Mojiri Anahita, Stoletov Konstantin, Carrillo Maria Areli Lorenzana, Willetts Lian, Jain Saket, Godbout Roseline, Jurasz Paul, Sergi Consolato M, Eisenstat David D, Lewis John D, Jahroudi Nadia
Department of Medicine, University of Alberta, Edmonton, Alberta, Canada.
Department of Oncology, University of Alberta, Edmonton, Alberta, Canada.
Oncotarget. 2017 Feb 21;8(8):13015-13029. doi: 10.18632/oncotarget.14273.
Von Willebrand factor (VWF) is a highly adhesive procoagulant molecule that mediates platelet adhesion to endothelial and subendothelial surfaces. Normally it is expressed exclusively in endothelial cells (ECs) and megakaryocytes. However, a few studies have reported VWF detection in cancer cells of non-endothelial origin, including osteosarcoma. A role for VWF in cancer metastasis has long been postulated but evidence supporting both pro- and anti-metastatic roles for VWF has been presented. We hypothesized that the role of VWF in cancer metastasis is influenced by its cellular origin and that cancer cell acquisition of VWF expression may contribute to enhanced metastatic potential. We demonstrated de novo expression of VWF in glioma as well as osteosarcoma cells. Endothelial monolayer adhesion, transmigration and extravasation capacities of VWF expressing cancer cells were shown to be enhanced compared to non-VWF expressing cells, and were significantly reduced as a result of VWF knock down. VWF expressing cancer cells were also detected in patient tumor samples of varying histologies. Analyses of the mechanism of transcriptional activation of the VWF in cancer cells demonstrated a pattern of trans-activating factor binding and epigenetic modifications consistent overall with that observed in ECs. These results demonstrate that cancer cells of non-endothelial origin can acquire de novo expression of VWF, which can enhance processes, including endothelial and platelet adhesion and extravasation, that contribute to cancer metastasis.
血管性血友病因子（VWF）是一种高度黏附的促凝血分子，可介导血小板黏附于内皮和内皮下表面。正常情况下，它仅在内皮细胞（ECs）和巨核细胞中表达。然而，一些研究报道在包括骨肉瘤在内的非内皮来源的癌细胞中检测到了VWF。长期以来，人们一直推测VWF在癌症转移中发挥作用，但也有证据支持VWF具有促转移和抗转移的作用。我们假设VWF在癌症转移中的作用受其细胞来源的影响，癌细胞获得VWF表达可能有助于增强转移潜能。我们证明了VWF在胶质瘤以及骨肉瘤细胞中从头表达。与不表达VWF的细胞相比，表达VWF的癌细胞的内皮单层黏附、迁移和外渗能力增强，并且由于VWF敲低而显著降低。在不同组织学类型的患者肿瘤样本中也检测到了表达VWF的癌细胞。对癌细胞中VWF转录激活机制的分析表明，反式激活因子结合和表观遗传修饰模式总体上与在ECs中观察到的一致。这些结果表明，非内皮来源的癌细胞可以从头获得VWF表达，这可以增强包括内皮和血小板黏附及外渗在内的、有助于癌症转移的过程。
