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

Oncotarget. 2014 May 15;5(9):2761-77. doi: 10.18632/oncotarget.1942.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antigens, CD / genetics
  • Antigens, CD / metabolism*
  • Apoptosis / drug effects
  • Blotting, Western
  • Cadherins / genetics
  • Cadherins / metabolism*
  • Carcinoma, Lewis Lung / blood supply
  • Carcinoma, Lewis Lung / metabolism
  • Carcinoma, Lewis Lung / pathology
  • Carcinoma, Lewis Lung / prevention & control*
  • Cell Movement / drug effects
  • Cell Proliferation / drug effects
  • Diabetic Retinopathy / metabolism
  • Diabetic Retinopathy / pathology
  • Diabetic Retinopathy / prevention & control
  • Endothelium, Vascular / drug effects*
  • Endothelium, Vascular / metabolism
  • Endothelium, Vascular / pathology
  • Epithelial-Mesenchymal Transition / drug effects
  • HeLa Cells
  • Humans
  • Immunoenzyme Techniques
  • Lung Neoplasms / blood supply
  • Lung Neoplasms / metabolism
  • Lung Neoplasms / prevention & control*
  • Lung Neoplasms / secondary
  • Lymphatic Metastasis
  • MCF-7 Cells
  • Male
  • Melanoma, Experimental / blood supply
  • Melanoma, Experimental / metabolism
  • Melanoma, Experimental / pathology
  • Melanoma, Experimental / prevention & control*
  • Mice
  • Mice, Inbred C57BL
  • Neovascularization, Pathologic / metabolism
  • Neovascularization, Pathologic / pathology
  • Neovascularization, Pathologic / prevention & control*
  • RNA, Messenger / genetics
  • Real-Time Polymerase Chain Reaction
  • Reverse Transcriptase Polymerase Chain Reaction
  • Saponins / pharmacology*
  • Tumor Cells, Cultured
  • Xenograft Model Antitumor Assays

Substances

  • Antigens, CD
  • Cadherins
  • RNA, Messenger
  • Sac-1004
  • Saponins
  • cadherin 5