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

Uribesalgo, Iris and Hoffmann, David and Zhang, Yin and Kavirayani, Anoop and Lazovic, Jelena and Berta, Judit and Novatchkova, Maria and Pai, Tsung-Pin and Wimmer, Reiner A and László, Viktória and Schramek, Daniel and Karim, Rezaul and Tortola, Luigi and Deswal, Sumit and Haas, Lisa and Zuber, Johannes and Szűcs, Miklós and Kuba, Keiji and Döme, Balázs and Cao, Yihai and Haubner, Bernhard J and Penninger, Josef M (2019) Apelin inhibition prevents resistance and metastasis associated with anti-angiogenic therapy. EMBO MOLECULAR MEDICINE. ISSN 1757-4676 (print); 1757-4684 (online)

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Abstract

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 inhibitorinduced 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.

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