Liver Tumor Study Group Research
Basic Science Research in Colon Cancer Liver Metastasis
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MD Anderson has a very active program investigating molecular mechanisms of colon cancer metastasis to the liver. The process of metastasis is dynamic, which requires the appropriate molecular machinery to allow a tumor cell to proliferate in the colon, establish its own blood supply, invade surrounding tissues, be released into the circulation, adhere to the blood vessels of the liver, invade into the liver, proliferate and acquire its own blood supply (angiogenesis). This complex process requires that the tumor cell interact with the microenvironment of the liver such that the tumor cell can utilize the growth factors and blood vessels of the liver in order to grow.
Mechanism of Tumor Growth and Metastasis
Identification of the molecular mechanisms that lead to colon cancer metastasis to the liver allows the development of rational therapeutic strategies. We currently have active programs investigating angiogenesis, growth factors and growth factor receptors, signal transduction pathways and mechanisms that promote tumor cell survival.
Molecular Mechanism of Tumor Growth and Metastasis
Factors which regulate colon cancer angiogenesis and metastasis have been studied in depth at MD Anderson. It has been established that vascular endothelial growth factor (VEGF), the most potent angiogenic factor identified to date, leads to metastasis of colon cancer and is associated with aggressive disease. Since VEGF is important for colon cancer to metastasize to the liver, we have utilized various strategies to inhibit VEGF activity. Recent studies have demonstrated that blocking VEGF activity decreases the number and size of colon cancer metastases, and the number of blood vessels within that metastasis. Furthermore, prolonged anti-VEGF therapy may actually lead to death of tumor blood vessels, as well as tumor cells.
Ongoing studies are investigating the mechanisms of tumor cell death secondary to anti-VEGF therapy. These strategies include down-regulating angiogenic factor expression, blocking the activity of angiogenic factors by utilizing antibodies that neutralize the factor itself or its receptor, inhibiting the enzyme activity of the angiogenic factor receptor, blocking invasion of blood vessels into the surrounding tissues and other inhibitors of endothelial cell proliferation.
In order for a tumor cell to divide, it must possess the appropriate growth factor receptors to be able to respond to growth factors released by the liver. These growth factor receptors are not only involved in tumor cell division, but also in tumor cell survival. An active research program investigating mechanisms of growth factor receptor augmentation of tumor growth has established that epidermal growth factor receptor, hepatocyte growth factor receptor and insulin-like growth factor receptor are all important in regulating tumor cell proliferation and survival. Numerous strategies have been utilized to inhibit activity of these receptors, including monoclonal antibodies and enzymes that inhibit the activity of these receptors. Preliminary analysis suggests that these strategies can slow tumor growth. Further analysis will be necessary to determine if survival of mice can be prolonged by these agents in an experimental model of colon cancer metastasis.
Tumor cells frequently receive outside signals which are then transmitted through the interior of the cell to the nucleus where genes are activated. This process, signal transduction, is an active area of investigation. In colon cancers that metastasize to the liver, we have found that specific enzymes (Src, MAP kinase and others) are associated with increases in tumor aggressiveness. Furthermore, these signal transduction pathways activate genes that lead to angiogenesis, cell survival or proliferation. Therefore, these signal transduction molecules are very important mediators in the formation of colon cancer metastasis.
For colon cancers to grow and metastasize it must first invade into the local tissues and eventually gain access to the lymphatic or blood circulation. Even after this initial invasion, tumor cells deposited in the liver must invade into the liver tissues. This process of invasion is regulated by specific factors released by tumor cells. These enzymes degrade the surrounding tissues allowing invasion of the tumor mass. Investigations into the mechanism of how these enzymes are regulated in cancer and normal tissues have led to the development of agents that inhibit such enzymes. However, initial clinical studies with these agents have been associated with unexpected side effects and disappointing results. Therefore, continued research in the field of colon cancer invasion may lead to optimal therapeutic benefit with fewer side effects.
Over the last five to 10 years, it has become apparent that tumor cells express factors which allow them to survive under adverse conditions. Typically, when normal cells encounter stress or develop a genetic mutation, they activate certain processes within the cell that lead to "programmed cell death". This process, apoptosis, is a process that prevents cells with genetic mutations from dividing and forming cancers. However, in cancer, the process of apoptosis is altered such that cells with genetic mutations are allowed to survive and divide even though there are alterations within the cell which normally would lead to cell death. Examining the genes which regulate the process of apoptosis allows us to identify targets which may make tumor cells more susceptible to chemotherapy, radiation therapy or other anti-tumor therapies (Figure 3).