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

Autor: Uribesalgo I; Institute of Molecular Biotechnology of the Austrian Academy of Sciences (IMBA), Vienna BioCenter, Vienna, Austria., Hoffmann D; Institute of Molecular Biotechnology of the Austrian Academy of Sciences (IMBA), Vienna BioCenter, Vienna, Austria., Zhang Y; Department of Microbiology, Tumor and Cell Biology, Biomedicum, Karolinska Institutet, Stockholm, Sweden.; Medicine and Pharmacy Research Center, Binzhou Medical University, Yantai, Shandong Province, China., Kavirayani A; VBCF Histopathology, Vienna BioCenter, Vienna, Austria., Lazovic J; VBCF Preclinical Imaging, Vienna BioCenter, Vienna, Austria., Berta J; Department of Tumor Biology, National Koranyi Institute of Pulmonology, Budapest, Hungary., Novatchkova M; Institute of Molecular Biotechnology of the Austrian Academy of Sciences (IMBA), Vienna BioCenter, Vienna, Austria., Pai TP; Institute of Molecular Biotechnology of the Austrian Academy of Sciences (IMBA), Vienna BioCenter, Vienna, Austria., Wimmer RA; Institute of Molecular Biotechnology of the Austrian Academy of Sciences (IMBA), Vienna BioCenter, Vienna, Austria., László V; 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., Schramek D; Institute of Molecular Biotechnology of the Austrian Academy of Sciences (IMBA), Vienna BioCenter, Vienna, Austria.; Department of Molecular Genetics, Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, University of Toronto, Toronto, ON, Canada., Karim R; Institute of Molecular Biotechnology of the Austrian Academy of Sciences (IMBA), Vienna BioCenter, Vienna, Austria., Tortola L; Institute of Molecular Biotechnology of the Austrian Academy of Sciences (IMBA), Vienna BioCenter, Vienna, Austria., Deswal S; Institute of Molecular Pathology (IMP), Vienna BioCenter, Vienna, Austria., Haas L; Institute of Molecular Pathology (IMP), Vienna BioCenter, Vienna, Austria., Zuber J; Institute of Molecular Pathology (IMP), Vienna BioCenter, Vienna, Austria., Szűcs M; Department of Urology, Semmelweis University, Budapest, Hungary., Kuba K; Institute of Molecular Biotechnology of the Austrian Academy of Sciences (IMBA), Vienna BioCenter, Vienna, Austria.; Department Biochemistry and Metabolic Science, Akita University Graduate School of Medicine, Akita, Japan., Dome B; 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.; Department of Thoracic Surgery, National Institute of Oncology-Semmelweis University, Budapest, Hungary., Cao Y; Department of Microbiology, Tumor and Cell Biology, Biomedicum, Karolinska Institutet, Stockholm, Sweden., Haubner BJ; Institute of Molecular Biotechnology of the Austrian Academy of Sciences (IMBA), Vienna BioCenter, Vienna, Austria.; Department of Internal Medicine III (Cardiology and Angiology), Medical University of Innsbruck, Innsbruck, Austria., Penninger JM; Institute of Molecular Biotechnology of the Austrian Academy of Sciences (IMBA), Vienna BioCenter, Vienna, Austria.; Department of Medical Genetics, Life Science Institute, University of British Columbia, Vancouver, BC, Canada.
Jazyk: angličtina
Zdroj: EMBO molecular medicine [EMBO Mol Med] 2019 Aug; Vol. 11 (8), pp. e9266. Date of Electronic Publication: 2019 Jun 24.
DOI: 10.15252/emmm.201809266
Abstrakt: 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.
(© 2019 The Authors. Published under the terms of the CC BY 4.0 license.)
Databáze: MEDLINE
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