Inhibition of Platelet GPIbα and Promotion of Melanoma Metastasis

Platelet glycoprotein Iba (GPIb alpha) is part of the receptor complex GPIb-V-IX, which has a critical role in hemostasis, especially through interactions with the subendothelial von Willebrand factor. As there is accumulating evidence for a contribution of platelet receptors to hematogenous tumor metastasis, GPIba is an interesting molecule to study in this context. We have investigated the effect of GPIba inhibition by monovalent Fab fragments on experimental pulmonary metastasis in a syngeneic mouse model using C57BL/6 mice and B16F10 melanoma cells. The early fate of green fluorescent protein (GFP)-transfected melanoma cells under GPIba blockade was also assessed, as was the effect of GPIba inhibition on pulmonary metastasis in mice lacking P-selectin. Surprisingly and, to our knowledge previously unreported, GPIba inhibition led to a significant increase in pulmonary metastasis, and assessment of the early fate of circulating GFP-labeled B16F10 showed improved survival and pulmonary arrest of tumor cells shortly after GPIba inhibition, indicating that inhibition of a platelet protein can, in some cases, promote metastasis of a malignant tumor. In contrast, GPIba blockade in P-selectin-deficient mice had no enhancing effect on metastasis, suggesting the involvement of GPIba in the initial, P-selectin-dependent steps of metastasis. These findings suggest that GPIba contributes to the control of tumor metastasis, in addition to its role in hemostasis.