Montreal Children's Hospital, RI MUHC, McGill University, Montreal, H3Z 2Z3 Quebec, Canada.
J Biol Chem. 2012 Dec 21;287(52):43565-72. doi: 10.1074/jbc.M112.401760. Epub 2012 Nov 1.
Aggressive epithelial cancer cells frequently adopt mesenchymal characteristics and exhibit aberrant interactions with their surroundings, including the vasculature. Whether the release/uptake of extracellular vesicles (EVs) plays a role during these processes has not been studied. EVs are heterogeneous membrane structures that originate either at the surface (microparticles), or within (exosomes) activated or transformed cells, and are involved in intercellular trafficking of bioactive molecules. Here, we show that epithelial cancer cells (A431, DLD-1) adopt mesenchymal features (epithelial-to-mesenchymal transition-like state) upon activation of epidermal growth factor receptor (EGFR) coupled with blockade of E-cadherin. This treatment leads to a coordinated loss of EGFR and tissue factor (TF) from the plasma membrane and coincides with a surge in emission of small, exosome-like EVs containing both receptors. TF (but not EGFR) is selectively up-regulated in EVs produced by mesenchymal-like cancer cells and can be transferred to cultured endothelial cells rendering them highly procoagulant. We postulate that epithelial-to-mesenchymal transition-like changes may alter cancer cell interactions with the vascular systems through altered vesiculation and TF shedding.
侵袭性上皮癌细胞常采用间充质特征，并表现出与周围环境（包括脉管系统）异常的相互作用。在这些过程中，细胞外囊泡（EVs）的释放/摄取是否发挥作用尚未得到研究。EVs 是异质的膜结构，要么起源于激活或转化细胞的表面（微颗粒），要么起源于细胞内部（外泌体），并参与生物活性分子的细胞间运输。在这里，我们表明，上皮癌细胞（A431、DLD-1）在表皮生长因子受体（EGFR）被激活并阻断 E-钙黏蛋白时，会采用间充质特征（上皮-间质转化样状态）。这种治疗方法导致 EGFR 和组织因子（TF）从质膜协调丢失，同时伴随着小的、类似外泌体的 EVs 的大量发射，其中包含这两种受体。TF（而不是 EGFR）在由间充质样癌细胞产生的 EVs 中被选择性地上调，并可转移到培养的内皮细胞，使它们具有高度促凝性。我们推测，上皮-间质转化样变化可能通过改变囊泡形成和 TF 脱落来改变癌细胞与血管系统的相互作用。
