Ponert Jan Moritz, Schwarz Svenja, Haschemi Reza, Müller Jens, Pötzsch Bernd, Bendas Gerd, Schlesinger Martin
Department of Pharmacy, Rheinische Friedrich-Wilhelms-University Bonn, Bonn, Germany.
Institute for Experimental Hematology and Transfusion Medicine, University of Bonn Medical Centre, Bonn, Germany.
PLoS One. 2018 Jan 18;13(1):e0191303. doi: 10.1371/journal.pone.0191303. eCollection 2018.
Metastasis is responsible for the majority of cancer associated fatalities. Tumor cells leaving the primary tumor and entering the blood flow immediately interact with platelets. Activated platelets contribute in different ways to cancer cell survival and proliferation, e.g. in formation of the early metastatic niche by release of different growth factors and chemokines. Here we show that a direct interaction between platelets and MV3 melanoma or MCF7 breast cancer cells induces platelet activation and a VEGF release in citrated plasma that cannot be further elevated by the coagulation cascade and generated thrombin. In contrast, the release of platelet-derived chemokines CXCL5 and CXCL7 depends on both, a thrombin-mediated platelet activation and a direct interaction between tumor cells and platelets. Preincubation of platelets with therapeutic concentrations of unfractionated heparin reduces the tumor cell initiated VEGF release from platelets. In contrast, tumor cell induced CXCL5 and CXCL7 release from platelets was not impacted by heparin pretreatment in citrated plasma. In defibrinated, recalcified plasma, on the contrary, heparin is able to reduce CXCL5 and CXCL7 release from platelets by thrombin inhibition. Our data indicate that different chemokines and growth factors in diverse platelet granules are released in tightly regulated processes by various trigger mechanisms. We show for the first time that heparin is able to reduce the mediator release induced by different tumor cells both in a contact and coagulation dependent manner.
转移是大多数癌症相关死亡的原因。离开原发肿瘤并进入血流的肿瘤细胞会立即与血小板相互作用。活化的血小板以不同方式促进癌细胞的存活和增殖，例如通过释放不同的生长因子和趋化因子形成早期转移微环境。在此我们表明，血小板与MV3黑色素瘤细胞或MCF7乳腺癌细胞之间的直接相互作用会诱导血小板活化，并在枸橼酸盐血浆中释放血管内皮生长因子（VEGF），而凝血级联反应和生成的凝血酶无法进一步提高其水平。相反，血小板衍生趋化因子CXCL5和CXCL7的释放既依赖于凝血酶介导的血小板活化，也依赖于肿瘤细胞与血小板之间的直接相互作用。用治疗浓度的普通肝素对血小板进行预孵育可减少肿瘤细胞引发的血小板VEGF释放。相比之下，在枸橼酸盐血浆中，肝素预处理不会影响肿瘤细胞诱导的血小板CXCL5和CXCL7释放。相反，在去纤维蛋白、重新钙化的血浆中，肝素能够通过抑制凝血酶来减少血小板CXCL5和CXCL7的释放。我们的数据表明，不同血小板颗粒中的不同趋化因子和生长因子通过各种触发机制在严格调控的过程中释放。我们首次表明，肝素能够以接触依赖和凝血依赖的方式减少不同肿瘤细胞诱导的介质释放。
