The ablation of the matricellular protein EMILIN2 causes defective vascularization due to impaired EGFR-dependent IL-8 production affecting tumor growth

Alice Paulitti, Eva Andreuzzi, Dario Bizzotto, Rosanna Pellicani, Giulia Tarticchio, Stefano Marastoni, Chiara Pastrello, Igor Jurisica, Giovanni Ligresti, Francesco Bucciotti, Roberto Doliana, Roberta Colladel, Paola Braghetta, Evelina Poletto, Alessia Di Silvestre, Giorgio Bressan, Alfonso Colombatti, Paolo Bonaldo, Maurizio Mongiat

Research output: Contribution to journalArticlepeer-review

Abstract

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.

Original languageEnglish
Pages (from-to)3399-3414
Number of pages16
JournalOncogene
Volume37
Issue number25
DOIs
Publication statusPublished - Jun 1 2018

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Cancer Research

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