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Blocking Angiopoietin-2 Promotes Vascular Damage and Growth Inhibition in Mouse Tumors Treated with Small Doses of Radiation

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  • معلومة اضافية
    • Contributors:
      CAN-PRO - Translational Cancer Medicine Program; University of Helsinki; Digital Precision Cancer Medicine (iCAN); Research Programs Unit; HUSLAB; Kari Alitalo / Principal Investigator
    • بيانات النشر:
      American Association for Cancer Research (AACR), 2020.
    • الموضوع:
      2020
    • نبذة مختصرة :
      Abnormal vasculature in tumors leads to poor tissue perfusion and cytostatic drug delivery. Although drugs inducing vascular normalization, for example, angiopoietin-2 (Ang2)-blocking antibodies, have shown promising results in preclinical tumor models, clinical studies have so far shown only little efficacy. Because Ang2 is known to play a protective role in stressed endothelial cells, we tested here whether Ang2 blocking could enhance radiation-induced tumor vascular damage. Tumor-bearing mice were treated with anti-Ang2 antibodies every 3 or 4 days starting 3 days before 3 × 2 Gy or 4 × 0.5 Gy whole-body or tumor-focused radiation. Combination treatment with anti-Ang2 and radiation improved tumor growth inhibition and extended the survival of mice with melanoma or colorectal tumors. Single-cell RNA-sequencing revealed that Ang2 blocking rescued radiation-induced decreases in T cells and cells of the monocyte/macrophage lineage. In addition, anti-Ang2 enhanced radiation-induced apoptosis in cultured endothelial cells. In vivo, combination treatment decreased tumor vasculature and increased tumor necrosis in comparison with tumors treated with monotherapies. These results suggest that a combination of Ang2-blocking antibodies with radiation increases tumor growth inhibition and extends the survival of tumor-bearing mice. Significance: These findings offer a preclinical rationale for further testing of the use of radiation in combination with Ang2-blocking antibodies to improve the overall outcome of cancer treatment.
    • ISSN:
      1538-7445
      0008-5472
    • الرقم المعرف:
      10.1158/0008-5472.can-20-0497
    • Rights:
      OPEN
    • الرقم المعرف:
      edsair.doi.dedup.....f55baabe99f85a4981b9d42513e6b7b6