Platelet Endothelial Interaction in Tumor Angiogenesis

The microvascular architecture of tumors has been studied in different experimental tumors. However, platelets in tumor microcirculation have rarely been described. Ultrastructural studies on different melanomas of the hamster revealed that platelets were attached to the microvascular endothelium only occasionally at sites of tumor invasion into the microvasculature [8]. In vivo observations of platelets in tumor microvessels were initially described in the amelanotic melanoma (A-Mel-3) implanted into the dorsal skinfold chamber of hamsters using intravital microscopy and intravenous application of fluorescence marker for platelets. When tumor necrosis became obvious, masses slowing down blood flow and partly occluding tumor blood vessels were detected. This phenomenon was interpreted as platelet aggregation and vascular thrombosis [5]. However, extensive ultrastructural studies on the microvasculature of the amelanotic melanoma revealed infrequent contact of platelets to the microvascular endothelium even at sites of endothelial leakage and erythrocyte a-granules

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Figure 1 Platelet adherence to the intact endothelial surface. (Left) Mechanisms of platelet rolling. (Right) Platelet adherence and aggregation on the endothelial surface. GP, glycoprotein; PSGL-1, P-selectin glycoprotein ligand-1; vWF, von Willebrand factor; WPB, Weibel-Palade body.

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Figure 1 Platelet adherence to the intact endothelial surface. (Left) Mechanisms of platelet rolling. (Right) Platelet adherence and aggregation on the endothelial surface. GP, glycoprotein; PSGL-1, P-selectin glycoprotein ligand-1; vWF, von Willebrand factor; WPB, Weibel-Palade body.

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Figure 2 Platelet interactions on the subendothelial matrix. (Left) Initial platelet rolling on immobilized vWF induces activation of glycoprotein (GP) Ib/IX/V and GP IIb/IIIa. (Right) Adherence on the subendothelial matrix and aggregation of platelets is mediated by glycoproteins and adhesion proteins. SEM, subendothelial matrix.

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Figure 2 Platelet interactions on the subendothelial matrix. (Left) Initial platelet rolling on immobilized vWF induces activation of glycoprotein (GP) Ib/IX/V and GP IIb/IIIa. (Right) Adherence on the subendothelial matrix and aggregation of platelets is mediated by glycoproteins and adhesion proteins. SEM, subendothelial matrix.

extravasation. Tumor microvessels were regularly composed of endothelial and tumor cells forming the vessel lumen [4].

We have studied platelet-endothelial interactions in angiogenesis and growth of Lewis lung carcinoma (LLC-1) and methylcholanthrene-induced fibrosarcoma (BFS-1). The study was carried out using the dorsal skinfold chamber on mice and intravital fluorescence microscopy. Ex vivo flu-orescently labeled syngenic platelets were transfused into experimental animals. Both tumors developed a typical heterogeneous tumor microcirculation. In contrast to the amelanotic melanoma of hamsters, tissue necrosis did not appear in LLC-1 carcinoma and BFS-1 fibrosarcoma within 14 days after tumor cell implantation into the dorsal skinfold chamber. Platelet-endothelial interaction was rarely observed in tumor microvessels. No differences in platelet-endothelial interactions were seen in tumor microvessels compared to subcutaneous venules in tumorfree tissue (Figure 3).

Under physiologic conditions, low interactions between platelets and endothelial cells have been described in different organ systems that might be due to weak platelet agonist (ADP, epinephrine, serotonin). We found equivalent baseline platelet-endothelial interactions in subcutaneous venules of tumor-free tissue. In the early phase of tumor growth, platelet rolling was slightly enhanced in angiogenic microvessels in close vicinity to implanted tumor cells. The angiogenic microvessels appeared as dilated and highly permeable microvessels due to growth factors and inflammatory cytokines.

Since tumor microcirculation was supposed to present a highly prothrombotic environment, we would have expected more significant platelet-endothelial interactions in tumor angiogenesis and tumor microcirculation. However, the compromised hemodynamics within the tumor microvascu-

12 1

Day after tumor cell implantation

Figure 3 Platelet-endothelial interaction is not an intense phenomenon during tumor angiogenesis. Platelet rolling was increased on day 1 in preexisting microvessels of the host in response to both LLC-1 (gray bars) and BFS-1 (hatched bars) and also on day 3 in LLC-1 tumor microvessels, but was only slightly above the low baseline level quantified in postcapillary venules of controls (open bars). n = 6 experimental animals per group, *p < 0.05 versus controls; #p < 0.05 versus day 1 and day 3 (Kruskal-Wallis test).

lature was not associated with activation or aggregation of platelets. Our results were confirmed by a study indicating that radioactively labeled fibrinogen accumulates in Lewis-lung carcinoma; however, the study failed to detect accumulation of radioactively labeled platelets within the same tumor. Furthermore, electron microscopy showed single platelets adhering to endothelial gaps in tumor microvessels only occasionally.

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