Université Laval, Centre Hospitalier Universitaire de QC (CHUQ), Hôpital St-François d'Assise, Unité des biomatériaux et biotechnologies.
Can J Physiol Pharmacol. 2009 Sep;87(9):694-701. doi: 10.1139/y09-063.
The expression of tissue factor (TF) in tumors reportedly exacerbates the aggressiveness of several types of cancers. The shedding of TF-containing membrane particles is believed to influence the ability of tumors to expand and metastasize, and these microparticles may also be harmful in the onset of disseminated intravascular coagulation in specific cancers. Furthermore, the intracellular signaling that is elicited after the formation of the TF / coagulation factor VIIa complex at the cell membrane modulates the activity of adhesion molecules and mitogen-activated protein (MAP) kinases. To evaluate whether TF overexpression in tumor cells modulates its shedding and neighboring stromal cells by its catalytic or intracellular activity, TF-GFP (green fluorescent protein) and a tailless form (TFDeltaC-GFP) were stably expressed in the rat Morris hepatoma and human HT1080 fibrosarcoma cell lines. Both TF proteins were efficiently produced by tumor cells and functionally active, and their clotting activity could be blocked by the active site-inhibited factor VIIa (ASIS). TF-expressing tumorigenic cells produced a soluble factor that increased the migration of arterial smooth muscle cells in vitro. This effect was abrogated by ASIS and the PAR-1 receptor antagonist ATAP-2, showing that it is dependent on the proteolytic activity of the TF ligand factor VIIa and the thrombin-activated cell membrane receptor. We propose that TF-containing microparticles that are released in the culture medium by tumor cells influence the migratory behavior of neighboring stromal cells, thus aiding the cancer cell's tumorigenic potential.
组织因子（TF）在肿瘤中的表达据称会加剧几种类型癌症的侵袭性。含有 TF 的膜颗粒的脱落被认为会影响肿瘤的扩张和转移能力，这些微粒在特定癌症中弥散性血管内凝血的发生中也可能是有害的。此外，在细胞膜上形成 TF/凝血因子 VIIa 复合物后引发的细胞内信号转导，调节着黏附分子和丝裂原激活蛋白（MAP）激酶的活性。为了评估肿瘤细胞中 TF 的过表达是否通过其催化或细胞内活性来调节其脱落和邻近的基质细胞，我们在大鼠 Morris 肝癌和人 HT1080 纤维肉瘤细胞系中稳定表达了 TF-GFP（绿色荧光蛋白）和无尾形式（TFDeltaC-GFP）。两种 TF 蛋白都被肿瘤细胞有效地产生并且具有功能活性，其凝血活性可以被活性位点抑制的因子 VIIa（ASIS）阻断。表达 TF 的肿瘤细胞产生了一种可溶性因子，可增加体外动脉平滑肌细胞的迁移。该效应被 ASIS 和 PAR-1 受体拮抗剂 ATAP-2 所阻断，表明它依赖于 TF 配体因子 VIIa 的蛋白水解活性和血栓酶激活的细胞膜受体。我们提出，肿瘤细胞在培养基中释放的含有 TF 的微粒会影响邻近基质细胞的迁移行为，从而有助于癌细胞的肿瘤形成潜力。
