Abrogation of EMILIN1-β1 integrin interaction promotes experimental colitis and colon carcinogenesis

Alessandra Capuano, Eliana Pivetta, Giulio Sartori, Giulia Bosisio, Andrea Favero, Eleonora Cover, Eva Andreuzzi, Alfonso Colombatti, Renato Cannizzaro, Eugenio Scanziani, Lucia Minoli, Francesco Bucciotti, Ana Isabel Amor Lopez, Katya Gaspardo, Roberto Doliana, Maurizio Mongiat, Paola Spessotto

Research output: Contribution to journalArticlepeer-review

Abstract

Colon cancer is one of the first tumor types where a functional link between inflammation and tumor onset has been described; however, the microenvironmental cues affecting colon cancer progression are poorly understood. Here we demonstrate that the expression of the ECM molecule EMILIN-1 halts the development of AOM-DSS induced tumors. In fact, upon AOM-DSS treatment the Emilin1−/− (E1−/−) mice were characterized by a higher tumor incidence, bigger adenomas and less survival. Similar results were obtained with the E933A EMILIN-1 (E1-E933A) transgenic mouse model, expressing a mutant EMILIN-1 unable to interact with α4/α9β1 integrins. Interestingly, upon chronic treatment with DSS, E1−/− and E1-E933A mice were characterized by the presence of increased inflammatory infiltrates, higher colitis scores and more severe mucosal injury respect to the wild type (E1+/+) mice. Since alterations of the intestinal lymphatic network are a well-established feature of human inflammatory bowel disease and EMILIN-1 is a key structural element in the maintenance of the integrity of lymphatic vessels, we assessed the lymphatic vasculature in this context. The analyses revealed that both E1−/− and E1-E933A mice displayed a higher density of LYVE-1 positive vessels; however, their functionality was severely compromised after colitis induction. Taken together, these results suggest that the loss of EMILIN-1 expression may cause the reduction of the inflammatory resolution during colon cancer progression due to a decreased lymph flow and impaired inflammatory cell drainage.

Original languageEnglish
Pages (from-to)97-115
Number of pages19
JournalMatrix Biology
Volume83
DOIs
Publication statusPublished - Oct 2019

Keywords

  • Colitis-associated cancer
  • Extracellular matrix
  • Lymphatic aberrations

ASJC Scopus subject areas

  • Molecular Biology

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