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Updated: Jun 24, 2026
Dual Bioluminescence Imaging of Tumor Progression and Angiogenesis
Published on: August 1, 2019
A double hit to kill tumor and endothelial cells by TRAIL and antiangiogenic 3TSR
Bin Ren1, Keli Song, Sareh Parangi
1Department of Pathology, Division of Cancer Biology and Angiogenesis, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA.
Abstract:
As tumor development relies on a coordination of angiogenesis and tumor growth, an efficient antitumor strategy should target both the tumor and its associated vessels. Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) induces apoptosis in a tumor-selective manner. Additionally, thrombospondin-1, a naturally occurring inhibitor of angiogenesis, and a recombinant protein containing functional domains of thrombospondin-1, 3TSR, have been shown to be necessary and sufficient to inhibit tumor angiogenesis. Here, we show that a combination of a TRAIL receptor 2 agonist antibody, Lexatumumab, and 3TSR results in a significantly enhanced and durable tumor inhibition. We further observed that 3TSR induces apoptosis in primary endothelial cells by up-regulating the expression of TRAIL receptors 1 and 2 in a CD36 and Jun NH(2)-terminal kinase-dependent manner leading to the activation of both intrinsic and extrinsic apoptotic machineries. The modulation of these pathways is critical for 3TSR-induced apoptosis as disrupting either via specific inhibitors reduced apoptosis. Moreover, 3TSR attenuates the Akt survival pathway. These studies indicate that 3TSR plays a critical role in regulating the proapoptotic signaling pathways that control growth and death in endothelial cells and that a combination of TRAIL and 3TSR acts as a double hit against tumor and tumor-associated vessels.
Insights
Combining a TRAIL receptor 2 agonist antibody (Lexatumumab) with 3TSR, an angiogenesis inhibitor, significantly enhances tumor inhibition. This dual approach targets both tumor cells and their associated vasculature for improved antitumor effects.
Area of Science:
- Oncology
- Molecular Biology
- Vascular Biology
Background:
- Tumor growth and angiogenesis are critical for cancer progression.
- Targeting both tumor cells and tumor vasculature is a key antitumor strategy.
- Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) induces tumor-selective apoptosis.
- Thrombospondin-1 (TSP-1) and its functional domain (3TSR) inhibit angiogenesis.
Purpose of the Study:
- To evaluate the combined efficacy of Lexatumumab (TRAIL-R2 agonist) and 3TSR against tumors.
- To elucidate the proapoptotic mechanisms of 3TSR in endothelial cells.
Main Methods:
- Combination therapy using Lexatumumab and 3TSR in preclinical models.
- Assessment of tumor growth inhibition and durability.
- Analysis of endothelial cell apoptosis induction by 3TSR.
- Investigation of TRAIL receptor expression, CD36, Jun NH(2)-terminal kinase (JNK), and Akt pathways.
Main Results:
- The combination of Lexatumumab and 3TSR demonstrated significantly enhanced and durable tumor inhibition.
- 3TSR induced apoptosis in primary endothelial cells.
- 3TSR up-regulated TRAIL receptors 1 and 2 in a CD36 and JNK-dependent manner.
- 3TSR activated both intrinsic and extrinsic apoptotic pathways while attenuating the Akt survival pathway.
Conclusions:
- The combination of TRAIL-R2 agonism and 3TSR provides a synergistic antitumor effect.
- 3TSR is a critical regulator of endothelial cell apoptosis via modulation of TRAIL receptors and apoptotic signaling.
- This dual-targeting strategy offers a potent approach against tumors and their associated vasculature.
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