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16.7: Metastasis

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  • The onset of metastasis signals a drastic change in the prognosis of a cancer patient. While pre-metastatic tumors can certainly be dangerous or painful, treatment can be fairly localized, e.g. surgical excision and directed radiation therapy. Once the tumor metastasizes it must be treated systemically due to the potential for secondary tumors literally anywhere in the body. This presents a problem because the tumor cells are derived from the body’s cells and are mostly indistinguishable by the body’s immune system. The primary mechanism for anti-cancer drugs is to target fast proliferation, since most cancer cells proliferate much faster than most normal cells, but this still kills off some of the body’s naturally fast-proliferating cells, such as the epithelial cells lining the gut. More recently, other approaches to anti-cancer drug treatments have been developed; most notably, anti-angiogenesis drugs to starve tumors by preventing them from developing or recruiting new blood vessels. As tumors grow, the ability to absorb nutrients from the environment decreases for the innermost cells of a solid tumor.

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    Figure 16. Metastasis.

    Metastasis (fig. 16) starts with downregulation of cell-cell adhesions (1). This may include inside-out signaling to integrin receptors, or downregulation of cadherin expression, and other methods for allowing the cell to separate from the rest of the tumor. Non-metastatic tumors are surrounded by a capsule of extracellular matrix that contains the tumor in its location. To escape this capsule, the metastasizing cell must secrete proteases (usually metalloproteases) that can break down the ECM proteins (2). Once out into the looser connective mesenchymal tissue, the metastatic cell increases its locomotive activity and heads for a blood vessel. Intravasation (3) into a small, low-flow blood vessel allows the cell to be carried to nearly any destination in the body by the circulatory system (4). At some point, the metastatic cell will attach to the interior wall of a blood vessel, and exit the circulation (5). The molecules and situations that determine the point of exit are not clear yet, although there are clearly preferred sites of metastasis for some types of tumors. Presumably, there is specific recognition and adhesion occurring based on cell adhesion molecule expression on tumor cell and target tissue surfaces.

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    Figure 17. Common sites (open yellow circles) for the metastasis of colon cancers (filled yellow circle).