Pharmacological activation of epidermal growth factor receptor signaling inhibits colitis-associated cancer in mice.
Pharmacological activation of epidermal growth factor receptor signaling inhibits colitis-associated cancer in mice.
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DOI：
10.1038/s41598-018-27353-w
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发表时间：
2018-06-14
影响因子：
4.6
通讯作者：
Polk DB
中科院分区：
文献类型：
--
作者：
Dubé PE;Liu CY;Girish N;Washington MK;Polk DB
目前治疗炎症性肠病（IBD）的目标是肠黏膜过度活跃的免疫反应。然而，表皮生长因子（EGF），一种表皮生长因子受体（EGFR）的激活配体，已被证明可以通过直接靶向肠粘膜愈合来诱导疾病缓解。尽管临床前和临床结果很有希望，但这种egfr激活疗法尚未取得进展，部分原因是长期使用可能致癌，并且IBD患者结肠炎相关癌症（CAC）的风险增加。在这里，我们测试了EGFR的药理学调节是否会改变小鼠偶氮氧甲烷/葡聚糖硫酸钠模型中CAC的结果。我们发现，在结肠炎严重程度最高的时期（“早期”）给予EGF，与肿瘤的发生和早期发展相一致，可以改善结肠炎的结局并减小肿瘤大小。相反，在肿瘤发生后2个月（“晚期”）开始每天给药EGF会增加肿瘤大小。EGFR激酶抑制剂吉非替尼在早期给药时增大肿瘤大小，在晚期给药时减小肿瘤大小。EGF的使用不仅降低了损伤时结肠细胞因子和趋化因子的表达，而且降低了稳态时基线趋化因子的表达。这些结果表明，在急性结肠炎发作期间激活EGFR可能会减轻CAC的长期负担。
Current treatments for inflammatory bowel disease (IBD) target the overactive immune response of the intestinal mucosa. However, epidermal growth factor (EGF), an activating ligand of the EGF receptor (EGFR), has been shown to induce disease remission through direct targeting of intestinal mucosal healing. Despite promising preclinical and clinical results, this EGFR-activating therapy has not progressed, in part due to the potential for carcinogenesis associated with long-term use and the increased risk of colitis-associated cancer (CAC) in IBD. Here we tested whether pharmacological modulation of EGFR altered outcomes of CAC in the murine azoxymethane/dextran sulfate sodium model. We found that administering EGF during the period of maximum colitis severity (“early”), coincident with the initiation and early promotion of tumors, improved outcomes of colitis and reduced tumor size. In contrast, daily EGF administration beginning ~2 months after tumor initiation (“late”) increased tumor size. Administration of the EGFR kinase inhibitor gefitinib increased the tumor size when the drug was given early and decreased the tumor size when the drug was administered late. EGF administration not only reduced colonic cytokine and chemokine expression during injury, but also baseline chemokine expression in homeostasis. These results suggest that EGFR activation during acute bouts of colitis may reduce the long-term burden of CAC.
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DOI：
10.1124/jpet.108.145862
发表时间：
2009-04-01
影响因子：
3.5
作者：
Farooq, Shukkur Muhammed;Stillie, RoseMarie;Stadnyk, Andrew W.
通讯作者：
Stadnyk, Andrew W.
影响因子：
29.4
作者：
Hanauer, SB;Sandborn, WJ;Pollack, P
通讯作者：
Pollack, P
上皮TNF受体信号传导促进炎症性肠病的粘膜修复。
DOI：
10.4049/jimmunol.1601066
发表时间：
2017-09-01
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
--
作者：
Bradford EM;Ryu SH;Singh AP;Lee G;Goretsky T;Sinh P;Williams DB;Cloud AL;Gounaris E;Patel V;Lamping OF;Lynch EB;Moyer MP;De Plaen IG;Shealy DJ;Yang GY;Barrett TA
通讯作者：
Barrett TA
影响因子：
30.8
作者：
Barrett, Jeffrey C.;Lee, James C.;Lees, Charles W.;Prescott, Natalie J.;Anderson, Carl A.;Phillips, Anne;Wesley, Emma;Parnell, Kirstie;Zhang, Hu;Drummond, Hazel;Nimmo, Elaine R.;Massey, Dunecan;Blaszczyk, Kasia;Elliott, Timothy;Cotterill, Lynn;Dallal, Helen;Lobo, Alan J.;Mowat, Craig;Sanderson, Jeremy D.;Jewell, Derek P.;Newman, William G.;Edwards, Cathryn;Ahmad, Tariq;Mansfield, John C.;Satsangi, Jack;Parkes, Miles;Mathew, Christopher G.;Donnelly, Peter;Peltonen, Leena;Blackwell, Jenefer M.;Bramon, Elvira;Brown, Matthew A.;Casas, Juan P.;Corvin, Aiden;Craddock, Nicholas;Deloukas, Panos;Duncanson, Audrey;Jankowski, Janusz;Markus, Hugh S.;McCarthy, Mark I.;Palmer, Colin N. A.;Plomin, Robert;Rautanen, Anna;Sawcer, Stephen J.;Samani, Nilesh;Trembath, Richard C.;Viswanathan, Ananth C.;Wood, Nicholas;Spencer, Chris C. A.;Bellenguez, Celine;Davison, Daniel;Freeman, Colin;Strange, Amy;Langford, Cordelia;Hunt, Sarah E.;Edkins, Sarah;Gwilliam, Rhian;Blackburn, Hannah;Bumpstead, Suzannah J.;Dronov, Serge;Gillman, Matthew;Gray, Emma;Hammond, Naomi;Jayakumar, Alagurevathi;McCann, Owen T.;Liddle, Jennifer;Perez, Marc L.;Potter, Simon C.;Ravindrarajah, Radhi;Ricketts, Michelle;Waller, Matthew;Weston, Paul;Widaa, Sara;Whittaker, Pamela;Attwood, Antony P.;Stephens, Jonathan;Sambrook, Jennifer;Ouwehand, Willem H.;McArdle, Wendy L.;Ring, Susan M.;Strachan, David P.
通讯作者：
Strachan, David P.
影响因子：
29.4
作者：
Colombel, Jean-Frederic;Sandborn, William J.;Pollack, Paul F.
通讯作者：
Pollack, Paul F.