Platelet glycoprotein Ibα supports experimental lung metastasis

Abstract

The platelet paradigm in hemostasis and thrombosis involves an initiation step that depends on platelet membrane receptors binding to ligands on a damaged or inflamed vascular surface. Once bound to the surface, platelets provide a unique microenvironment supporting the accumulation of more platelets and the elaboration of a fibrin-rich network produced by coagulation factors. The platelet-specific receptor glycoprotein (GP) Ib-IX, is critical in this process and initiates the formation of a platelet-rich thrombus by tethering the platelet to a thrombogenic surface. A role for platelets beyond the hemostasis/thrombosis paradigm is emerging with significant platelet contributions in both tumorigenesis and inflammation. We have established congenic (N10) mouse colonies (C57BL/6J) with dysfunctional GP Ib-IX receptors in our laboratory that allow us an opportunity to examine the relevance of platelet GP Ib-IX in syngeneic mouse models of experimental metastasis. Our results demonstrate platelet GP Ib-IX contributes to experimental metastasis because a functional absence of GP Ib-IX correlates with a 15-fold reduction in the number of lung metastatic foci using B16F10.1 melanoma cells. The results demonstrate that the extracellular domain of the ␣-subunit of GP Ib is the structurally relevant component of the GP Ib-IX complex contributing to metastasis. Our results support the hypothesis that platelet GP Ib-IX functions that support normal hemostasis or pathologic thrombosis also contribute to tumor malignancy.adhesion ͉ tumor ͉ hemostasis ͉ knockout ͉ melanoma C irculating blood platelets have an inherent adhesive potential long recognized as essential for hemostasis and thrombosis. Beyond the platelet paradigm for blood clotting and thrombosis, it is becoming apparent that the platelet's adhesive potential influences pathological events outside its role in hemostasis. Indeed, emerging hypotheses suggest the platelet paradigm in hemostasis and thrombosis, an accumulation of platelets and the elaboration of a fibrin matrix, may provide a mechanism for circulating tumor cells to metastasize. Experimental proof that platelets effect tumor metastasis was provided in models where an experimental lowering of circulating platelet counts reduced metastasis (1-3).Evidence suggests that carcinoma cells entering the circulation interact with both platelets and leukocytes to form tumor cell aggregates (1, 4). Data have suggested one mechanism linking the platelet to metastasis is a platelet ''cloak'' surrounding the tumor cell and protecting the tumor cell from immune surveillance (5, 6). Tumorigenesis has been linked to several molecules essential for blood coagulation and normal platelet function. These include thrombin, tissue factor, platelet P-selectin, fibrinogen, and lysophosphatidic acid (3,4,(7)(8)(9)(10)(11)(12)(13)(14)(15)(16). Together, these results suggest that platelets and their procoagulant activity support tumor metastasis, possibly by aiding tumor cells to lodge in the microvasculature and either extravasate...

Engagement of αIIbβ3 (GPIIb/IIIa) with ανβ3 Integrin Mediates Interaction of Melanoma Cells with Platelets

“…Adherent platelets present potent adhesion receptors such as JAM-C, P-Selectin, GPIb␣, or GPIIb/IIIa to other circulating cells providing a platform for a potent cellular bridging mechanism to the vascular wall (20,25,(52)(53)(54)(55)(56). Recently, glycoprotein Ib␣ (GPIb␣), the second most abundant receptor expressed on platelets, has been reported to be significantly involved in melanoma metastasis, as the functional absence of GPIb␣ correlated with a clear reduction in the number of lung metastatic foci in vivo (57). In contrast, another report showed that GPIb␣ inhibition led to a significant increase in pulmonary metastasis, improved survival, and pulmonary arrest of tumor cells (58), presumably reflecting the complexity of tumor cellplatelet-endothelial interactions and manifesting the need for continued experimental studies.…”

Multi-omics Analysis of Serum Samples Demonstrates Reprogramming of Organ Functions Via Systemic Calcium Mobilization and Platelet Activation in Metastatic Melanoma

“…The identified molecules may not only serve as disease markers, but are evidently eminent contributors to disease progression. To give examples, GP1BA and 12S-HETE are known as powerful tumor promoters (47,61). Most importantly, the altered platelet functions may be considered as surrogate markers for manifest systemic reprogramming of distant organ sites in metastatic melanoma, mainly resulting from calcium mobilization.…”

EphB4 Promotes Site-Specific Metastatic Tumor Cell Dissemination by Interacting with Endothelial Cell–Expressed EphrinB2

“…Tumor cell lodging and subsequent adhesion to endothelial cells may be one of the most rate-limiting steps of the metastatic cascade (41,42). Different mechanisms have previously been implicated in the adhesion of tumor cells to endothelial cells including the involvement of E-selectin and P-selectin, the binding to coagulation factors like fibrin or tissue factor as well as a contribution of platelets (43)(44)(45)(46). Likewise, several lung endothelial cell-expressed molecules have been implicated in lung-specific metastasis.…”