Montreal Children's Hospital, Research Institute of McGill University Health Centre, McGill University, Montreal, QC, Canada H3Z 2Z3.
Proc Natl Acad Sci U S A. 2014 Mar 4;111(9):3544-9. doi: 10.1073/pnas.1314118111. Epub 2014 Feb 11.
The coagulation system links immediate (hemostatic) and late (inflammatory, angiogenic) tissue responses to injury, a continuum that often is subverted in cancer. Here we provide evidence that tumor dormancy is influenced by tissue factor (TF), the cancer cell-associated initiator of the coagulation system and a signaling receptor. Thus, indolent human glioma cells deficient for TF remain viable but permanently dormant at the injection site for nearly a year, whereas the expression of TF leads to a step-wise transition to latent and overt tumor growth phases, a process that is preceded by recruitment of vascular (CD105(+)) and myeloid (CD11b(+) and F4/80(+)) cells. Importantly, the microenvironment orchestrated by TF expression drives permanent changes in the phenotype, gene-expression profile, DNA copy number, and DNA methylation state of the tumor cells that escape from dormancy. We postulate that procoagulant events in the tissue microenvironment (niche) may affect the fate of occult tumor cells, including their biological and genetic progression to initiate a full-blown malignancy.
凝血系统将即时（止血）和晚期（炎症、血管生成）组织对损伤的反应联系起来，这是一个连续的过程，而在癌症中经常被颠覆。在这里，我们提供的证据表明，组织因子（TF）影响肿瘤休眠，TF 是凝血系统的癌症细胞相关启动子，也是信号受体。因此，缺乏 TF 的惰性人类神经胶质瘤细胞仍然具有活力，但在注射部位几乎一年都处于永久休眠状态，而 TF 的表达导致潜伏和显性肿瘤生长阶段的逐步过渡，这一过程之前是血管（CD105(+)）和髓样（CD11b(+)和 F4/80(+)）细胞的募集。重要的是，TF 表达协调的微环境驱动从休眠中逃脱的肿瘤细胞表型、基因表达谱、DNA 拷贝数和 DNA 甲基化状态的永久性变化。我们假设组织微环境（生态位）中的促凝事件可能会影响隐匿性肿瘤细胞的命运，包括它们向完全恶性转化的生物学和遗传进展。
