Abstract
Vascular endothelial growth factor (VEGF) signaling is critical for tumor angiogenesis. However, therapies based on inhibition of VEGF receptors (VEGFRs) have shown modest results for patients with cancer. Surprisingly little is known about mechanisms underlying the regulation of VEGFR1 and VEGFR2 expression, the main targets of these drugs. Here, analysis of tissue microarrays revealed an inversely reciprocal pattern of VEGFR regulation in the endothelium of human squamous-cell carcinomas (high VEGFR1, low VEGFR2), as compared with the endothelium of control tissues (low VEGFR1, high VEGFR2). Mechanistic studies demonstrated that VEGF signals through the Akt/ERK pathway to inhibit constitutive ubiquitination and induce rapid VEGFR1 accumulation in endothelial cells. Surprisingly, VEGFR1 is primarily localized in the nucleus of endothelial cells. In contrast, VEGF signals through the JNK/c-Jun pathway to induce endocytosis, nuclear translocation, and downregulation of VEGFR2 via ubiquitination. VEGFR1 signaling is required for endothelial-cell survival, while VEGFR2 regulates capillary tube formation. Notably, the antiangiogenic effect of bevacizumab (anti-VEGF antibody) requires normalization of VEGFR1 and VEGFR2 levels in human squamous-cell carcinomas vascularized with human blood vessels in immunodeficient mice. Collectively, this work demonstrates that VEGF-induced angiogenesis requires inverse regulation of VEGFR1 and VEGFR2 in tumor-associated endothelial cells.
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Abbreviations
- VEGF:
-
vascular endothelial growth factor
- VEGFR1:
-
vascular endothelial growth factor receptor-1
- VEGFR2:
-
vascular endothelial growth factor receptor-2
- RTK:
-
receptor tyrosine kinase
- EGF:
-
epidermal growth factor
- EGFR:
-
epidermal growth factor receptor
- PlGF:
-
placental growth factor
- IL-6:
-
interleukin-6
- PI3K/Akt:
-
phosphoinositol-3-kinase/Akt
- ERK:
-
extracellular signal-regulated kinase
- JNK:
-
c-Jun N-terminal kinase
- STAT3:
-
signal transducer and activator of transcription-3
- HDMEC:
-
human dermal microvascular endothelial cell
- HPEC:
-
human pulmonary endothelial cell
- FBS:
-
fetal bovine serum
- CM:
-
conditioned medium
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Acknowledgements
We thank Dr Zhihong Dong for assistance with the SCID Mouse Model of Human Tumor Angiogenesis, and Dr Seungwon Kim for critically reading the paper and providing invaluable suggestions. This work was supported by grant R01-CA112390 from the NIH/NCI (LME); grant R01-DE12322 from the NIH/NIDCR (MWL); grant P50-CA97248 (University of Michigan Head and Neck SPORE) from the NIH/NCI (JEN); and grants R01-DE14601, R01-DE15948, R01-DE16586, and R21-DE19279 from the NIH/NIDCR (JEN).
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Zhang, Z., Neiva, K., Lingen, M. et al. VEGF-dependent tumor angiogenesis requires inverse and reciprocal regulation of VEGFR1 and VEGFR2. Cell Death Differ 17, 499–512 (2010). https://doi.org/10.1038/cdd.2009.152
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DOI: https://doi.org/10.1038/cdd.2009.152
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