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Identification and characterization of a very low density lipoprotein receptor-binding peptide from tissue factor
Todd A Hembrough1, Jose F Ruiz, Bonnie M Swerdlow
1EntreMed, Inc, 9640 Medical Center Dr, Rockville, MD 20850,USA. toddh@entremed.com
Abstract:
Tissue factor pathway inhibitor (TFPI) is the major physiologic inhibitor of the extrinsic coagulation pathway. We have previously shown that TFPI is also a potent inhibitor of endothelial proliferation in vitro and of primary and metastatic tumor growth in vivo. Surprisingly, the antitumor activity of TFPI was demonstrated to be independent of its anticoagulant activity, suggesting a possible nonhemostatic mechanism of action for TFPI in these models. This antitumor mechanism may involve the very low density lipoprotein (VLDL) receptor because the in vitro antiproliferative activity of TFPI is mediated through interaction with the VLDL receptor. In the current study, we identify a 23-amino acid fragment of TFPI (TFPIc23) localized to the C-terminus, which mediates binding to the VLDL receptor. The TFPIc23 peptide inhibits endothelial cell proliferation through an apoptotic mechanism and blocks vessel outgrowth in the in vitro assays, and this activity is mediated through interaction with the VLDL receptor. In vivo, this peptide potently inhibits angiogenesis in Matrigel and chick chorioallantoic membrane models and also inhibits metastatic tumor growth. Our data demonstrate that this VLDL receptor-binding fragment of the TFPI molecule has apoptotic, antiangiogenic, and antitumor activity and suggests a possible mechanism whereby TFPI can regulate angiogenesis and tumor growth independently of its anticoagulant activity.
Insights
A fragment of tissue factor pathway inhibitor (TFPI) binds to the VLDL receptor, inhibiting endothelial cell proliferation, angiogenesis, and tumor growth independently of its anticoagulant properties.
Area of Science:
- Biochemistry
- Molecular Biology
- Oncology
Background:
- Tissue factor pathway inhibitor (TFPI) is a key regulator of the extrinsic coagulation cascade.
- Previous studies indicated TFPI inhibits tumor growth and endothelial proliferation independent of its anticoagulant function.
- The very low density lipoprotein (VLDL) receptor was implicated in TFPI's antiproliferative effects.
Purpose of the Study:
- To identify the TFPI domain responsible for VLDL receptor interaction.
- To investigate the antiangiogenic and antitumor properties of this TFPI fragment.
- To elucidate the mechanism of TFPI's non-hemostatic antitumor activity.
Main Methods:
- Identification of a 23-amino acid C-terminal fragment of TFPI (TFPIc23) that binds the VLDL receptor.
- In vitro assays assessing endothelial cell proliferation and vessel outgrowth.
- In vivo studies using Matrigel and chick chorioallantoic membrane models for angiogenesis and tumor growth inhibition.
Main Results:
- TFPIc23 binds to the VLDL receptor and induces endothelial cell apoptosis.
- TFPIc23 effectively inhibits angiogenesis in vitro and in vivo.
- TFPIc23 demonstrates potent inhibition of metastatic tumor growth.
Conclusions:
- A TFPI-derived peptide (TFPIc23) mediates VLDL receptor binding and exhibits apoptotic, antiangiogenic, and antitumor effects.
- TFPI regulates angiogenesis and tumor growth through VLDL receptor interaction, independent of its anticoagulant activity.
- This TFPI fragment represents a potential therapeutic target for cancer treatment.
