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Blood, 1 June 2005, Vol. 105, No. 11, pp. 4463-4469.
Prepublished online as a Blood First Edition Paper on January 25, 2005; DOI 10.1182/blood-2004-09-3540.
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NEOPLASIA
Rapamycin induces tumor-specific thrombosis via tissue factor in the presence of VEGF
Markus Guba,
Maksim Yezhelyev,
Martin E. Eichhorn,
Gerald Schmid,
Ivan Ischenko,
Armine Papyan,
Christian Graeb,
Hendrik Seeliger,
Edward K. Geissler,
Karl-Walter Jauch, and
Christiane J. Bruns
From the Department of Surgery, Klinikum Grosshadern, Ludwig-Maximilians-University, Munich, Germany; Institute for Surgical Research, Klinikum Grosshadern, Ludwig-Maximilians-University, Munich, Germany; and the Department of Surgery, University of Regensburg, Regensburg, Germany.
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.
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