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.
Highlights
Tumor angiogenesis features leaky, dilated, saccular, and tortuous blood vessels; the extent and type of abnormality varies with tumor type and location [1,2,3]
Since vascular hyperpermeability is a long recognized hallmark of tumors [19], we evaluated the effect of Sac-1004 on vascular leakage in vivo
VEGF is one of the prominent molecules responsible for leakiness of tumor vessels [20,21,22]; we initially investigated the effect of Sac-1004 in retinas of VEGF-treated and diabetic mice [23, 24]
Summary
Tumor angiogenesis features leaky, dilated, saccular, and tortuous blood vessels; the extent and type of abnormality varies with tumor type and location [1,2,3]. Leaky blood vessels result in hemorrhage that increases interstitial fluid pressure and limits vascular perfusion, leading to a hypoxic and acidotic microenvironment [1, 3, 4] In this microenvironment, cancer, endothelial, and stromal cells secrete various growth factors (e.g., vascular endothelial growth factor [VEGF], angiopoietin [Ang]2, platelet derived growth www.impactjournals.com/oncotarget factor (PDGF), placental growth factor, transforming growth factor (TGF)-alpha, and hepatocyte growth factor), establishing an endless loop of non-productive angiogenesis [2, 3]. It was suggested that anti-angiogenic therapy, to some extent, corrects the flaw in structure and function of tumor blood vessels This normalization of vessels decreases leakiness and improves perfusion resulting in enhanced delivery and efficacy of cytotoxic agents [7,8,9]. The effects of direct potentiation of endothelial junction on tumor vascular normalization and metastasis has not been clearly demonstrated
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