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Apelin inhibition prevents resistance and metastasis associated with anti‐angiogenic therapy
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Journal Article
Apelin inhibition prevents resistance and metastasis associated with anti‐angiogenic therapy
2019
Overview
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.
Synopsis
Apelin is an angiogenic peptide implicated in embryonic and tumor angiogenesis. This study highlights Apelin targeting as a cancer therapy alone or in combination with current anti‐angiogenic therapies to reduce tumour growth and improve vessel structure and functionality, and thus survival.
Apelin deficiency reduced tumour growth and vessel number but improved vessel function.
Apelin deficiency led to a remodelling of the tumour microenvironment by altering immune cell infiltration.
Combining Apelin inhibition with the anti‐angiogenic therapy Sunitinib markedly reduced tumour growth and improved survival in breast and lung cancer models.
Combinatorial therapy reduced intratumoral vessel numbers compared with single treatments, but simultaneously improved blood vessel pericyte coverage, reduced hypoxia in the tumour microenvironment and prevented Sunitinib‐induced metastasis.
Graphical Abstract
Apelin is an angiogenic peptide implicated in embryonic and tumor angiogenesis. This study highlights Apelin targeting as a cancer therapy alone or in combination with current anti‐angiogenic therapies to reduce tumour growth and improve vessel structure and functionality, and thus survival.
Publisher
Nature Publishing Group UK,EMBO Press,John Wiley and Sons Inc,Springer Nature
Subject
/ Angiogenesis Inhibitors - pharmacology
/ Animals
/ Apelin - antagonists & inhibitors
/ Apelin Receptors - antagonists & inhibitors
/ Apelin Receptors - deficiency
/ Apelin Receptors - metabolism
/ Cell Movement - drug effects
/ EMBO03
/ EMBO46
/ Endothelial Cells - drug effects
/ Endothelial Cells - metabolism
/ Endothelial Cells - pathology
/ Female
/ Funding
/ Gene Expression Regulation, Neoplastic
/ Humans
/ Hypoxia
/ Kinases
/ Lung Neoplasms - drug therapy
/ Mammary Neoplasms, Experimental - drug therapy
/ Mammary Neoplasms, Experimental - genetics
/ Mammary Neoplasms, Experimental - metabolism
/ Mammary Neoplasms, Experimental - pathology
/ Mice
/ Mouse Embryonic Stem Cells - drug effects
/ Mouse Embryonic Stem Cells - metabolism
/ Mouse Embryonic Stem Cells - pathology
/ Neovascularization, Pathologic
/ Protein Kinase Inhibitors - pharmacology
/ Protein-tyrosine kinase receptors
/ Small & medium sized enterprises-SME
/ Tumors
