2. Academic Validation
  3. Endothelial Tie1-mediated angiogenesis and vascular abnormalization promote tumor progression and metastasis

Endothelial Tie1-mediated angiogenesis and vascular abnormalization promote tumor progression and metastasis

  • J Clin Invest. 2018 Feb 1;128(2):834-845. doi: 10.1172/JCI94674.
Silvia La Porta 1 2,  Lise Roth 1 2,  Mahak Singhal 1 2,  Carolin Mogler 1 3,  Carleen Spegg 1,  Benjamin Schieb 1 2,  Xianghu Qu 4 5,  Ralf H Adams 6 7,  H Scott Baldwin 4 5,  Soniya Savant 1,  Hellmut G Augustin 1 2 8
Affiliations

Affiliations

  • 1 Division of Vascular Oncology and Metastasis, German Cancer Research Center (DKFZ-ZMBH Alliance), Heidelberg, Germany.
  • 2 Department of Vascular Biology and Tumor Angiogenesis (CBTM), Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.
  • 3 Institute of Pathology, Technical University Munich, Munich, Germany.
  • 4 Department of Pediatrics, Division of Cardiology, and.
  • 5 Department of Cell and Developmental Biology, Vanderbilt University School of Medicine, Nashville, Tennessee, USA.
  • 6 Department of Tissue Morphogenesis, Max Planck Institute for Molecular Biomedicine, Münster, Germany.
  • 7 Faculty of Medicine, University of Münster, Münster, Germany.
  • 8 German Cancer Consortium (DKTK), Heidelberg, Germany.
PMID: 29355844 DOI: 10.1172/JCI94674
Abstract

The endothelial tyrosine kinase receptor Tie1 remains poorly characterized, largely owing to its Orphan Receptor status. Global Tie1 inactivation causes late embryonic lethality, thereby reflecting its importance during development. Tie1 also plays pivotal roles during pathologies such as atherosclerosis and tumorigenesis. In order to study the contribution of Tie1 to tumor progression and metastasis, we conditionally deleted Tie1 in endothelial cells at different stages of tumor growth and metastatic dissemination. Tie1 deletion during primary tumor growth in mice led to a decrease in microvessel density and an increase in mural cell coverage with improved vessel perfusion. Reduced angiogenesis and enhanced vascular normalization resulted in a progressive increase of intratumoral necrosis that caused a growth delay only at later stages of tumor progression. Concomitantly, surgical removal of the primary tumor decreased the number of circulating tumor cells, reduced metastasis, and prolonged overall survival. Additionally, Tie1 deletion in experimental murine metastasis models prevented extravasation of tumor cells into the lungs and reduced metastatic foci. Taken together, the data support Tie1 as a therapeutic target by defining its regulatory functions during angiogenesis and vascular abnormalization and identifying its role during metastasis.

Keywords

Angiogenesis; Cancer; Oncology; endothelial cells.

Figures