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Published on: October 16, 2017
Rapamycin induces tumor-specific thrombosis via tissue factor in the presence of VEGF
Markus Guba1, Maksim Yezhelyev, Martin E Eichhorn
1Department of Surgery, Klinikum Grosshadern, Ludwig-Maximilians-University, Munich, Germany. markus.guba@.med.uni-muenchen.de
Abstract:
Therapeutic strategies that target and disrupt the already-formed vessel networks of growing tumors are actively pursued. The goal of these approaches is to induce a rapid shutdown of the vascular function of the tumor so that blood flow is arrested and tumor cell death occurs. Here we show that the mammalian target of rapamycin (mTOR) inhibitor rapamycin, when administered to tumor-bearing mice, selectively induced extensive local microthrombosis of the tumor microvasculature. Importantly, rapamycin administration had no detectable effect on the peritumoral or normal tissue. Intravital microscopy analysis of tumors implanted into skinfold chambers revealed that rapamycin led to a specific shutdown of initially patent tumor vessels. In human umbilical vein endothelial cells vascular endothelial growth factor (VEGF)-induced tissue factor expression was strongly enhanced by rapamycin. We further show by Western blot analysis that rapamycin interferes with a negative feedback mechanism controlling this pathologic VEGF-mediated tissue factor expression. This thrombogenic alteration of the endothelial cells was confirmed in a one-step coagulation assay. The circumstance that VEGF is up-regulated in most tumors may explain the remarkable selectivity of tumor vessel thrombosis under rapamycin therapy. Taken together, these data suggest that rapamycin, besides its known antiangiogenic properties, has a strong tumor-specific, antivascular effect in tumors.
Insights
Rapamycin, a mammalian target of rapamycin (mTOR) inhibitor, selectively causes blood clots in tumor blood vessels. This targeted vascular shutdown in tumors, without affecting normal tissues, offers a novel anti-cancer therapeutic strategy.
Area of Science:
- Oncology
- Vascular Biology
- Pharmacology
Background:
- Targeting established tumor vasculature is a key therapeutic strategy.
- Disrupting tumor blood flow aims to induce tumor cell death.
- Existing therapies often lack specificity for tumor vasculature.
Purpose of the Study:
- To investigate the effect of rapamycin on established tumor vasculature.
- To determine the selectivity of rapamycin's vascular effects in tumors.
- To elucidate the molecular mechanisms underlying rapamycin's antivascular activity.
Main Methods:
- Administration of rapamycin to tumor-bearing mice.
- Intravital microscopy of tumor microvasculature in skinfold chambers.
- Analysis of tissue factor expression in endothelial cells using Western blot.
- Coagulation assays to assess thrombogenic potential.
Main Results:
- Rapamycin selectively induced microthrombosis in tumor vasculature.
- No significant effects were observed in peritumoral or normal tissues.
- Rapamycin enhanced vascular endothelial growth factor (VEGF)-induced tissue factor expression.
- Interference with a negative feedback loop controlling VEGF-mediated tissue factor expression was identified.
Conclusions:
- Rapamycin exhibits a potent, tumor-specific antivascular effect by promoting thrombosis.
- This effect is mediated by enhancing pathological VEGF-induced tissue factor expression.
- Rapamycin's selectivity may stem from elevated VEGF levels in tumors.
- Beyond antiangiogenesis, rapamycin demonstrates significant tumoricidal potential via vascular disruption.
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