title: Rapamycin induces tumor-specific thrombosis via tissue factor in the presence of VEGF.
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.
authors.affiliation: Department of Surgery, Klinikum Grosshadern, Ludwig-Maximilians-University, Munich, Germany. markus.guba@.med.uni-muenchen.de
authors.forename: Markus
authors.initials: M
authors.lastname: Guba
authors.forename: Maksim
authors.initials: M
authors.lastname: Yezhelyev
authors.forename: Martin E
authors.initials: ME
authors.lastname: Eichhorn
authors.forename: Gerald
authors.initials: G
authors.lastname: Schmid
authors.forename: Ivan
authors.initials: I
authors.lastname: Ischenko
authors.forename: Armine
authors.initials: A
authors.lastname: Papyan
authors.forename: Christian
authors.initials: C
authors.lastname: Graeb
authors.forename: Hendrik
authors.initials: H
authors.lastname: Seeliger
authors.forename: Edward K
authors.initials: EK
authors.lastname: Geissler
authors.forename: Karl-Walter
authors.initials: KW
authors.lastname: Jauch
authors.forename: Christiane J
authors.initials: CJ
authors.lastname: Bruns
mesh_terms: D020533:Angiogenesis Inhibitors / Q000008:administration & dosage / Q000494:pharmacology; D000818:Animals; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects; D025461:Feedback, Physiological / Q000187:drug effects; D006801:Humans; D051379:Mice; D008833:Microcirculation / Q000473:pathology; D018715:Microscopy, Video; D009368:Neoplasm Transplantation; D009369:Neoplasms / Q000098:blood supply* / Q000188:drug therapy*; D020123:Sirolimus / Q000008:administration & dosage / Q000494:pharmacology*; D013925:Thromboplastin; D013927:Thrombosis / Q000139:chemically induced*; D042461:Vascular Endothelial Growth Factor A
chemical_list: D020533:Angiogenesis Inhibitors; D042461:Vascular Endothelial Growth Factor A; D013925:Thromboplastin; D020123:Sirolimus