TY - JOUR
T1 - Abrogation of EMILIN1-β1 integrin interaction promotes experimental colitis and colon carcinogenesis
AU - Capuano, Alessandra
AU - Pivetta, Eliana
AU - Sartori, Giulio
AU - Bosisio, Giulia
AU - Favero, Andrea
AU - Cover, Eleonora
AU - Andreuzzi, Eva
AU - Colombatti, Alfonso
AU - Cannizzaro, Renato
AU - Scanziani, Eugenio
AU - Minoli, Lucia
AU - Bucciotti, Francesco
AU - Amor Lopez, Ana Isabel
AU - Gaspardo, Katya
AU - Doliana, Roberto
AU - Mongiat, Maurizio
AU - Spessotto, Paola
PY - 2019/10
Y1 - 2019/10
N2 - 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.
AB - 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.
KW - Colitis-associated cancer
KW - Extracellular matrix
KW - Lymphatic aberrations
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U2 - 10.1016/j.matbio.2019.08.006
DO - 10.1016/j.matbio.2019.08.006
M3 - Article
C2 - 31479698
AN - SCOPUS:85071836843
VL - 83
SP - 97
EP - 115
JO - Matrix Biology
JF - Matrix Biology
SN - 0945-053X
ER -