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

Uribesalgo, Iris; Hoffmann, David; Zhang, Yin; Kavirayani, Anoop; Lazović, Jelena; Berta, Judit; Novatchkova, Maria; Pai, Tsung-Pin; Wimmer, Reiner; László, Viktória; Schramek, Daniel; Karim, Rezaul; Tortola, Luigi; Deswal, Sumit; Haas, Linda; Zuber, Johannes; Szűcs, Miklós; Kuba, Keiji; Döme, Balázs; Cao, Yihai; Haubner, Bernhard J.; Penninger, Josef

doi:10.15252/emmm.201809266

Cited by 85 publications

(93 citation statements)

References 77 publications

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“…The results of our study fit with previous in vivo observations made, where ectopic apelin overexpression enhanced angiogenesis and tumor cell proliferation in subcutaneous tumor models [26,48,49]. Moreover, recent results obtained in a mouse model of breast cancer showed that loss-of-APLN markedly reduced tumor angiogenesis leading to impaired tumor growth and, consequently, improved survival of these animals [50,51].…”

Section: Discussionsupporting

confidence: 91%

Apelin Controls Angiogenesis-Dependent Glioblastoma Growth

Frisch

Kälin

Monk

et al. 2020

IJMS

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Glioblastoma (GBM) present with an abundant and aberrant tumor neo-vasculature. While rapid growth of solid tumors depends on the initiation of tumor angiogenesis, GBM also progress by infiltrative growth and vascular co-option. The angiogenic factor apelin (APLN) and its receptor (APLNR) are upregulated in GBM patient samples as compared to normal brain tissue. Here, we studied the role of apelin/APLNR signaling in GBM angiogenesis and growth. By functional analysis of apelin in orthotopic GBM mouse models, we found that apelin/APLNR signaling is required for in vivo tumor angiogenesis. Knockdown of tumor cell-derived APLN massively reduced the tumor vasculature. Additional loss of the apelin signal in endothelial tip cells using the APLN-knockout (KO) mouse led to a further reduction of GBM angiogenesis. Direct infusion of the bioactive peptide apelin-13 rescued the vascular loss-of-function phenotype specifically. In addition, APLN depletion massively reduced angiogenesis-dependent tumor growth. Consequently, survival of GBM-bearing mice was significantly increased when APLN expression was missing in the brain tumor microenvironment. Thus, we suggest that targeting vascular apelin may serve as an alternative strategy for anti-angiogenesis in GBM.

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Section: Discussionsupporting

confidence: 91%

Apelin Controls Angiogenesis-Dependent Glioblastoma Growth

Frisch

Kälin

Monk

et al. 2020

IJMS

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“…Our findings demonstrated that endothelial cells do not respond to anti-VEGF therapeutics in the presence of activated apelin signaling. In parallel with our studies, other groups have shown that inhibition of the apelin/APJ pathway improves efficacy of established anti-angiogenic treatments in glioblastoma, and prevents the metastasis associated with anti-angiogenic therapy in breast carcinomas [41,42]. Importantly, we showed that in patients treated with bevacizumab, increased apelin expression correlated with worsened prognosis.…”

Section: Discussionsupporting

confidence: 88%

Identification of signature genes associated with therapeutic resistance to anti-VEGF therapy

et al. 2020

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VEGF-mediated tumor angiogenesis is a validated clinical target in many cancers, but modest efficacy and rapid development of resistance are major challenges of VEGF-targeted therapies. To establish a molecular signature of this resistance in ovarian cancer, we developed preclinical tumor models of adaptive resistance to chronic anti-VEGF treatment. We performed RNA-seq analysis and reverse-phase protein array to compare changes in gene and protein expressions in stroma and cancer cells from resistant and responsive tumors. We identified a unique set of stromal-specific genes that were strongly correlated with resistance phenotypes against two different anti-VEGF treatments, and selected the apelin/APJ signaling pathway for further in vitro validation. Using various functional assays, we showed that activation of apelin/APJ signaling reduces the efficacy of a VEGF inhibitor in endothelial cells. In patients with ovarian cancer treated with bevacizumab, increased expression of apelin was associated with significantly decreased disease-free survival. These findings link signature gene expressions with anti-VEGF response, and may thus provide novel targetable mechanisms of clinical resistance to anti-VEGF therapies.

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“…The clinical outcome of targeting APLN/APLNR pathway for cancer therapy depends on the tumor type. In models of lung and breast cancer, targeting Apelin prevented resistance associated with anti-angiogenic therapy by reducing tumor growth, metastasis and improving vessel function [188]. In models of glioma, targeting Apelin promoted invasiveness of tumor cells positive for APLNR.…”

Section: Apelin/aplnr Pathwaymentioning

confidence: 99%

Tumor angiogenesis: causes, consequences, challenges and opportunities

Lugano

Ramachandran

Dimberg

2019

Cell. Mol. Life Sci.

1,157

834

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Tumor vascularization occurs through several distinct biological processes, which not only vary between tumor type and anatomic location, but also occur simultaneously within the same cancer tissue. These processes are orchestrated by a range of secreted factors and signaling pathways and can involve participation of non-endothelial cells, such as progenitors or cancer stem cells. Anti-angiogenic therapies using either antibodies or tyrosine kinase inhibitors have been approved to treat several types of cancer. However, the benefit of treatment has so far been modest, some patients not responding at all and others acquiring resistance. It is becoming increasingly clear that blocking tumors from accessing the circulation is not an easy task to accomplish. Tumor vessel functionality and gene expression often differ vastly when comparing different cancer subtypes, and vessel phenotype can be markedly heterogeneous within a single tumor. Here, we summarize the current understanding of cellular and molecular mechanisms involved in tumor angiogenesis and discuss challenges and opportunities associated with vascular targeting.

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

Cited by 85 publications

References 77 publications

Apelin Controls Angiogenesis-Dependent Glioblastoma Growth

Apelin Controls Angiogenesis-Dependent Glioblastoma Growth

Identification of signature genes associated with therapeutic resistance to anti-VEGF therapy

Tumor angiogenesis: causes, consequences, challenges and opportunities

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