Direct endothelial junction restoration results in significant tumor vascular normalization and metastasis inhibition in mice
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Vijayendra Agrawal1, Sony Maharjan1, Kyeojin Kim2, Nam-Jung Kim3, Jimin Son1, Keunho Lee1, Hyun-Jung Choi1, Seung-Sik Rho1, Sunjoo Ahn4, Moo-Ho Won5, Sang-Jun Ha1, Gou Young Koh6, Young-Myeong Kim7, Young-Ger Suh2 and Young-Guen Kwon1
1 Department of Biochemistry, College of Life Science and Biotechnology, Yonsei University, Seoul 120-749, Republic of Korea,
2 College of Pharmacy, Seoul National University, 599 Gwanak-ro, Gwanak-gu, Seoul 151-742, Republic of Korea,
3 Department of Pharmacy, College of Pharmacy, Kyung Hee University, Seoul 130-701, Republic of Korea,
4 Korea Research Institute of Chemical Technology (KRICT), 141 Gajeong-ro, Yuseong-gu, Daejeon 305-343, Republic of Korea,
5 Department of Neurobiology, School of Medicine, Kangwon National University, Chuncheon 200-701, Republic of Korea,
6 National Research Laboratory of Vascular Biology and Stem Cells, Korea Advanced Institute of Science and Technology (KAIST), Daejeon 305-701, Republic of Korea,
7 Vascular System Research Center, Kangwon National University, Kangwon-Do, Republic of Korea.
Young-Guen Kwon, email:
Keywords: Vascular permeability, Hypoxia, Normalization, Epithelial-to-mesenchymal transition, Sac-1004
Received: April 18, 2014 Accepted: April 30, 2014 Published: May 2, 2014
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.
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