Platelets and fibrin(ogen) increase metastatic potential by impeding natural killer cell-mediated elimination of tumor cells.
To test the hypothesis that platelet activation contributes to tumor dissemination, we studied metastasis in mice lacking Galphaq, a G protein critical for platelet activation. Loss of platelet activation resulted in a profound diminution in both experimental and spontaneous metastases. Analyses of the distribution of radiolabeled tumor cells demonstrated that platelet function, like fibrinogen, significantly improved the survival of circulating tumor cells in the pulmonary vasculature. More detailed studies showed that the increase in metastatic success conferred by either platelets or fibrinogen was linked to natural killer cell function. Specifically, the pronounced reduction in tumor cell survival observed in fibrinogen- and Galphaq-deficient mice relative to control animals was eliminated by the immunologic or genetic depletion of natural killer cells. These studies establish an important link between hemostatic factors and innate immunity and indicate that one mechanism by which the platelet-fibrin(ogen) axis contributes to metastatic potential is by impeding natural killer cell elimination of tumor cells.
Palumbo
Joseph S
JS
Division of Hematology/Oncology, Children's Hospital Research Foundation, and University of Cincinnati College of Medicine, Cincinnati, OH, USA.
Talmage
Kathryn E
KE
Massari
Jessica V
JV
La Jeunesse
Christine M
CM
Flick
Matthew J
MJ
Kombrinck
Keith W
KW
Jirousková
Markéta
M
Degen
Jay L
JL
D000818:Animals; D001792:Blood Platelets / Q000502:physiology*; D002470:Cell Survival; D005337:Fibrin / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D005340:Fibrinogen / Q000235:genetics / Q000378:metabolism*; D043802:GTP-Binding Protein alpha Subunits, Gq-G11 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D007694:Killer Cells, Natural / Q000276:immunology*; D008168:Lung / Q000378:metabolism / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D009362:Neoplasm Metastasis; D009369:Neoplasms / Q000235:genetics / Q000276:immunology* / Q000473:pathology*; D015539:Platelet Activation; D013927:Thrombosis / Q000235:genetics / Q000378:metabolism / Q000473:pathology
D005337:Fibrin; D005340:Fibrinogen; D043802:GTP-Binding Protein alpha Subunits, Gq-G11