Thrombin-Activated Platelets Protect Vascular Endothelium against Tumor Cell Extravasation by Targeting Endothelial VCAM-1

Abstract

When activated by thrombin, the platelets release their granular store of factors. These thrombin-activated platelets (TAPLT) have been shown to be capable of ameliorating pro-inflammatory processes. In this study, we tested if TAPLT could also protect the endothelium against tumor-related pro-inflammatory changes that promote angiogenesis and metastasis. Using endothelial cell (EC) models in vitro, we demonstrated that TAPLT protected EC against tumor conditioned medium (TCM)-induced increases of reactive oxygen species (ROS) production, EC permeability and angiogenesis, and inhibited transendothelial migration that was critical for cancer cell extravasation and metastasis. In vivo observations of TAPLT-mediated inhibition of angiogenesis and pulmonary colonization in a BALB/c nude mouse model were consistent with the in vitro findings. Neutralization of vascular cell adhesion molecule-1 (VCAM-1) binding significantly inhibited the ability of TAPLT to interact with EC and abrogated the TAPLT-mediated protection of EC against tumor angiogenesis and metastasis. Taken together, these findings suggest that VCAM-1-mediated linkage to EC is required for TAPLT to confer protection of EC against tumor-induced permeation and angiogenesis, thereby resisting tumor extravasation and metastasis.

Subacute Coronary Stent Thrombosis as the Initial Presentation of Acute Myeloid Leukemia: A Case Report and Literature Review

“… 8 In addition, interactions between circulating blasts, platelets, and the vascular endothelium may have enhanced local thrombin generation and platelet activation at the stent surface. 9 The combination of systemic inflammation, leukemia-associated procoagulant activity, and endothelial disruption from stent implantation created a highly thrombogenic environment, predisposing to rapid stent occlusion despite standard antiplatelet therapy. 10 …”

Subacute Coronary Stent Thrombosis as the Initial Presentation of Acute Myeloid Leukemia: A Case Report and Literature Review

“… 8 In addition, interactions between circulating blasts, platelets, and the vascular endothelium may have enhanced local thrombin generation and platelet activation at the stent surface. 9 The combination of systemic inflammation, leukemia-associated procoagulant activity, and endothelial disruption from stent implantation created a highly thrombogenic environment, predisposing to rapid stent occlusion despite standard antiplatelet therapy. 10 …”

Liver Metastasis in Cancer: Molecular Mechanisms and Management

“…Activated platelets also release ATP, which binds to P2Y 2 receptors on LSECs, modulating their cytoskeleton and endothelial junctions [214]. However, some studies suggest that thrombin‐activated platelets protect LSECs from tumor‐derived damage by forming tight junctions mediated by VCAM‐1, thereby inhibiting metastatic tumor cell extravasation [215].…”

The Duality of Collagens in Metastases of Solid Tumors

“…Evidence for the role of integrins, cadherins, and selectins in vitro has been demonstrated [ 291 ]. For cancer cell adhesion to the vessel walls, adhesion molecule expression, including immunoglobulin superfamily member gene 3 [ 379 ], CD44 [ 380 ], MUC1 [ 381 ], CD146 [ 382 ], platelet endothelial cell adhesion molecule-1 [ 383 ], or VCAM (vascular cell adhesion molecule)-1 [ 384 ] has been upregulated. Osteonectin has been demonstrated to promote extravasation in melanoma cells, upregulating VCAM-1 [ 385 ].…”

Subacute Coronary Stent Thrombosis as the Initial Presentation of Acute Myeloid Leukemia: A Case Report and Literature Review

“… 8 In addition, interactions between circulating blasts, platelets, and the vascular endothelium may have enhanced local thrombin generation and platelet activation at the stent surface. 9 The combination of systemic inflammation, leukemia-associated procoagulant activity, and endothelial disruption from stent implantation created a highly thrombogenic environment, predisposing to rapid stent occlusion despite standard antiplatelet therapy. 10 …”

Liver Metastasis in Cancer: Molecular Mechanisms and Management

“…Activated platelets also release ATP, which binds to P2Y 2 receptors on LSECs, modulating their cytoskeleton and endothelial junctions [214]. However, some studies suggest that thrombin‐activated platelets protect LSECs from tumor‐derived damage by forming tight junctions mediated by VCAM‐1, thereby inhibiting metastatic tumor cell extravasation [215].…”

The Duality of Collagens in Metastases of Solid Tumors

“…Evidence for the role of integrins, cadherins, and selectins in vitro has been demonstrated [ 291 ]. For cancer cell adhesion to the vessel walls, adhesion molecule expression, including immunoglobulin superfamily member gene 3 [ 379 ], CD44 [ 380 ], MUC1 [ 381 ], CD146 [ 382 ], platelet endothelial cell adhesion molecule-1 [ 383 ], or VCAM (vascular cell adhesion molecule)-1 [ 384 ] has been upregulated. Osteonectin has been demonstrated to promote extravasation in melanoma cells, upregulating VCAM-1 [ 385 ].…”

Subacute Coronary Stent Thrombosis as the Initial Presentation of Acute Myeloid Leukemia: A Case Report and Literature Review

“… 8 In addition, interactions between circulating blasts, platelets, and the vascular endothelium may have enhanced local thrombin generation and platelet activation at the stent surface. 9 The combination of systemic inflammation, leukemia-associated procoagulant activity, and endothelial disruption from stent implantation created a highly thrombogenic environment, predisposing to rapid stent occlusion despite standard antiplatelet therapy. 10 …”

Liver Metastasis in Cancer: Molecular Mechanisms and Management

“…Activated platelets also release ATP, which binds to P2Y 2 receptors on LSECs, modulating their cytoskeleton and endothelial junctions [214]. However, some studies suggest that thrombin‐activated platelets protect LSECs from tumor‐derived damage by forming tight junctions mediated by VCAM‐1, thereby inhibiting metastatic tumor cell extravasation [215].…”

The Duality of Collagens in Metastases of Solid Tumors

“…Evidence for the role of integrins, cadherins, and selectins in vitro has been demonstrated [ 291 ]. For cancer cell adhesion to the vessel walls, adhesion molecule expression, including immunoglobulin superfamily member gene 3 [ 379 ], CD44 [ 380 ], MUC1 [ 381 ], CD146 [ 382 ], platelet endothelial cell adhesion molecule-1 [ 383 ], or VCAM (vascular cell adhesion molecule)-1 [ 384 ] has been upregulated. Osteonectin has been demonstrated to promote extravasation in melanoma cells, upregulating VCAM-1 [ 385 ].…”