Direct endothelial junction restoration results in significant tumor vascular normalization and metastasis inhibition in mice

Vijayendra Agrawal, Sony Maharjan, Kyeojin Kim, Nam Jung Kim, Jimin Son, Keunho Lee, Hyun Jung Choi, Seung Sik Rho, Sunjoo Ahn, Moo Ho Won, Sang Jun Ha, Gou Young Koh, Young Myeong Kim, Young Ger Suh, Young Guen Kwon

Research output: Contribution to journalArticle

25 Citations (Scopus)

Abstract

Tumor blood vessels are leaky and immature, which causes inadequate blood supply to tumor tissues resulting in hypoxic microenvironment and promotes metastasis. Here we have explored tumor vessel modulating activity of Sac-1004, a recently developed molecule in our lab, which directly potentiates VE-cadherin-mediated endothelial cell junction. Sac-1004 could enhance vascular junction integrity in tumor vessels and thereby inhibit vascular leakage and enhance vascular perfusion. Improved perfusion enabled Sac-1004 to have synergistic anti-tumor effect on cisplatin-mediated apoptosis of tumor cells. Interestingly, characteristics of normalized blood vessels namely reduced hypoxia, improved pericyte coverage and decreased basement membrane thickness were readily observed in tumors treated with Sac-1004. Remarkably, Sac-1004 was also able to inhibit lung and lymph node metastasis in MMTV and B16BL6 tumor models. This was in correlation with a reduction in epithelial-to-mesenchymal transition of tumor cells with considerable diminution in expression of related transcription factors. Moreover, cancer stem cell population dropped substantially in Sac-1004 treated tumor tissues. Taken together, our results showed that direct restoration of vascular junction could be a significant strategy to induce normalization of tumor blood vessels and reduce metastasis.

Original languageEnglish
Pages (from-to)2761-2777
Number of pages17
JournalOncotarget
Volume5
Issue number9
DOIs
Publication statusPublished - 2014

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Blood Vessels
Neoplasm Metastasis
Neoplasms
Vascular Tissue Neoplasms
Perfusion
Pericytes
Epithelial-Mesenchymal Transition
Intercellular Junctions
Neoplastic Stem Cells
Basement Membrane
Cisplatin
Sac-1004
Transcription Factors
Endothelial Cells
Lymph Nodes
Apoptosis
Lung
Population

All Science Journal Classification (ASJC) codes

  • Oncology

Cite this

Agrawal, Vijayendra ; Maharjan, Sony ; Kim, Kyeojin ; Kim, Nam Jung ; Son, Jimin ; Lee, Keunho ; Choi, Hyun Jung ; Rho, Seung Sik ; Ahn, Sunjoo ; Won, Moo Ho ; Ha, Sang Jun ; Koh, Gou Young ; Kim, Young Myeong ; Suh, Young Ger ; Kwon, Young Guen. / Direct endothelial junction restoration results in significant tumor vascular normalization and metastasis inhibition in mice. In: Oncotarget. 2014 ; Vol. 5, No. 9. pp. 2761-2777.
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abstract = "Tumor blood vessels are leaky and immature, which causes inadequate blood supply to tumor tissues resulting in hypoxic microenvironment and promotes metastasis. Here we have explored tumor vessel modulating activity of Sac-1004, a recently developed molecule in our lab, which directly potentiates VE-cadherin-mediated endothelial cell junction. Sac-1004 could enhance vascular junction integrity in tumor vessels and thereby inhibit vascular leakage and enhance vascular perfusion. Improved perfusion enabled Sac-1004 to have synergistic anti-tumor effect on cisplatin-mediated apoptosis of tumor cells. Interestingly, characteristics of normalized blood vessels namely reduced hypoxia, improved pericyte coverage and decreased basement membrane thickness were readily observed in tumors treated with Sac-1004. Remarkably, Sac-1004 was also able to inhibit lung and lymph node metastasis in MMTV and B16BL6 tumor models. This was in correlation with a reduction in epithelial-to-mesenchymal transition of tumor cells with considerable diminution in expression of related transcription factors. Moreover, cancer stem cell population dropped substantially in Sac-1004 treated tumor tissues. Taken together, our results showed that direct restoration of vascular junction could be a significant strategy to induce normalization of tumor blood vessels and reduce metastasis.",
author = "Vijayendra Agrawal and Sony Maharjan and Kyeojin Kim and Kim, {Nam Jung} and Jimin Son and Keunho Lee and Choi, {Hyun Jung} and Rho, {Seung Sik} and Sunjoo Ahn and Won, {Moo Ho} and Ha, {Sang Jun} and Koh, {Gou Young} and Kim, {Young Myeong} and Suh, {Young Ger} and Kwon, {Young Guen}",
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Agrawal, V, Maharjan, S, Kim, K, Kim, NJ, Son, J, Lee, K, Choi, HJ, Rho, SS, Ahn, S, Won, MH, Ha, SJ, Koh, GY, Kim, YM, Suh, YG & Kwon, YG 2014, 'Direct endothelial junction restoration results in significant tumor vascular normalization and metastasis inhibition in mice', Oncotarget, vol. 5, no. 9, pp. 2761-2777. https://doi.org/10.18632/oncotarget.1942

Direct endothelial junction restoration results in significant tumor vascular normalization and metastasis inhibition in mice. / Agrawal, Vijayendra; Maharjan, Sony; Kim, Kyeojin; Kim, Nam Jung; Son, Jimin; Lee, Keunho; Choi, Hyun Jung; Rho, Seung Sik; Ahn, Sunjoo; Won, Moo Ho; Ha, Sang Jun; Koh, Gou Young; Kim, Young Myeong; Suh, Young Ger; Kwon, Young Guen.

In: Oncotarget, Vol. 5, No. 9, 2014, p. 2761-2777.

Research output: Contribution to journalArticle

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AU - Agrawal, Vijayendra

AU - Maharjan, Sony

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AU - Son, Jimin

AU - Lee, Keunho

AU - Choi, Hyun Jung

AU - Rho, Seung Sik

AU - Ahn, Sunjoo

AU - Won, Moo Ho

AU - Ha, Sang Jun

AU - Koh, Gou Young

AU - Kim, Young Myeong

AU - Suh, Young Ger

AU - Kwon, Young Guen

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