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EMBO Mol Med. 2019 Aug;11(8):e9266. doi: 10.15252/emmm.201809266. Epub 2019 Jun 24.

Apelin inhibition prevents resistance and metastasis associated with anti-angiogenic therapy.

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Institute of Molecular Biotechnology of the Austrian Academy of Sciences (IMBA), Vienna BioCenter, Vienna, Austria.
Department of Microbiology, Tumor and Cell Biology, Biomedicum, Karolinska Institutet, Stockholm, Sweden.
Medicine and Pharmacy Research Center, Binzhou Medical University, Yantai, Shandong Province, China.
VBCF Histopathology, Vienna BioCenter, Vienna, Austria.
VBCF Preclinical Imaging, Vienna BioCenter, Vienna, Austria.
Department of Tumor Biology, National Koranyi Institute of Pulmonology, Budapest, Hungary.
Division of Thoracic Surgery, Department of Surgery, Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria.
Division of Molecular and Gender Imaging, Department of Biomedical Imaging and Image-guided Therapy, Medical University of Vienna, Vienna, Austria.
Department of Molecular Genetics, Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, University of Toronto, Toronto, ON, Canada.
Institute of Molecular Pathology (IMP), Vienna BioCenter, Vienna, Austria.
Department of Urology, Semmelweis University, Budapest, Hungary.
Department Biochemistry and Metabolic Science, Akita University Graduate School of Medicine, Akita, Japan.
Department of Thoracic Surgery, National Institute of Oncology-Semmelweis University, Budapest, Hungary.
Department of Internal Medicine III (Cardiology and Angiology), Medical University of Innsbruck, Innsbruck, Austria.
Department of Medical Genetics, Life Science Institute, University of British Columbia, Vancouver, BC, Canada.


Angiogenesis is a hallmark of cancer, promoting growth and metastasis. Anti-angiogenic treatment has limited efficacy due to therapy-induced blood vessel alterations, often followed by local hypoxia, tumor adaptation, progression, and metastasis. It is therefore paramount to overcome therapy-induced resistance. We show that Apelin inhibition potently remodels the tumor microenvironment, reducing angiogenesis, and effectively blunting tumor growth. Functionally, targeting Apelin improves vessel function and reduces polymorphonuclear myeloid-derived suppressor cell infiltration. Importantly, in mammary and lung cancer, Apelin prevents resistance to anti-angiogenic receptor tyrosine kinase (RTK) inhibitor therapy, reducing growth and angiogenesis in lung and breast cancer models without increased hypoxia in the tumor microenvironment. Apelin blockage also prevents RTK inhibitor-induced metastases, and high Apelin levels correlate with poor prognosis of anti-angiogenic therapy patients. These data identify a druggable anti-angiogenic drug target that reduces tumor blood vessel densities and normalizes the tumor vasculature to decrease metastases.


Apelin-Apelin receptor; VEGF-VEGFR; anti-angiogenic therapy; therapy-induced resistance; tumor angiogenesis

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