Inactivation of the serine protease HTRA1 inhibits tumor growth by deregulating angiogenesis
| Autor: | Andreas Fischer, Eva-Maria Weis, M Gordian Adam, Fabian Tetzlaff, Joycelyn Wüstehube-Lausch, Ralph Klose, Chio Oka, Michael Ehrmann, Iris Moll |
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| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Cancer Research JAG1 Angiogenesis Melanoma Experimental Notch signaling pathway Protein degradation Biology Mural cell Mice 03 medical and health sciences Cell Movement Cell Line Tumor Neoplasms Human Umbilical Vein Endothelial Cells Genetics Animals Humans Molecular Biology Cells Cultured Cell Proliferation Sprouting angiogenesis Tube formation Neovascularization Pathologic Receptors Notch Intracellular Signaling Peptides and Proteins Membrane Proteins High-Temperature Requirement A Serine Peptidase 1 Vascular Endothelial Growth Factor Receptor-2 eye diseases Cell biology Mice Inbred C57BL 030104 developmental biology Tumor progression Biologie Jagged-1 Protein Signal Transduction |
| Zdroj: | Oncogene. 37:4260-4272 |
| ISSN: | 1476-5594 0950-9232 |
| DOI: | 10.1038/s41388-018-0258-4 |
| Popis: | The serine protease HTRA1 is involved in several vascular diseases and its expression is often deregulated in cancer. We aimed at identifying how HTRA1 in the vasculature affects tumor growth. Here we report that silencing of HTRA1 in cultured endothelial cells increased migration rate and tube formation, whereas forced HTRA1 expression impaired sprouting angiogenesis. Mechanistically, endothelial HTRA1 expression enhanced Delta/Notch signaling by reducing the amount of the weak Notch ligand JAG1. HTRA1 physically interacted with JAG1 and cleaved it within the intracellular domain, leading to protein degradation. Expression of a constitutive active Notch1 prevented the hypersprouting phenotype upon silencing of HTRA1. In HtrA1-deficient mice, endothelial Notch signaling was diminished and isolated endothelial cells had increased expression of VEGF receptor-2. Growth of syngeneic tumors was strongly impaired in HtrA1-/- mice. The tumor vasculature was much denser in HtrA1-/- mice and less covered with mural cells. This chaotic and immature vascular network was poorly functional as indicated by large hypoxic tumor areas and low tumor cell proliferation rates. In summary, inhibition of HTRA1 in the tumor stroma impaired tumor progression by deregulating angiogenesis. |
| Databáze: | OpenAIRE |
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