Much available evidence indicates that cancer cells, fibrinogen and macrophages act cooperatively during metastasis. Heparin appears to disrupt that cooperation. As yet, there is no mechanistic understanding that adequately explains either the cooperation or its disruption by heparin. In this regard, we have made relevant discoveries. Following their intraperitoneal administration to a mouse, cell-size polymeric microspheres coated with fibrinogen disseminate, first to regional lymph nodes, then to other organs. Microspheres outside the abdomen are associated with macrophages, either within them or alongside them. Heparin prevents microsphere dissemination. In tissue culture, both fibrinogen-coated microspheres and fibrinogen-coated cancer cells form complexes with macrophages, and such complexes can move across a porous membrane in response to a chemotactic agent. Heparin both prevents complex formation and dissociates pre-existing complexes, thereby preventing translocation of particles/cancer cells. We will test the hypothesis that fibrinogen bound to either microspheres or cancer cells enables the extracellular transport of the particles/cells by macrophages. In vitro studies will involve exposing macrophages to fibrinogen-coated microspheres or to fibrinogen-coated cancer cells, and then monitoring and quantifying the macrophage-mediated extracellular transport of the microspheres/cancer cells. Agents will be identified that prevent macrophage-mediated extracellular transport in vitro by interfering with recognition of microsphere-/cancer cell-bound fibrinogen by macrophage fibrinogen receptors. Those agents and normal mice and fibrinogen """"""""knockout"""""""" mice will then be used in correlative studies designed to establish the fibrinogen dependence of microsphere/cancer cell dissemination in vivo. This research should lead to the development of new therapies that prevent/limit the metastasis of cancer cells. It should also lead to new ways to assess the metastatic potential of individual cancers.
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