All too often a cancer patient appears to be successfully treated, only to suffer a relapse years later. The problem is metastasis, when cancer cells break off from the primary tumor, and quietly remain in hiding to await their chance to reemerge more aggressively than ever. Since metastasis usually leads to a grim prognosis, the nature of the metastatic process has been a topic of intense research activity. Recently, studies have gone beyond the nature of the metastasized cell itself to the means by which they communicate and modify their environment.
Epithelial Tissue Structure
Since the majority of cancers arise from epithelial tissue, it is important to understand the basic structure of these tissues. Epithelial tissue is a thin layer of cells that cover organs, cavities, and other surfaces throughout the body. A large protein called E-cadherin extends the length of the epithelial cells, and is bound to another protein called catenin. The catenins link one cell to another in a strong network. Directly beneath the epithelial lining is the basement membrane, followed by an underlying layer of connective tissue cells called the stroma. (Weinberg) Integrins are cell surface receptors that serve to link epithelial cells to the basement membrane. The basement membrane is a type of mesenchyme.
Tumor Cells Must Overcome Many Obstacles to Spread to Other Parts of the Body Olle2002
- The cancer cell must break free from neighboring cells. In cancer cells, E-cadherin molecules are poorly differentiated and few in number. Additionally, the catenin proteins are absent or non-functioning. Finally, the integrin molecules are changed in structure. Instead of maintaining structural integrity, the integrin sends signals that seem to help the cancer cell migrate through the connective tissue or blood vessel wall. Furthermore, the epithelial cells undergo a process termed the epithelial-mesenchymal transition. After this process, the cells change their shape and structure to resemble more that of mesenchymal cells, lose E-cadherin, and acquire motility and invasiveness. Protease enzymes, such as plasmin and matrix metalloprotease, appear to be essential for breaking down connective-tissue walls to permit cancer cell migration. Van Noorden
- The cancer cell must enter a blood or lymphatic vessel, a process termed intravasation. Once in the stroma, the cancer cell is in close proximity to blood capillaries and a source of nutrients and oxygen. The cancer cells' invasiveness allows them to pass through the endothelial wall of the blood vessel to enter the interior (lumen) of the vessel.
- The cancer cell must successfully navigate the circulation. The bloodstream holds many perils for cancer cells and few survive the journey. They could be mechanically destroyed by the physical fluxes of the blood stream, or could be engulfed by macrophages or killed by natural killer cells. Researchers think that the migrating cancer cell may become covered by platelets that protect them form immune cell attack.
- They must attach to the blood vessel at a distant site. Why are metastasized cells attracted to certain tissues? Studies (Hujanen) have shown that certain tissues have unique factors that serve as chemical attractants for specific metastasic tumor cell lines. Cancer cells may use specific cell surface receptors to attach to, or more likely they become physically trapped in small capillaries.
- They must pass through the blood vessel by the process of extravasation. This process is almost the reverse of intravasation. Another theory (Weinberg) states that cancer cells begin to form a small tumor in the lumen, which eventually forces its way through the vessel wall.
- The cancer cell must establish a new micrometastasis colony in the new tissue. The foreign environment does not provide familiar growth and survival factors. If the cancer cell survives, it may remain dormant or slow growing while a period of adaptation takes place.
The Process of Metastasis is Very Complex
Details of the metastatic process have emerged through painstaking research. How this knowledge could lead to new and more effective treatment methods will be the next topic of this series.
- Hujanen, E and Terranova, V. Migration of Tumor Cells to Organ-derived Chemoattractants. Cancer Res. 1985 Aug; 45: 3517-3521.
- Olle, D. Metastasis Suppressors. Suite 101.com. 2003 Jan 29
- Olle, D. Understanding and Controlling Metastasis. Suite 101.com. 2002 Aug 28
- Van Noorden, C. et.al. Metastasis. American Scientist. 1998 March-April; 86(2)
- Weinberg, Moving Out: Invasion and Metastasis. In: The Biology of Cancer. New York: Garland Science; 2007: 587-653.
- Weis, J. et al. Migratory Neighbors and Distant Invaders: Tumor-associated Niche Cells. Genes & Development. 2008; 22: 559-574.
- Weis, J. et al. Endothelial Barrier Disruption by VEGF-mediated Src Activity Potentiates Tumor Cell Extravasation and Metastasis. J Cell Biol. 2004 Oct 25; 167 (2): 223-229
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