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Query: UMLS:C0027651 (tumor)
 685,946 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Tumor cell motility and the passage of tumor cells through various tissue matrices, including basement membrane, are important components of the metastatic process. Proteolytic enzymes, including a type IV collagen-specific collagenase, have been demonstrated to play a significant role in extracellular matrix and basement membrane degradation. In addition, exogenous collagenase has been shown to enhance the motility of some tumor cells independent of its effect on collagen-containing material. Previous studies have also indicated that collagen fragments are chemotactic for many tumor cells. We therefore studied the effect of type I and type IV collagen-specific collagenases, other enzymes involved in collagenase activation and connective tissue degradation, and subsequent collagen degradation products on the directed migration of tumor cells. We report that type I and type IV collagen-specific mammalian collagenases were potent chemoattractants as were native type I and type IV collagens and collagen fragments. Collagenase inhibitor SC44483 inhibited the type IV collagenase-stimulated migration. Collagenase pretreatment of the tumor cells potentiated the migratory response of the tumor cells to collagen and collagen fragments. The plasminogen activator, urokinase, as well as plasminogen itself also enhanced the directed migration of tumor cells in concentrations that suggest involvement of the appropriate cell surface receptor. The chemotactic response of tumor cells to the proteases studied extends the prior report of a role for collagenases and other matrix-active enzymes in tumor cell behavior in addition to matrix degradation.
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PMID:Directed migration of murine and human tumor cells to collagenases and other proteases. 254 19

We previously reported that v-fos transfer to a src-transformed rat 3Y1 cell line enhanced lung metastasis. To clarify the mechanism of this enhancement, we compared various biological factors related to metastatic potential between a fos-transferred highly metastatic cell line (fos-SR-3Y1-202) and the control cell line transferred with genetic marker (pSV2-neo) plus pBR322, neo-SR-3Y1-200. Lung arrest, the effect of lung extract on cell growth, or sensitivity to natural killer cells could not explain the higher metastasis of fos-SR-3Y1-202, compared to findings with neo-SR-3Y1-200. The invasiveness, assessed by penetration through a Matrigel-coated filter was about 5 times higher in fos-SR-3Y1-202 than in neo-SR-3Y1-200; high invasiveness in vitro was also observed in a fos-transferred mixed-population cell line (fos-SR-3Y1-200) and fos-transferred highly metastatic clones. Histopathological evidence of an in vivo tumor also showed the high invasiveness of fos-SR-3Y1-202 cells. To elucidate the causes of the increased invasiveness of fos-SR-3Y1-202, attachment of the cells to Matrigel and its components, such as laminin and type IV collagen, type IV collagenase activity, and motility were examined. Attachment of the cells to the substrate coated on Petri dishes or the activity of type IV collagenase did not differ significantly. On the other hand, cell motility, determined by a new method to directly quantitate alteration of cell shape continuously, using video image analysis and computer techniques, was higher in fos-SR-3Y1-202 than in neo-SR-3Y1-200. Thus, the fos-transferred cell line, fos-SR-3Y1-202 has a high invasiveness, in association with augmentation of motility, hence the enhancement of metastatic potential.
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PMID:High invasiveness associated with augmentation of motility in a fos-transferred highly metastatic rat 3Y1 cell line. 268 97

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

Human melanoma cells secret a 21-kDa protein, termed CSC-21K, which binds with 1:1 molar stoichiometry to the matrix metalloproteinase type IV collagenase proenzyme (70-kDa gelatinase) secreted by the same cells. This binding protein has been purified and its complete primary structure determined by sequencing overlapping peptides which span the entire protein. The amino acid sequence demonstrates that this protein shares significant homology with human TIMP (tissue inhibitor of metalloproteinase), including conservation of the positions of the 12 cysteine residues and 3 of 4 tryptophan residues. The identification of CSC-21K now indicates that a family of TIMP-related proteins exists. Individual members of this family may possess selective affinities for different members of the matrix metalloproteinase family. CSC-21K produced by tumor cells is isolated as a 1:1 molar complex with type IV procollagenase, as demonstrated by amino acid composition analysis. Addition of purified CSC-21K to the activated metalloproteinase results in inhibition of the collagenolytic activity in a stoichiometric fashion. Based on its sequence homology to TIMP and ability to inhibit type IV collagenolysis we propose the name TIMP-2 for this inhibitor.
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PMID:Tissue inhibitor of metalloproteinase (TIMP-2). A new member of the metalloproteinase inhibitor family. 279 61

Cancer invasion and metastases is a complex multi-step 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 in a variety of human carcinoma cells correlated with the number of laminin receptors on the 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 collagen. A genetic linkage between type IV collagenase secretion and metastases was studied using our new genetic system for inducing metastases by 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 100 x) stimulation of cell locomotion. AMF may play a major role in the autonomous invasive behavior of tumor cells.
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PMID:Biochemical mechanisms of tumor invasion and metastasis. 283 60

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.
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PMID:Biochemical mechanisms of tumor invasion and metastases. 283 81

Using both human and murine cell lines, we show that malignant cells are able to invade through basement membrane and also secrete elevated amounts of collagenase IV, an enzyme implicated in the degradation of basement membranes. Using serine proteinase inhibitors and antibodies to plasminogen activators as well as a newly described collagenase inhibitor we demonstrate that a protease cascade leads to the activation of an enzyme(s) that cleaves collagen IV. Inhibition at each step reduces the invasion of the tumor cells through reconstituted basement membrane in vitro. Treatment with a collagenase inhibitor reduced the incidence of lung lesions in mice given i.v. injections of malignant melanoma cells.
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PMID:Effects of inhibitors of plasminogen activator, serine proteinases, and collagenase IV on the invasion of basement membranes by metastatic cells. 283 52

Type IV collagenase is a metalloproteinase associated with metastatic tumor cells. It specifically cleaves the triple helical basement membrane (type IV) collagen molecule at a single site. Monoclonal antibodies which block the activity of the human type IV collagenase were developed and used to purify this antigen. The purified type IV collagenase was partially sequenced following cyanogen bromide and trypsin cleavage. The amino acid sequence of the human type IV collagenase fragments revealed a region homologous to the human interstitial collagenase and stromelysin. However, several sequences in type IV collagenase were identified which are distinct from the latter. Polyclonal antibodies were raised against a synthetic peptide derived from such a sequence. Following affinity purification, the antibodies recognized the denatured human type IV collagenase in Western immunoblotting. These data indicate that type IV collagenase is a distinct member of a general family of metalloproteinases.
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PMID:Monoclonal antibodies to type IV collagenase recognize a protein with limited sequence homology to interstitial collagenase and stromelysin. 283 21

A potent polypeptide inhibitor of mammalian collagenases was purified to homogeneity from medium conditioned by bovine aortic smooth muscle cells maintained in culture. This inhibitor was purified by a series of molecular sieve and heparin-Sepharose chromatographic procedures; it had an apparent Mr of 28,500 and was a major protein secreted by the smooth muscle cells. It was found to be active against several mammalian collagenases including those obtained from rabbit and human fibroblasts and a tumor-specific type IV collagenase. In contrast, it had minimal inhibitory activity for bacterial collagenase and was inactive against the serine proteases plasmin and trypsin. The inhibitor shared many characteristics with tissue inhibitor of metalloproteinases including the ability to irreversibly inhibit susceptible proteinases, heat and acid resistance, and sensitivity to trypsin degradation and reduction-alkylation. A polyclonal rabbit antiserum with blocking activity which recognized the Mr 28,500 protein was obtained. This inhibitor, which is likely produced by bovine vascular smooth muscle cells in vivo to protect the collagen matrix of blood vessels, may play an important role in pathological conditions associated with alteration of collagen metabolism in tissues.
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PMID:Purification and characterization of a collagenase inhibitor produced by bovine vascular smooth muscle cells. 284 2

Connective tissue matrix-degrading metalloproteinases play an important role in cancer invasion. In this report we describe the isolation of a metalloproteinase exhibiting both type IV collagenolytic and gelatinolytic activities from the conditioned medium of NIH-3T3 fibroblasts transformed with DNA containing an activated c-Harvey-ras oncogene from T24 bladder cancer cells. This tumor proteinase was purified by anion exchange chromatography, zinc-chelate Sepharose chromatography, and gel permeation chromatography. The final product was homogeneous on sodium dodecyl sulfate-polyacrylamide gel electrophoresis (relative molecular mass = 67,000). Gelatin zymography revealed two bands of gelatinolytic activity, corresponding to molecular weights of 67,000 and 62,000. Upon immunoblotting with the use of an affinity-purified polyclonal rabbit antibody to a peptide region of type IV collagenase that lacks homology with interstitial collagenase or stromelysin, the purified tumor enzyme was identified as type IV collagenase.
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PMID:Purification of a gelatin-degrading type IV collagenase secreted by ras oncogene-transformed fibroblasts. 284 10


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