Tumor-Specific Silencing of Tissue Factor Suppresses Metastasis and Prevents Cancer-Associated Hypercoagulability

Shaoli Liu, Yinlong Zhang, Xiao Zhao, Jing Wang, Chunzhi Di, Ying Zhao, Tianjiao Ji, Keman Cheng, Yongwei Wang, Long Chen, Yingqiu Qi, Suping Li, Guangjun Nie

Research output: Contribution to journalArticle

13 Scopus citations

Abstract

Within tumors, the coagulation-inducing protein tissue factor (TF), a major initiator of blood coagulation, has been shown to play a critical role in the hematogenous metastasis of tumors, due to its effects on tumor hypercoagulability and on the mediation of interactions between platelets and tumor cells. Targeting tumor-associated TF has therefore great therapeutic potential for antimetastasis therapy and preventing thrombotic complication in cancer patients. Herein, we reported a novel peptide-based nanoparticle that targets delivery and release of small interfering RNA (siRNA) into the tumor site to silence the expression of tumor-associated TF. We showed that suppression of TF expression in tumor cells blocks platelet adhesion surrounding tumor cells in vitro. The downregulation of TF expression in intravenously administered tumor cells (i.e., simulated circulating tumor cells [CTCs]) prevented platelet adhesion around CTCs and decreased CTCs survival in the lung. In a breast cancer mouse model, siRNA-containing nanoparticles efficiently attenuated TF expression in the tumor microenvironment and remarkably reduced the amount of lung metastases in both an experimental lung metastasis model and tumor-bearing mice. What's more, this strategy reversed the hypercoagulable state of the tumor bearing mice by decreasing the generation of thrombin-antithrombin complexes (TAT) and activated platelets, both of which are downstream products of TF. Our study describes a promising approach to combat metastasis and prevent cancer-associated thrombosis, which advances TF as a therapeutic target toward clinic applications.

Original languageEnglish (US)
Pages (from-to)4721-4730
Number of pages10
JournalNano Letters
Volume19
Issue number7
DOIs
StatePublished - Jul 10 2019

Keywords

  • peptide self-assembled nanoparticle
  • siRNA
  • tissue factor
  • tumor hypercoagulability
  • tumor metastasis

ASJC Scopus subject areas

  • Bioengineering
  • Chemistry(all)
  • Materials Science(all)
  • Condensed Matter Physics
  • Mechanical Engineering

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