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Title: Investigating the relationship between apoptosis and the matrix metalloproteinases
Author: Whiting, John Lee.
ISNI:       0000 0001 3567 4310
Awarding Body: University of Birmingham
Current Institution: University of Birmingham
Date of Award: 2003
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Apoptosis and matrix metalloproteinases remove redundant tissue. They are independently described in similar situations but no causal relationship has been identified. This thesis hypothesizes that the process of apoptosis induces MMP expression. A new cell separation technique was developed allowing rapid separation of apoptotic and non-apoptotic cells with 95% purity, something not previously described. Biotinylated Annexin- V was used to label apoptotic cells and streptavadin-coated dynabeads and a magnetic particle separator used to extract them. Apoptosis was induced in cell lines derived from colon and gastric cancers and the cells separated and analysed using quantitative RT-PCR and real-time PCR. In fibrosarcoma cells apoptosis effects large increases in MMP7 mRNA and decreases for the inhibitor TIMP 4 whereas in malignant epithelial cells apoptosis increases production of MTI-MMP, MMP2 and TIMP2 mRNA. In co-culture, apoptotic epithelial cells induce mRNA production in fibrosarcoma cells for MTI-MMP and TIMP2~ MTI-MMP' combined with TIMP2 is pivotal in the activation of MMP2. These results support the hypothesis that the process of apoptosis leads to increased MMP production. As chemotherapy largely functions by inducing apoptosis, the demonstration that apoptosis may lead to increased matrix destruction and potential tumour shedding could explain why, for many malignancies adjuvant or nee-adjuvant therapy is ineffective and why, for others, efficacy is not as good in-vivo as predicted in-vitro.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (M.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available