Role of Natural Killer Cells in Control of Cancer Metastasis

There is a close association between levels of natural killer (NK) cell activity and the ability of the host to eliminate circulating tumor cell emboli. Mice that exhibit low levels of NK-cell-mediated cytotoxicity (3-week-old syngeneic mice, 3-week-old allogeneic nude mice, cyclophosphamide- or beta-estradiol-treated mice, and beige mice) also exhibit enhanced survival of tumor cells in the vascular bed of the lung and increased incidence of pulmonary tumor metastasis. Conversely, hosts with high NK cell activity (adult nude mice and syngeneic mice treated with NK-cell-stimulating biological response modifiers (BRM) ) are very resistant to metastasis. Lymphoid adoptive transfer studies have shown that the effector cell responsible for the antimetastatic activity is the NK cell. In these studies, NK cells were highly effective in destroying circulating tumor cells before their extravasation into the organ parenchyma, whereas they exerted only a minimal inhibiting effect on already established micrometastases. The ability to activate NK cells selectively (without subsequently inducing suppressor macrophages) provides a valuable tool for the evaluation of the role of activated NK cells in therapy of tumor metastasis. The validity of this approach is supported by the finding that NK cells activated by BRM are effective in killing, both in vivo and in vitro, solid tumor cells that developed NK-cell-resistance as a result of adaptive growth in vivo or selection during the metastatic process. An understanding of the mechanisms that regulate NK cell activation or suppression as well as elucidation of the circulatory patterns and anatomical compartmentalization of activated NK cells will help achieve a sustained systemic and/or in situ activation of NK cells which may prove effective in the control of cancer metastasis.