EMILIN2 is an extracellular matrix constituent playing an important role in angiogenesis; however, the underlying mechanism is unknown. Here we show that EMILIN2 promotes angiogenesis by directly binding epidermal growth factor receptor (EGFR), which enhances interleukin-8 (IL-8) production. In turn, IL-8 stimulates the proliferation and migration of vascular endothelial cells. Emilin2 null mice were generated and exhibited delayed retinal vascular development, which was rescued by the administration of the IL-8 murine ortholog MIP-2. Next, we assessed tumor growth and tumor-associated angiogenesis in these mice. Tumor cell growth in Emilin2 null mice was impaired as well as the expression of MIP-2. The vascular density of the tumors developed in Emilin2 null mice was prejudiced and vessels perfusion, as well as response to chemotherapy, decreased. Accordingly, human tumors expressing high levels of EMILIN2 were more responsive to chemotherapy. These results point at EMILIN2 as a key microenvironmental cue affecting vessel formation and unveil the possibility to develop new prognostic tools to predict chemotherapy efficacy.
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We thank Dr. Veljkovic Veljko for the in silico interaction analyses, Dr. Schiappacassi Monica for the help with the adenoviral and lentiviral constructs, Gustavo Baldassarre for the constructive discussions, Mark Frey and Polk D-Brent for the EGFR mutants, and Raimund Wagener for the anti-mouse EMILIN2 antibody. We thank AIRC the Italian Ministry of Health, the Italian Ministry of University and Research, and the University of Padova for the financial support.
This work was supported by AIRC (grant # IG-2012-12718 to MM, IG-13126 AColombatti), the Italian Ministry of Health (grant# RF-2010-2312580 to MM), the Italian Ministry of University and Research (grants PRIN 2007 and Progetto Strategico 01.00858.ST97 to GB), and the University of Padova (grants CDPA075559/07 to PBraghetta and CPDA148982/14 to PBonaldo).
Conflict of interest
The authors declare that they have no conflict of interest.
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Paulitti, A., Andreuzzi, E., Bizzotto, D. et al. The ablation of the matricellular protein EMILIN2 causes defective vascularization due to impaired EGFR-dependent IL-8 production affecting tumor growth. Oncogene 37, 3399–3414 (2018) doi:10.1038/s41388-017-0107-x
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