Investigation of mechanisms of breast cancer invasion : the role of matrix metalloproteinases and cell adhesion molecules
thesisposted on 15.12.2014, 10:31 by Janet Louise Jones
A defining feature of cancer is the ability of malignant cells to invade and metastasise. Orchestrated changes in cell adhesion molecules (CAM) and proteolytic enzymes are associated with the onset of cell invasion in both physiological and pathological situations. The hypothesis is that (i) co-ordinated changes in Matrix Metalloproteinases (MMP) enzymes and E-Cadherin and integrin cell adhesion molecules (CAM) are important in the control of breast cancer invasion, (ii) a factor contributing to these changes is the tumour-fibroblast relationship, and (iii) re-establishing a more normal CAM profile or altering the tumour-fibroblast relationship would therefore inhibit tumour invasion.;Breast carcinomas (114) were examined for expression of the MMP-2/TIMP-2/MT1-MMP and MMP-9/TIMP-1 systems using immunohistochemistry, in-situ hybridisation and zymography. All components are expressed by fibroblasts, but the level of tumour cell membrane MMP-2 and MT1-MMP correlates both with MMP-2 activity and the presence of lymph node metastases. MMP-9 expression is associated with the infiltrating lobular phenotype and with reduced E-Cadherin. Reduced 2, 3 and 1 integrin is related to loss of tumour differentiation, and expression of 6 and 4 integrin is associated with high tumour grade.;Evidence from in-vitro studies confirms a relationship between cell adhesion, MMP expression and invasion. Lack of E-Cadherin in MDA-MB 231 and MDA-MB 468 cells is associated with MMP-9 expression and disrupting E-Cadherin in MCF-7 and T47D cells induces MMP-9. The high invasive capacity of MDA-MB 231 is 64 dependent, however, the redistribution of 64 to hemidesmosome-like structures is associated with a significant reduction in invasion and increase in both MMPs and TIMPs.;Tumour cell-fibroblast co-culture enhances tumour cell invasion and is associated with up-regulation of MMP expression in both cell populations with increased net proteolytic activity. Introducing normal myoepithelial cells into this culture system inhibits tumour cell invasion and MMP expression in tumour cells and fibroblasts.;These results indicate the importance of co-ordinate changes in MMPs and CAM in the process of invasion in-vivo and in-vitro, and identify a potential invasion-suppressor role for the myoepithelial cell.