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.

中文翻译：

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EMILIN1-β1整联蛋白相互作用的废止促进实验性结肠炎和结肠癌发生。

结肠癌是最早的一种肿瘤类型，其中已描述了炎症和肿瘤发作之间的功能联系。然而，人们对影响结肠癌进展的微环境线索知之甚少。在这里，我们证明了ECM分子EMILIN-1的表达阻止了AOM-DSS诱导的肿瘤的发展。实际上，经AOM-DSS处理后，Emilin1-/-（E1-/-）小鼠的特征是肿瘤发生率更高，腺瘤更大，存活率更低。使用E933A EMILIN-1（E1-E933A）转基因小鼠模型获得了类似的结果，该模型表达了无法与α4/α9β1整联蛋白相互作用的EMILIN-1突变体。有趣的是，经DSS长期治疗后，E1-/-和E1-E933A小鼠的特征是存在炎性浸润增加，与野生型（E1 + / +）小鼠相比，结肠炎评分更高，黏膜损伤更严重。由于肠道淋巴管网络的改变是人类炎症性肠病的公认特征，而EMILIN-1是维持淋巴管完整性的关键结构要素，因此我们在这种情况下评估了淋巴管系统。分析显示，E1-/-和E1-E933A小鼠均显示出更高密度的LYVE-1阳性血管；但是，它们的功能在诱发结肠炎后严重受损。综上所述，这些结果表明，由于淋巴流量减少和炎性细胞引流受损，EMILIN-1表达的丧失可能会导致结肠癌进展过程中炎性分辨率的降低。由于肠道淋巴网络的改变是人类炎症性肠病的公认特征，而EMILIN-1是维持淋巴管完整性的关键结构要素，因此我们在这种情况下评估了淋巴管系统。分析显示，E1-/-和E1-E933A小鼠均显示出更高密度的LYVE-1阳性血管；但是，它们的功能在诱发结肠炎后严重受损。综上所述，这些结果表明，由于淋巴流量减少和炎性细胞引流受损，EMILIN-1表达的丧失可能会导致结肠癌进展过程中炎性分辨率的降低。由于肠道淋巴网络的改变是人类炎症性肠病的公认特征，而EMILIN-1是维持淋巴管完整性的关键结构要素，因此我们在这种情况下评估了淋巴管系统。分析显示，E1-/-和E1-E933A小鼠均显示出更高密度的LYVE-1阳性血管；但是，它们的功能在诱发结肠炎后严重受损。综上所述，这些结果表明，由于淋巴流量减少和炎性细胞引流受损，EMILIN-1表达的丧失可能会导致结肠癌进展过程中炎性分辨率的降低。