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Translational Therapeutics

The role of anlotinib-mediated EGFR blockade in a positive feedback loop of CXCL11-EGF-EGFR signalling in anaplastic thyroid cancer angiogenesis

Abstract

Background

Hypoxia-induced angiogenesis functions importantly in anaplastic thyroid cancer (ATC) progression. However, the therapeutic potential of broad-spectrum anti-angiogenic agent remains undefined. Anlotinib conventionally targets VEGFR, FGFR and PDGFR. Here, a novel role of anlotinib on ATC angiogenesis was illustrated.

Methods

Molecular expressions were established via tissue microarray. Multiple assays (tubule formation, 3D sprouting and chicken chorioallantoic membrane model) were used for angiogenic evaluation. Panels of molecular screening were achieved by antibody and PCR arrays. The loop binding motif of EGFR for homology modelling was prepared using Maestro.

Results

Anlotinib could dose- and time-dependently inhibit cell viability under normoxia and hypoxia and could repress hypoxia-activated angiogenesis more efficiently in vitro and in vivo. CXCL11 and phospho-EGFR were hypoxia-upregulated with a positive correlation. The cancer–endothelium crosstalk could be mediated by the positive CXCL11-EGF-EGFR feedback loop, which could be blocked by anlotinib directly targeting EGFR via a dual mechanism by simultaneous inhibitory effects on cancer and endothelial cells. The AKT-mTOR pathway was involved in this regulatory network.

Conclusions

The newly identified CXCL11-EGF-EGFR signalling provided mechanistic insight into the interaction between cancer and endothelial cells under hypoxia, and EGFR was a novel target. Anlotinib may be the encouraging therapeutic candidate in ATC.

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Fig. 1: Anlotinib suppresses hypoxia-activated angiogenesis in ATC.
Fig. 2: CXCL11 mediates anlotinib inhibition of hypoxia-activated angiogenesis.
Fig. 3: CXCL11 promotes angiogenesis by promoting EGF expression in ATC.
Fig. 4: EGFR upregulates CXCL11 in a positive feedback loop in ATC.
Fig. 5: Anlotinib directly targets EGFR kinase.
Fig. 6: Anlotinib delays tumorigenesis in vivo.

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Authors

Contributions

W.Q., X.C., B.S. and J.Y. designed the study. W.C. and J.K. analysed the data and revised the manuscript. J.L. wrote the manuscript. J.L. and Z.J. performed most of the experiments. H.F., Q.Z., Z.Y. and L.Z. performed the experiments. All of the authors discussed the results, reviewed and approved the final manuscript.

Corresponding authors

Correspondence to Wei Cai or Xi Cheng or Weihua Qiu.

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Ethics approval was granted by the Ethics Committee of Ruijin Hospital, Shanghai Jiao Tong University School of Medicine. Animal experiments were carried out according to the Ruijin Hospital Animal Care and Use Guidelines, and the experimental protocols were approved by the Shanghai Resource Center of Laboratory Animals of the Chinese Academy of Science. The manuscript was in accordance with the reporting ARRIVE guideline, and with the Declaration of Helsinki. Written informed consents were obtained from all patients.

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This work was supported by the Nature Science Foundation of China (NSFC, 81772558, 82072948).

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Liang, J., Jin, Z., Kuang, J. et al. The role of anlotinib-mediated EGFR blockade in a positive feedback loop of CXCL11-EGF-EGFR signalling in anaplastic thyroid cancer angiogenesis. Br J Cancer (2021). https://doi.org/10.1038/s41416-021-01340-x

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