1. Abrogation of EMILIN1-β1 integrin interaction promotes experimental colitis and colon carcinogenesis.
- Author
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Capuano A, Pivetta E, Sartori G, Bosisio G, Favero A, Cover E, Andreuzzi E, Colombatti A, Cannizzaro R, Scanziani E, Minoli L, Bucciotti F, Amor Lopez AI, Gaspardo K, Doliana R, Mongiat M, and Spessotto P
- Subjects
- Animals, Azoxymethane adverse effects, Cell Line, Tumor, Cell Proliferation, Colitis chemically induced, Colitis metabolism, Colonic Neoplasms etiology, Colonic Neoplasms metabolism, Dextran Sulfate adverse effects, Disease Models, Animal, Humans, Integrin beta1 chemistry, Membrane Glycoproteins chemistry, Membrane Transport Proteins metabolism, Mice, Mice, Knockout, Protein Binding, Colitis complications, Colitis genetics, Colonic Neoplasms genetics, Integrin beta1 metabolism, Membrane Glycoproteins genetics, Membrane Glycoproteins metabolism
- 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., (Copyright © 2019 The Authors. Published by Elsevier B.V. All rights reserved.)- Published
- 2019
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