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A study of the proteinase, cathepsin L, in the context of tumour invasion.Pike, Robert Neil. January 1990 (has links)
The proteinase, cathepsin L, has been strongly implicated in the processes of tumour invasion and metastasis. A new purification method, three-phase partitioning, characterised in terms of the parameters which affected its fractionation of proteins, was found to simplify the purification of cathepsin L from sheep liver. This method, together with a novel cation-exchange step on S-Sepharose and molecular exclusion chromatography, enabled the enzyme to
be purified to homogeneity, in a single-chain form. A further enzyme fraction was isolated as a proteolytically active complex with the endogenous inhibitor of cysteine proteinases, cystatin. Studies on the proteolytically active
complex revealed that approximately 60% of it was covalently bound and proteolytically active, while the other 40% was non-covalently bound and proteolytically inactive, in the manner normally found for the binding of cystatin to cysteine proteinases. A cystatin fraction from sheep liver containing variants of cystatin B, was shown to be able
to form complexes with free cathepsin L in vitro in a pH-dependent, rapid process, which was mildly stimulated by a reducing agent. Cathepsin L was also isolated from human spleen, but only as a protcolytically inactive complex, presumably also with cystatin(s). The complexed and free cathepsin L from sheep liver were analysed for their pH-dependent characteristics, and it was found that both forms of the enzyme were more active and stable at, or near, neutral pH, than would have been expected from published values. Specific polyclonal antibodies to pure sheep cathepsin L were raised in rabbits and chickens. The chicken egg yolk antibodies were of a much higher titre and were immunoinhibitory towards the enzyme, which the rabbit antibodies were not. Anti-peptide antibodies, raised in rabbits against a peptide sequence selected from the active site of human cathepsin L, were highly specific for cathepsin L and immunoinhibitory towards the enzyme. Together with the polyclonal anti-cathepsin L antibodies, they show promise for immunoinhibitory and immunocytochemical studies on the enzyme, and as potential anti-tumour
drugs. / Thesis (Ph.D.)-University of Natal, Pietermaritzburg, 1990.
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Properties of Cathepsin L in relation to a role in invasive cancer.Dehrmann, Frieda Marie. 21 October 2013 (has links)
Cathepsin L, which has been implicated in many tissue degradative pathologies by virtue of its ability to degrade extracellular matrix components, was isolated by a novel, scaled-up protein purification method and purified to homogeneity in the single-chain form. In addition, the high molecular weight variant of cathepsin L covalently complexed with stefin B was isolated. Both cathepsin L and the complex were stable, in respect of their proteolytic activity, to the chaotropic agent urea, both showing enhanced activity in the presence of urea. Urea did not dissociate the
complex. The suitability of cathepsin L for a purported extracellular role was addressed by investigating its pH optimum and pH stability. Cathepsins L and B are affected by ionic strength and so buffers of constant ionic strength (rather than constant molarity, and therefore varying ionic strength) were used in determining their pH optima and stability. Cathepsins L and B had apparent pH optima of pH 6.5 and 7.5, respectively, (measured with synthetic substrates) and, contrary to the previous belief, were substantially stable at physiological pH. In Hanks' balanced salt solution, a model of the extracellular fluid, they were shown to be active and stable, cathepsin L having a half-life of 179 s at pH 7.2 and 657 s at pH 6.8 (the peritumour pH). It was also shown that prior reductive activation of these enzymes increased their stability to extracellular conditions, supporting the hypothesis that the active site thiolate-imidazolium ion pair contributes to their stability. The nature of the bond between cathepsin L and stefin B in the covalent complex was
examined, using CNBr cleavage, HPLC and amino acid sequencing. Stefin B was shown to be associated with residues 1-137 of cathepsin L via a reduction sensitive linkage which was deduced to be a thioester bond betwen Asp-71 of cathepsin L and Cys-3 of stefin B. Polyclonal antibodies to cathepsin L and stefin B-complexed cathepsin L were raised in rabbits and chickens, and characterised with respect to their suitability for
immunocytochemical localisation of these forms of cathepsin L. / Thesis (Ph.D.)-University of Natal, Pietermaritzburg, 1998.
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The role of integrins in the differential upregulation of tumor cell motility by endothelial extracellular matrix proteinsWright, Adele Hart 12 1900 (has links)
No description available.
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Novel MIG-7 expression increases tumor cell invasion and tumor progressionPetty, Aaron, January 2008 (has links) (PDF)
Thesis (M.S. in genetics and cell biology)--Washington State University, May 2008. / Includes bibliographical references.
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A study of p120-catenin and its tyrosine phosphorylation in cancer cell adhesion and invasionMacpherson, Iain Roderick James. January 2007 (has links)
Thesis (Ph.D.) - University of Glasgow, 2007. / Includes bibliographical references. Print version also available.
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Mathematical modelling of tumour invasion : from biochemical networks to tissue dynamicsKooner, Priya January 2006 (has links)
No description available.
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The development and evaluation of molecular biological techniques to detect solid tumour cells in peripheral blood / Kenneth Brian Pittman.Pittman, Kenneth Brian. January 1995 (has links)
Erratum is pasted onto back endpaper. / Bibliography: leaves 189-219. / xxiii, 221 leaves : / Title page, contents and abstract only. The complete thesis in print form is available from the University Library. / Current understanding of metastatic processes and the clinical significance of these processes is discussed. The study of circulating solid tumour cells in peripheral blood is reviewed from an historical perspective. Newer molecular and cell biological techniques which may facilitate more reliable tumour evaluation are reviewed with special reference given to polymerase chair reaction (PCR) / Thesis (M.D.)--University of Adelaide, Dept. of Surgery, 1997?
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Aberrant activation of ERK/FOXM1 signaling axis promotes cell migration/invasion in ovarian cancerLok, Tsz-mei., 駱芷薇. January 2010 (has links)
published_or_final_version / Obstetrics and Gynaecology / Master / Master of Philosophy
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Type IV collagenase and cathepsins L and H : proteinases involved in tumour invasion.Coetzer, Theresa Helen Taillefer. January 1992 (has links)
The collagenolytic proteinases, type IV collagenase and cathepsins Land H, have been
implicated in tumour invasion and metastasis, by virtue of their degradative action on the
extracellular matrix barriers traversed by migrating tumour cells. Type IV collagenase was
isolated from human leucocytes using anti-peptide antibody immunoaffinity
chromatography. The highly specific targeting of both native and denatured forms of human
type IV collagenase by these anti-peptide antibodies holds much promise for
immunolocalisation studies in human tumour tissue. Cathepsin L was purified in both a
free; single-chain form from sheep liver, and as complexes with the endogenous cysteine
proteinase inhibitor, stefin B. These complexes comprised mixtures of the usual tight-binding
non-covalent, inhibitory complexes, and novel, proteolytically active, covalent
cathepsin L/stefin B complexes. The latter form spontaneously in a pH-dependent manner in
vitro from purified, active constituents. The primary structures of these complexing moieties
from sheep liver are reported here for the first time, and showed a high degree of sequence
homology with their human counterparts. Single-chain cathepsin L, both in the free, and
novel, covalently complexed forms, manifested stability and increased activity at neutral pH,
thus suggesting a role in extracellular tissue destruction. This potential involvement in
tumour invasion was strengthened by demonstrating that the single-chain form of the
enzyme, and similar covalent complexes, active under physiological conditions, could be
isolated from liver tissue homogenates of higher primates, baboon (Papio ursinus) and man.
A battery of versatile polyclonal anti-sheep cathepsin L and anti-human cathepsins L
and H peptide antibodies were raised in chickens and rabbits. The chicken egg yolk
antibodies were often of a higher titre than the corresponding rabbit serum antibodies, and
additionally manifested unique immunoinhibitory properties. In the case of the polyclonal
chicken anti-sheep cathepsin L antibodies, this was derived from their ability to target a
peptide located in the active site of cathepsin L. The chicken anti-human cathepsins L and H
peptide antibodies constitute the immunological probes of choice for immunolocalisation and
in vitro tumour invasion studies to elucidate the relative contributions of these collagenolytic
cathepsins to tumour invasion, and could ultimately find application in tumour
immunotherapy. / Thesis (Ph.D.)-University of Natal, Pietermaritzburg, 1992.
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Proteinases and extracellular matrix degradation in breast cancer.Fortgens, Philip Hendrik. 11 October 2013 (has links)
A variety of proteases have been shown to promote the progression of cancer by virtue of their ability to degrade extracellular proteinaceous barriers, such as
basement membrane and interstitial stroma. At the outset of this study available
evidence strongly implicated cathepsin D in breast cancer metastasis. It was
envisaged that an antibody inhibitory to the activity of this enzyme might retard
invasion, and restrain a tumour from spreading. To this end anti-peptide
antibodies were generated against a peptide sequence derived from the substrate
capturing "flap" of the enzyme. Inhibition of enzyme activity by these antibodies
could not be demonstrated, probably due to the lack of a suitably sensitive
enzyme assay. However, the rationale of this study and the expertise gained from
it could be applied, in the future, to enzymes that have since been found to be
more relevant to tumour invasion.
A feature of many transformed cells is an anomalous lysosomal enzyme
trafficking system, and concomitant hyper-secretion of some enzymes. The
distribution of low pH compartments and lysosomal enzyme-containing
compartments was investigated in human breast epithelial cells, and their c-Ha-ras-
transformed counterparts. Immunofluorescence and immunoelectron
microscopy showed that these compartments have a more peripheral cellular
distribution with respect to normal cells, and cathepsins B and D were cell
surface-associated.
Studies were undertaken to reveal the extracellular matrix degrading ability of c-Ha-
ras-transformed cells. Transformed cells exhibited increased degradation of
fluorescein-labelled extracellular matrix in serum free medium, and increased motility, and degradation and disruption of extracellular matrix in serum-containing
medium. In vitro invasion through artificial basement membrane by
transformed cells was investigated using scanning electron microscopy, and was
further used to preliminarily identify the proteases involved in invasion by
specific inhibition. By this means, greatest inhibition of in vitro invasion was
obtained using a specific metalloproteinase inhibitor. Overexpression by
transformed cells of a metalloproteinase was detected by gelatin zymography.
Together these results suggest that the increased invasive capacity of ras-transformed
breast epithelial cells may be largely due to increased
metalloproteinase activity. / Thesis (Ph.D.)-University of Natal, Pietermaritzburg , 1996.
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