Role of nk cells in the antimetastatic effect of anticoagulant drugs

Abstract

The antimetastatic effects of heparin (40 units) and prostacyclin (PGI2, 100 microgram)1 were investigated in normal mice and in mice with depressed or activated natural killer (NK) cell activity. Both anticoagulants inhibited the formation of lung metastases after inoculation of the FI or F10 sublines of B16 melanoma. Inhibition of NK activity by treatment of mice with anti-asialo GM1 serum abrogated the antimetastatic effects of PGI2 or heparin. Conversely, augmentation of NK-cell activity by poly I:C plus treatment with anticoagulants produced synergistic antimetastatic effects. A similar pattern of results was obtained with heparin treatment of mice challenged with the Madison lung carcinoma (M109), but PGI2 alone or in combination with theophylline had little or no detectable antimetastatic effect on M109 or on the parental B16 melanoma. Studies of the mechanism of the interaction between heparin nd NK cells revealed that the anticoagulant treatment did not affect splenic NK activity in vitro. However, heparin treatment caused a significant increase in the clearance of radiolabelled tumor cells from the lungs of normal mice. Combined treatment of mice with poly I:C and heparin synergistically accelerated the elimination of radiolabelled tumor cells. In contrast, heparin did not affect the clearance of tumor cells from the lungs of mice with depressed NK activity. Thus the antimetastatic effects of heparin and PGI2 are dependent on levels of NK activity in the host. Platelet aggregation and fibrin coating of the surface of tumor cells may be among the mechanisms by which hematogenously spread tumor cells are protected from destruction by NK cells. Anticoagulant drugs may exert antimetastatic effects by making tumor cells more vulnerable to the cytotoxic effects of NK cells, rather than by blocking adherence of tumor cells to vascular endothelium.

Tissue Factor Induced by Epithelial–Mesenchymal Transition Triggers a Procoagulant State That Drives Metastasis of Circulating Tumor Cells

“…This network could protect CTCs against hostile signals including shear stress, modifications of cell-cell and cell-matrix interactions, or immune cells, and would promote their metastatic potential. A mechanism involving a protective role of fibrin and/or platelets in NK-induced cytotoxicity against tumor cells has, for instance, been demonstrated in vitro and using NK-deficient mice in experimental metastasis assays by Degen and colleagues (21,(44)(45)(46)(47)(48). On the other hand, NK-independent processes have also been evidenced (21), one of which implicates the recruitment of monocytes/macrophages in microthrombi favoring the establishment of so-called premetastatic niches (49).…”

Platelet-Derived MHC Class I Confers a Pseudonormal Phenotype to Cancer Cells That Subverts the Antitumor Reactivity of Natural Killer Immune Cells

“…Anticoagulant drugs also attenuated metastasis in the same model. About 15 years later Gorelik and colleagues reported that interfering with the hemostatic system prevents metastasis by a NK cell-dependent mechanism (33). Although fibrinogen and factor XIII, components of the plasmatic coagulation system, were found to reduce NK cell reactivity (13,15), the available data point to a more prominent role of platelets for inhibiting NK cell reactivity in metastasis (8).…”

GITR Ligand Provided by Thrombopoietic Cells Inhibits NK Cell Antitumor Activity

“…The latter may promote tumor cell survival, as metastasis is effectively inhibited in the absence of platelets (8)(9)(10). Interestingly, concomitant depletion of platelets and NK cells reverts the antimetastatic phenotype of thrombocytopenic mice (11)(12)(13)(14)(15)(16). It has thus been proposed that platelets may protect tumor cells from NK-dependent antitumor immunity during their passage from the primary tumor to a metastatic site.…”