Division of Gastroenterology, Hepatology and Nutrition, Department of Pediatrics, Tulane University School of Medicine, New Orleans, LA 70112, USA.
Am J Physiol Gastrointest Liver Physiol. 2012 Jan 15;302(2):G195-206. doi: 10.1152/ajpgi.00209.2011. Epub 2011 Nov 3.
Tumor necrosis factor (TNF) is a key player in inflammatory bowel disease and has been variably associated with carcinogenesis, but details of the cross talk between inflammatory and tumorigenic pathways remain incompletely understood. It has been shown that, in C57BL/6 mice, signaling via TNF receptor 1 (TNFR1) is protective from injury and inflammation in experimental colitis. Therefore, we hypothesized that loss of TNFR1 signaling would confer increased risk of developing colitis-associated carcinoma. Using three models of murine tumorigenesis based on repeated bouts of inflammation or systemic tumor initiator, we sought to determine the roles of TNF and TNFR1 with regard to neoplastic transformation in the colon in wild-type (WT), TNFR1 knockout (R1KO), and TNF knockout (TNFKO) mice. We found R1KO animals to have more severe disease, as defined by weight loss, hematochezia, and histology. TNFKO mice demonstrated less weight loss but were consistently smaller, and rates and duration of hematochezia were comparable to WT mice. Histological inflammation scores were higher and neoplastic lesions occurred more frequently and earlier in R1KO mice. Apoptosis is not affected in R1KO mice although epithelial proliferation following injury is more ardent even before tumorigenesis is apparent. Lastly, there is earlier and more intense expression of activated β-catenin in these mice, implying a connection between TNFR1 and Wnt signaling. Taken together, these findings show that in the context of colitis-associated carcinogenesis TNFR1 functions as a tumor suppressor, exerting this effect not via apoptosis but by modulating activation of β-catenin and controlling epithelial proliferation.
肿瘤坏死因子（TNF）是炎症性肠病中的关键因子，与致癌作用的关系也存在差异，但炎症和肿瘤形成途径之间的相互作用的细节仍不完全清楚。已经表明，在 C57BL/6 小鼠中，TNF 受体 1（TNFR1）的信号传递可防止实验性结肠炎中的损伤和炎症。因此，我们假设 TNFR1 信号的丧失会增加发生结肠炎相关癌的风险。我们使用三种基于反复炎症发作或全身性肿瘤启动子的小鼠肿瘤发生模型，旨在确定 TNF 和 TNFR1 在野生型（WT）、TNFR1 敲除（R1KO）和 TNF 敲除（TNFKO）小鼠的结肠中发生肿瘤转化方面的作用。我们发现 R1KO 动物的疾病更严重，表现为体重减轻、血便和组织学。TNFKO 小鼠的体重减轻程度较低，但始终较小，血便的发生率和持续时间与 WT 小鼠相当。组织学炎症评分较高，R1KO 小鼠中的肿瘤病变发生更频繁且更早。尽管在肿瘤发生之前，上皮细胞增殖更加活跃，但 R1KO 小鼠中的细胞凋亡不受影响。最后，这些小鼠中激活的β-连环蛋白的表达更早且更强烈，暗示 TNFR1 与 Wnt 信号之间存在联系。总之，这些发现表明，在结肠炎相关致癌作用的背景下，TNFR1 作为肿瘤抑制因子发挥作用，不是通过细胞凋亡，而是通过调节β-连环蛋白的激活和控制上皮细胞增殖来发挥作用。
