Platelets and fibrin(ogen) increase metastatic potential by impeding natural killer cell–mediated elimination of tumor cells

Abstract

To test the hypothesis that platelet activation contributes to tumor dissemination, we studied metastasis in mice lacking G␣q, a G protein critical for platelet activation. Loss of platelet activation resulted in a profound diminution in both experimental and spontaneous metastases. IntroductionA persuasive body of evidence has accumulated associating hemostatic factors with tumor growth, stroma formation, and tumor dissemination. [1][2][3] Clinical studies have shown that expression of procoagulants by cancer cells is prognostic of poor outcome. [4][5][6] Furthermore, the expression of tissue factor by tumor cells has been shown to promote metastatic disease in experimental animals, 7 whereas inhibitors of thrombin and other coagulation factors diminished metastatic potential. 1,8 The available data support the general hypothesis that local thrombin generation enhances tumor dissemination. However, it is presently not clear which specific thrombin substrates are important mediators of the metastatic process. Recent studies revealed that fibrinogen deficiency significantly diminishes metastatic potential, suggesting that fibrinogen is at least one thrombin substrate important in metastasis. 9,10 However, it is likely that other thrombin substrates also contribute to tumor cell metastasis based on the finding that pharmacologic inhibition of thrombin resulted in decreased metastatic potential even in the absence of fibrinogen. 10 Several studies support the view that thrombin-mediated platelet activation may play a role in tumor biology. The elimination of circulating platelets with antiplatelet antibodies was shown to result in a significant diminution in metastases using several transplantable murine tumor models. 11,12 Competitive inhibition of the key platelet integrin, ␣ IIb ␤ 3 , either pharmacologically or with antibodies to ␤ 3 , also diminished metastatic potential. 13,14 Similarly, pharmacologic inhibitors of platelet activation have been shown to decrease the metastatic potential of circulating tumor cells. 15,16 More recently, the genetic loss of the integrin ␤ 3 subunit in mice was shown to diminish metastasis. 17 Platelets could influence metastatic potential via several mechanisms. Platelet granules contain a variety of cellular growth factors (eg, platelet-derived growth factor [PDGF], vascular endothelial growth factor [VEGF]), matrix proteins (eg, vitronectin, fibronectin), and inflammatory mediators (eg, platelet factor-4, interleukin-8, macrophage inflammatory protein 1␣ , RANTES [regulated on activation, normal T expressed, and secreted], CCL17, CCXL1, CXCL5) that might influence tumor cell behavior and stroma formation. [18][19][20] Platelets may also contribute to the physical interaction between circulating tumor cells and vascular endothelial cells by supporting the stable adhesion to endothelium and/or transmigration of tumor cells out of the vasculature. Local platelet activation could promote the migration of inflammatory cells, enhancing tumor stroma formation. Alternatively, tumor c...

Inhibition of pulmonary metastasis in a human MT3 breast cancer xenograft model by dual liposomes preventing intravasal fibrin clot formation

“…2b). Several studies showed that an impaired platelet aggregation or a reduced platelet number results in the reduction of metastasis [35]. Our data suggest a direct role of platelets in metastasis in the MT3 model, because the into the surrounding tissue [36].…”

“…It was shown before that the fibrin clots protect the tumor cells from natural killer cell attack [35]. So, the prevention of fibrin clot formation by the D/O-L might enable an easier access of immune cells to the tumor cells facilitating their elimination from the blood stream [35] that resulted in a reduced metastases formation.…”

Single-molecule binding of CD44 to fibrin versus P-selectin predicts their distinct shear-dependent interactions in cancer

“…It is believed that platelet-fibrin(ogen) clots surrounding tumor cells protect them from immunological and physiological stresses in the bloodstream, and facilitate their lodging to the pulmonary vasculature (Nieswandt et al, 1999). This hypothesis is corroborated by in vivo data, which disclose that in mice lacking functional natural killer (NK) cells, fibrin(ogen) deficiency was no longer a significant determinant of metastatic potential (Palumbo et al, 2005).…”

Colorectalis daganatokban a 2-es típusú cukorbetegség és a thrombocytosis előfordulása, a túlélésre gyakorolt hatásuk, a primer tumor műtéti eltávolítása előtt és után

“…Bár a metasztatikus tumorsejtek és a thrombocyták közös aggregátumképzése a keringés-ben több mint 150 éve ismert, a jelenség pontos molekuláris háttere máig tisztázatlan. Számos genetikai és modell állatokkal végzett vizsgálat alapján a keringésbe lépő tumorsejtek sejtfelszínén specifikus, a thrombocyták tumorsejthez való kapcsolódását segítő, azaz thrombocytaaggregációt indukáló fehérjék jelennek meg [2][3][4][5][6][7]. E mechanizmus hiányában a tumorsejtek kevesebb mint 1%-a élné csak túl a keringésben történő vándorlást [8,9].…”