Guba, M. and Yezhelyev, M. and Eichhorn, M. E. and Schmid, G. and Ischenko, I. and Papyan, A. and Graeb, C. and Seeliger, H. and Geissler, Edward K. and Jauch, K. W. and Bruns, C. J. (2005) Rapamycin induces tumor-specific thrombosis via tissue factor in the presence of VEGF. BLOOD, 105 (11). pp. 4463-4469. ISSN 0006-4971,
Full text not available from this repository. (Request a copy)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.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | ENDOTHELIAL GROWTH-FACTOR; VESSEL THROMBOSIS; FACTOR EXPRESSION; CANCER-THERAPY; IN-VIVO; SIROLIMUS; CELLS; TRANSPLANTATION; MICROANGIOPATHY; PATHWAY; |
| Subjects: | 600 Technology > 610 Medical sciences Medicine |
| Divisions: | Medicine > Lehrstuhl für Chirurgie |
| Depositing User: | Dr. Gernot Deinzer |
| Date Deposited: | 10 May 2021 11:41 |
| Last Modified: | 10 May 2021 11:41 |
| URI: | https://pred.uni-regensburg.de/id/eprint/36027 |
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