A comprehensive study of matrix metalloproteinases and their inhibitors in colorectal cancer
The most important prognostic factor in patient with colorectal cancer is disease stage at the time of diagnosis. Disease stage is a reflection of the degree of local invasion of the tumour and the extent of distant spread (metastasis). In order to improve the present 50% five-year survival rate for CRC, it will be necessary to devise improved treatments or to target existing therapies more effectively. Therefore, it is desirable to identify the specific molecular changes in cancer cells associated with their malignant behaviour. The matrix metalloproteinases (MMPs) are a group of proteolytic enzymes, which are known to play multiple roles in tumour growth, invasion and spread. Their main physiological inhibitors are the tissue inhibitors of metalloproteinases (TIMPs). This study uses immunohistochemistry to determine the presence of all the major MMPs and TIMPs, in a well-characterised series of 249 colorectal cancers. This work is the largest number of MMPs and TIMPs examined in any published study to date. I have assessed each of the MMPs and TIMPs separately and correlated the findings with all the known prognostic factors in order to ascertain the significance of this group of molecules in colorectal cancer. Furthermore, I have collectively evaluated all of the results, using unsupervised hierarchical cluster analysis, thereby identifying two distinct groups of patients with different MMP/TIMP profiles and significantly different survival outcomes. Comparison of these groupings with existing prognostic factors in multivariate analysis showed the MMP/TIMP profile to be the single most powerful prognostic variable. This is the first study to demonstrate that the MMP/TIMP system produces an aggressive phenotype in colorectal cancer. My findings represent a breakthrough in understanding the molecular characteristics of colorectal cancer and provide the basis for the re-evaluation of the use of MMP inhibitors as anti-cancer drugs.