Experimental Colorectal Cancer Liver Metastasis

With estimated 1 080 000 diagnosed cases each year, which account for 1.1% of all deaths, colorectal carcinoma (CRC) ranks fourth in cancer-related deaths in both sexes worldwide (WHOSIS, 2008). In Europe, CRC is the third most lethal malignancy after lung and stomach cancers in men, and it ranks second after breast cancer in women (WHOSIS, 2008). CRC progression is characterized by increased growth of the primary carcinoma as well as lymphatic and haematogenic spread. The liver is often the first vascular bed in which disseminating colorectal cancer cells are trapped and therefore is affected in up to 10-20% of CRC patients at the time of presentation (Berney, et al., 1998). Another 40-50% of patients will eventually develop liver metastasis during the course of their illness, which is commonly the cause of death (Bentrem, et al., 2005, Stangl, et al., 1994, Sugarbaker, 1990). At present, liver resection is considered the treatment of choice for suited patients with colorectal liver metastases, offering a five-year survival rate of 25-44% (Choti, et al., 2002, Garden, et al., 2006, Zacharias, et al., 2004) to those 20-25% of patients with isolated liver metastasis (Adson, et al., 1984, Bismuth, et al., 1996, Fong, et al., 1999). Unfortunately, this procedure is feasible only in patients with no signs of irresectable extra-hepatic disease, whereas the median survival is only 9–19 months for patients with unresectable disease who receive systemic chemotherapy (de Gramont, et al., 2000, Giacchetti, et al., 2000, Meyerhardt and Mayer, 2005, Saltz, et al., 2000). However, the fact that CRC malignancy develops over a long period and can only be efficiently controlled if detected early provokes many efforts to better understand the neoplastic progression of this cancer. It is well known, that there is a continuous shedding of tumor cells from a primary CRC (Chambers, et al., 2002), but not all disseminated CRC cells develop into macrometastases. It was hypothesized that sub-populations of malignant cells evolve a genetic advantage to become “highly metastatic”. These clones are skilled to dissociate from the primary cancer, to intravasate into nearby blood and lymphatic vessels, to travel through the lymphatic and hematogenous systems, to survive the immune surveillance, to extravasate into distant tissues forming micrometastases, and to eventually colonize the target organ. In this cascade, the epithelial-mesenchymal transition (EMT), characterized by the loss of cell-to-cell adhesion and cell polarity (Thiery, 2003), plays a crucial role in different stages;