in vivo and in vitro derived sublines was assayed in vitro and compared with the ability of the cells lines to spontaneously metastasize in vivo. No correlation between the ability to secrete type IV collagenase and metastatic propensity was detected. Although all cell lines secreted type IV collagenase, the highest activity was recorded for a nonmetastatic variant.
 ...
PMID:Type IV collagenase activity of a primary HSV-2-induced hamster fibrosarcoma and its in vivo metastases and in vitro clones. 304 Feb 11


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>