AbstractSoft tissue sarcomas (STS) are rare human malignant neoplasms, arising mostly from stem cells within non-skeletal connective tissues. They account for approximately 1% of all human malignancies. Matrix metalloproteinases (MMPs) are enzymes involved in degradation of the extracellular matrix and their expression by cancer cells allows the cells to penetrate basement membranes and tissue matrix, thereby invading and metastasising. The most studied malignant tumours from the perspective of MMP expression and its relationship to malignant behaviour are epithelial-derived carcinomas. MMPs role in invasion and metastasis of sarcomas has been very little investigated. This is in part because of the difficulty in accumulating sufficient tumour tissue to enable statistically relevant analysis of sufficient tumours. The purpose of this thesis was to examine the expression of key MMPs - MMP-2, MMP-7, MMP-9, and MMP-14 and their inhibitors (TIMP-1 and TIMP-2) at the invasive/subcapsular edge of human malignant and benign connective tissue tumours using immunohistochemistry, a technique that allows a very high level of reaction product localisation within tumours. In three different STS types and appropriate benign equivalents, the expression of MMPs -2, -7, -9, and -14 and their inhibitors (TIMPs -1 and -2) were measured using intensity of staining and the percentage area of staining by image analysis. The results were compared between tumour types and against histological grading that is widely used as a prognostic factor. The findings from this research indicated that metalloproteinases were commonly expressed in STS and benign equivalents. There were differences in expression of some benign versus malignant neoplasms of the same group. No uniform pattern of expression of any of MMPs was observed across the tumours, but some of the data, most notably that for expression of MMP-2 and -9 indicate, a role for MMPs in malignant behaviour and some showed (e.g. MMPs -7 and -14) change in expression with the grade of malignant tumours in the same broad category. There is some evidence of an inverse relationship between MMP and appropriate TIMP expression suggesting that a failure of inhibition, as much as increased expression, is a feature of malignancy.
|Date of Award||1 Aug 2012|
- The University of Manchester
|Supervisor||Maria Jeziorska (Supervisor) & Anthony Freemont (Supervisor)|
- Matrix Metalloproteinases
- Soft Tissue Sarcoma