Tissue factor-activated coagulation cascade in the tumor microenvironment is critical for tumor progression and an effective target for therapy. Academic Article uri icon

Overview

abstract

  • Tissue factor (TF), a rate-limiting enzyme cofactor in activating coagulation, is highly expressed in a wide spectrum of human tumor and tumor stromal cells. Using TF-deficient cancer cells and a conditional TF-knockout mouse model, we show that TF expressed by cancer cells, but not by the host stromal cells, plays a critical role in tumor growth. In the tumor microenvironment, serum coagulation factors are readily extravasated and therefore lead to continuous TF-mediated activation of coagulation proteases. To target this highly specific cascade of serine proteases, we used both a TF:VIIa inhibitor and doxorubicin-based prodrugs that are selectively activated by TF:FVIIa, FXa, and thrombin. Treatment with the TF:FVIIa inhibitor led to growth retardation in breast tumor models. In contrast, treatment with the prodrug eliminated primary tumor cells and lung metastases without apparent toxicity. Our findings offer preclinical proof of principle that targeting the coagulation cascade that is activated in the tumor microenvironment can be a highly effective approach for cancer therapy.

publication date

  • August 31, 2011

Research

keywords

  • Blood Coagulation
  • Molecular Targeted Therapy
  • Thromboplastin
  • Tumor Microenvironment

Identity

Scopus Document Identifier

  • 80054022353

Digital Object Identifier (DOI)

  • 10.1158/0008-5472.CAN-11-1145

PubMed ID

  • 21880589

Additional Document Info

volume

  • 71

issue

  • 20