Inhibition of Platelet GPIbα and Promotion of Melanoma Metastasis
Inhibition of Platelet GPIbα and Promotion of Melanoma Metastasis
复制标题
DOI：
10.1038/jid.2009.278
复制
发表时间：
2010-02-01
影响因子：
6.5
通讯作者：
Schoen, Michael P.
中科院分区：
文献类型：
--
作者：
Erpenbeck, Luise;Nieswandt, Bernhard;Schoen, Michael P.
血小板糖蛋白Iba（GPIb α）是受体复合物GPIb-V-IX的一部分，其在止血中具有关键作用，尤其是通过与内皮下血管性血友病因子相互作用。随着血小板受体对血行性肿瘤转移的贡献的证据越来越多，GPIba是在此背景下研究的有趣分子。我们研究了GPIba抑制单价Fab片段对实验性肺转移的影响，在同基因小鼠模型中使用C57 BL/6小鼠和B16 F10黑色素瘤细胞。还评估了GPIba阻断下绿色荧光蛋白（GFP）转染的黑素瘤细胞的早期命运，以及GPIba抑制对缺乏P-选择素的小鼠肺转移的影响。令人惊讶的是，据我们以前未报道的知识，GPIba抑制导致肺转移的显著增加，并且对循环GFP标记的B16 F10的早期命运的评估显示GPIba抑制后不久肿瘤细胞的存活率和肺停滞改善，表明血小板蛋白的抑制在某些情况下可以促进恶性肿瘤的转移。与此相反，GPIba阻断在P-选择素缺陷的小鼠转移没有增强作用，表明GPIba参与的初始，P-选择素依赖的转移步骤。这些发现表明GPIba除了在止血中的作用外，还有助于控制肿瘤转移。
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.