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Abstract
Mortality associated with colorectal carcinoma is, with few exceptions, due to metastatic rather than primary disease; the most common site of metastasis is the liver. Surgery remains the only chance for cure, but the vast majority of patients treated with resection re-present with recurrent liver lesions. Techniques used for minimizing blood kiss during hepatic surgery result in ischemia-reperfusion (I/R) injury which has well-documented detrimental effects on liver function. However, the contribution of I/R to recurrent metastatic liver disease is not well understood. I/R is known to induce growth factors and cytokines, including matrix metalloproteinases (MMP's). The MMP's are important mediators of extracellular matrix (ECM) degradation, a process centrally involved in the metastatic cascade of stromal invasion, intravasation of the circulatory system at the primary site, extravasation at the secondary site and outgrowth of neoplasm. The most common MMP's associated with colorectal carcinoma are MMP-9 and -2. To address the role of I/R on MMP activation and metastatic tumor growth, my dissertation research focused on analyzing the effect of I/R on circulating and tissue MMP-9 in relation to tumor seeding and growth using a model of circulating colorectal carcinoma that forms metastases exclusively in the liver. This research has identified that I/R promotes growth of micrometastatic liver lesions; the use of the MMP inhibitor, doxycycline, or genetic deletion of MMP-9 significantly protect the liver from developing metastases after I/R. These studies will serve as the basis for further evaluation of the mechanism by which MMP-9 contributes to hepatic metastases of colorectal carcinoma and for rational design of clinical trials using MMP inhibitors in patients undergoing hepatic resection, with the ultimate goal of decreasing mortality and increasing quality of life.
