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

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.

Sac-1004, a vascular leakage blocker, reduces cerebral ischemia—reperfusion injury by suppressing blood–brain barrier disruption and inflammation

“…The Sac-1004-mediated restoration of these proteins can be an important step to preserve an intact brain region from ischemic damage. Endothelial junction stability by Sac-1004 would have caused enhanced pericyte recruitment, and this efficiently resulted in increased vascular normalization, as suggested in our previous report on tumor vessels [31]. It was supported by CD31 immunoreactivity pattern that morphology of abnormal vessels after I/R injury were normalized by Sac-1004 treatment.…”

“…In addition, Sac-1004 has been shown to block vascular leakage in some conditions including diabetes and cancer [29–31]. In this study, we examined the protective effects of Sac-1004 on BBB disruption using an in vitro BBB model and a rat model of focal cerebral ischemia, which are known to be suitable for evaluating neuroprotective agents and studying the mechanisms of neuroprotective effects [32].…”

Erlotinib-Conjugated Iron Oxide Nanoparticles as a Smart Cancer-Targeted Theranostic Probe for MRI

“…Mice body weights were monitored using digital scale, and tumor dimensions were measured using digital caliper. Tumor volumes were calculated using the formula [Tumor volume = 0.523 × Length × Width 2 ]53.…”

Autophagy in cellular metabolism and cancer

“…During the progression of solid tumors, an increase in tumor size produces stress on cells within central regions, as these areas become hypoxic and nutrient deficient due to inadequate blood supply (94). Even as angiogenesis occurs, regions within solid tumors may still experience metabolic stress as a result of low glucose and glutamine availability (95)(96)(97), due to the leakiness of tumor-associated vessels as well as continued hypovascularization (98). Under such conditions, tumor cells can use autophagy to provide an alternative energy source for survival and proliferation (99,100).…”