From the above, it should be clear that production of hyaluronidase or collagenase by tumor cells or other adjacent cells can lead to matrix digestion, which subsequently allows tumor cell invasion. One more aspect of this process is the mechanism by which tumor cells "walk" during invasion. It is useful to consider the close analogy between the migration of immune cells toward an infection site and the movement of cancer cells away from the central tumor. In both cases, the cells rely on the attraction of their surface adhesion proteins to other proteins in the extracellular matrix. Immune cells and cancer cells "walk" to their intended targets by gripping and then internalizing proteins of the ECM.47,48
The "legs" of immune cells, fibroblasts, and some cancer cells appear to be RHAMM proteins (RHAMM = receptor for hyaluronic acid mediated motility) and variants of the CD44 family of proteins. CD44 proteins are surface receptors for both hyaluronic acid and collagen, and they mediate attachment, cellular uptake, and degradation of these proteins. RHAMM proteins are receptors for hyaluronic acid. CD44 and RHAMM proteins facilitate the uptake of hyaluronic acid and collagen into the cell, which are then degraded by enzymes.
In a number of human breast cancer cell lines, high CD44 expression has been associated with high invasive capacity.49 One human study reported that elevated levels of soluble CD44 occurred in a high percentage of patients with metastatic disease, and removal of the primary tumor reduced these levels.47 Accordingly, other human studies have reported that levels of soluble CD44
Resting immune cells produce normal CD44 proteins, which do not facilitate movement, whereas stimulated cells produce CD44 variants that do. Cancer cells appear to mimic stimulated immune cells by also expressing CD44 variants, thereby allowing increased migration.51 The expression of CD44 variants may also play a role in metastasis. The basement membrane surrounding capillaries contains hyaluronic acid, and CD44 variants on blood-borne tumor cells help the cells attach to the vasculature.52 In one study, intravenous injection of CD44 inhibitors (CD44 antibodies) reduced the proliferation and metastatic potential of CD44-expressing melanoma cells in mice.
In addition to CD44 activity, cell migration is dependent on a number of other events, such as the presence of chemoattractant compounds (such as leukotrienes), growth factor signaling, and the interactions of other cell adhesion molecules (CAMs) with matrix components. These other adhesion molecules include integrins, se-lectins, cadherins, and the immunoglobulin superfamily of adhesion proteins (see Chapter 6).
A number of natural compounds inhibit cancer cell migration. Many of these also inhibit immune cell migration, since the mechanisms that govern both can be similar. However, at least some natural compounds, such as PSK, appear to inhibit cancer cell migration preferentially. Ginseng may do the same. The reason some natural compounds inhibit cancer cell migration but not that of immune cells is probably because cancer cells rely on such abnormal signals for activity that their activity is more easily inhibited.
Table 9.3 summarizes the effects of natural compounds on cancer cell and immune cell migration. Inhibitors of immune cell migration are included because these compounds are also likely to inhibit cancer cell migration. Note that as with Table 9.1, the data in Table 9.3 are probably incomplete. Future studies will identify additional compounds that affect cell migration and likely show that most of these compounds inhibit migration in both cell types (with cancer cells generally being more sensitive).
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