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

Iris Uribesalgo, David Hoffmann, Yin Zhang, Anoop Kavirayani, Jelena Lazovic, Judit Berta, Maria Novatchkova, Tsung Pin Pai, Reiner A. Wimmer, Viktória László, Daniel Schramek, Rezaul Karim, Luigi Tortola, Sumit Deswal, Lisa Haas, Johannes Zuber, Miklós Szűcs, Keiji Kuba, B. Döme, Yihai CaoBernhard J. Haubner, Josef M. Penninger

Research output: Contribution to journalArticle

4 Citations (Scopus)

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 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.

Original languageEnglish
Article numbere9266
JournalEMBO Molecular Medicine
Volume11
Issue number8
DOIs
Publication statusPublished - Jan 1 2019

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Neoplasm Metastasis
Tumor Microenvironment
Receptor Protein-Tyrosine Kinases
Lung Neoplasms
Growth
Vascular Tissue Neoplasms
Breast Neoplasms
Therapeutics
Neoplasms
Angiogenesis Inhibitors
Blood Vessels

Keywords

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

ASJC Scopus subject areas

  • Molecular Medicine

Cite this

Uribesalgo, I., Hoffmann, D., Zhang, Y., Kavirayani, A., Lazovic, J., Berta, J., ... Penninger, J. M. (2019). Apelin inhibition prevents resistance and metastasis associated with anti-angiogenic therapy. EMBO Molecular Medicine, 11(8), [e9266]. https://doi.org/10.15252/emmm.201809266

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

In: EMBO Molecular Medicine, Vol. 11, No. 8, e9266, 01.01.2019.

Research output: Contribution to journalArticle

Uribesalgo, I, Hoffmann, D, Zhang, Y, Kavirayani, A, Lazovic, J, Berta, J, Novatchkova, M, Pai, TP, Wimmer, RA, László, V, Schramek, D, Karim, R, Tortola, L, Deswal, S, Haas, L, Zuber, J, Szűcs, M, Kuba, K, Döme, B, Cao, Y, Haubner, BJ & Penninger, JM 2019, 'Apelin inhibition prevents resistance and metastasis associated with anti-angiogenic therapy', EMBO Molecular Medicine, vol. 11, no. 8, e9266. https://doi.org/10.15252/emmm.201809266
Uribesalgo I, Hoffmann D, Zhang Y, Kavirayani A, Lazovic J, Berta J et al. Apelin inhibition prevents resistance and metastasis associated with anti-angiogenic therapy. EMBO Molecular Medicine. 2019 Jan 1;11(8). e9266. https://doi.org/10.15252/emmm.201809266
Uribesalgo, Iris ; Hoffmann, David ; Zhang, Yin ; Kavirayani, Anoop ; Lazovic, Jelena ; Berta, Judit ; Novatchkova, Maria ; Pai, Tsung Pin ; Wimmer, Reiner A. ; László, Viktória ; Schramek, Daniel ; Karim, Rezaul ; Tortola, Luigi ; Deswal, Sumit ; Haas, Lisa ; Zuber, Johannes ; Szűcs, Miklós ; Kuba, Keiji ; Döme, B. ; Cao, Yihai ; Haubner, Bernhard J. ; Penninger, Josef M. / Apelin inhibition prevents resistance and metastasis associated with anti-angiogenic therapy. In: EMBO Molecular Medicine. 2019 ; Vol. 11, No. 8.
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