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A double hit to kill tumor and endothelial cells by TRAIL and antiangiogenic 3TSR.

Publication ,  Journal Article
Ren, B; Song, K; Parangi, S; Jin, T; Ye, M; Humphreys, R; Duquette, M; Zhang, X; Benhaga, N; Lawler, J; Khosravi-Far, R
Published in: Cancer Res
May 1, 2009

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.

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Published In

Cancer Res

DOI

EISSN

1538-7445

Publication Date

May 1, 2009

Volume

69

Issue

9

Start / End Page

3856 / 3865

Location

United States

Related Subject Headings

  • Xenograft Model Antitumor Assays
  • Thrombospondins
  • TNF-Related Apoptosis-Inducing Ligand
  • Recombinant Proteins
  • Receptors, TNF-Related Apoptosis-Inducing Ligand
  • Peptide Fragments
  • Oncology & Carcinogenesis
  • Neovascularization, Pathologic
  • Mice, Nude
  • Mice
 

Citation

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Chicago
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MLA
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Ren, B., Song, K., Parangi, S., Jin, T., Ye, M., Humphreys, R., … Khosravi-Far, R. (2009). A double hit to kill tumor and endothelial cells by TRAIL and antiangiogenic 3TSR. Cancer Res, 69(9), 3856–3865. https://doi.org/10.1158/0008-5472.CAN-08-2940
Ren, Bin, Keli Song, Sareh Parangi, Taiguang Jin, Min Ye, Robin Humphreys, Mark Duquette, et al. “A double hit to kill tumor and endothelial cells by TRAIL and antiangiogenic 3TSR.Cancer Res 69, no. 9 (May 1, 2009): 3856–65. https://doi.org/10.1158/0008-5472.CAN-08-2940.
Ren B, Song K, Parangi S, Jin T, Ye M, Humphreys R, et al. A double hit to kill tumor and endothelial cells by TRAIL and antiangiogenic 3TSR. Cancer Res. 2009 May 1;69(9):3856–65.
Ren, Bin, et al. “A double hit to kill tumor and endothelial cells by TRAIL and antiangiogenic 3TSR.Cancer Res, vol. 69, no. 9, May 2009, pp. 3856–65. Pubmed, doi:10.1158/0008-5472.CAN-08-2940.
Ren B, Song K, Parangi S, Jin T, Ye M, Humphreys R, Duquette M, Zhang X, Benhaga N, Lawler J, Khosravi-Far R. A double hit to kill tumor and endothelial cells by TRAIL and antiangiogenic 3TSR. Cancer Res. 2009 May 1;69(9):3856–3865.

Published In

Cancer Res

DOI

EISSN

1538-7445

Publication Date

May 1, 2009

Volume

69

Issue

9

Start / End Page

3856 / 3865

Location

United States

Related Subject Headings

  • Xenograft Model Antitumor Assays
  • Thrombospondins
  • TNF-Related Apoptosis-Inducing Ligand
  • Recombinant Proteins
  • Receptors, TNF-Related Apoptosis-Inducing Ligand
  • Peptide Fragments
  • Oncology & Carcinogenesis
  • Neovascularization, Pathologic
  • Mice, Nude
  • Mice