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Inactivation of the serine protease HTRA1 inhibits tumor growth by deregulating angiogenesis

Oncogene volume 37, pages 4260–4272 (2018)Cite this article

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Abstract

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.

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Acknowledgements

We thank the members of these DKFZ core facilities for excellent support: Genomics and Proteomics, Imaging and Flow Cytometry, and Center for Preclinical Research. We also thank the core facility for Mass Spectrometry and Proteomics of the ZMBH Heidelberg.

Funding

This work was supported by the Fritz-Thyssen Foundation (10.13.1.160), the Deutsche Forschungsgemeinschaft (SFB-TR23, project A7), the Deutsche Krebshilfe (110638), and the Helmholtz Society to AF.

Author contributions

RK, MGA, E-MW, IM, JW-L, FT, and AF conceived and designed the experiments and analyzed the data; CO and ME provided essential reagents and discussed the data; RK and AF wrote the manuscript.

Author information

Author notes

  1. M. Gordian Adam

    Present address: Metanomics Health GmbH, Berlin, Germany

  2. Joycelyn Wüstehube-Lausch

    Present address: BioNTech AG, Mainz, Germany

Authors and Affiliations

  1. Division Vascular Signaling and Cancer (A270), German Cancer Research Center, Heidelberg, 69120, Germany

    Ralph Klose, M. Gordian Adam, Eva-Maria Weis, Iris Moll, Joycelyn Wüstehube-Lausch, Fabian Tetzlaff & Andreas Fischer

  2. European Center for Angioscience, Medical Faculty Mannheim, Heidelberg University, Mannheim, 68167, Germany

    Joycelyn Wüstehube-Lausch & Andreas Fischer

  3. Laboratory of Gene Function in Animals, Nara Institute of Science and Technology, 8916-5 Takayama, Ikoma, Nara, 630-0192, Japan

    Chio Oka

  4. Centre of Medical Biotechnology, Faculty of Biology, University Duisburg-Essen, Essen, 45117, Germany

    Michael Ehrmann

  5. Medical Clinic I, Endocrinology and Clinical Chemistry, Heidelberg University Hospital, Heidelberg, 69120, Germany

    Andreas Fischer

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Correspondence to Andreas Fischer.

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Klose, R., Adam, M.G., Weis, EM. et al. Inactivation of the serine protease HTRA1 inhibits tumor growth by deregulating angiogenesis. Oncogene 37, 4260–4272 (2018). https://doi.org/10.1038/s41388-018-0258-4

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