Mustafi Reba, Dougherty Urszula, Mustafi Devkumar, Ayaloglu-Butun Fatma, Fletcher Michelle, Adhikari Sarbani, Sadiq Farhana, Meckel Katherine, Haider Haider I, Khalil Abdurahman, Pekow Joel, Konda Vani, Joseph Loren, Hart John, Fichera Alessandro, Li Yan Chun, Bissonnette Marc
Department of Medicine, University of Chicago, Chicago IL 60637.
Department of Radiology, University of Chicago, Chicago IL 60637.
Clin Cancer Res. 2017 Jan 15;23(2):549-561. doi: 10.1158/1078-0432.CCR-15-3140. Epub 2016 Aug 3.
Epidermal growth factor receptors (EGFR) are required for tumor promotion by Western diet. The metalloprotease, ADAM17 activates EGFR by releasing pro-EGFR ligands. ADAM17 is regulated by G-protein-coupled receptors, including CXCR4. Here we investigated CXCR4-ADAM17 crosstalk and examined the role of ADAM17 in tumorigenesis.
We used CXCR4 inhibitor, AMD3100 and ADAM17 inhibitor, BMS566394 to assess CXCR4-ADAM17 crosstalk in colon cancer cells. We compared the expression of CXCR4 ligand, CXCL2, and ADAM17 in mice fed Western diet versus standard diet. Separately, mice were treated with marimastat, a broad-spectrum ADAM17 inhibitor, or AMD3100 to assess EGFR activation by ADAM17 and CXCR4. Using Apc-mutant Min mice, we investigated the effects of ADAM17/10 inhibitor INCB3619 on tumorigenesis. To assess the effects of colonocyte ADAM17, mice with ADAM17 conditional deletion were treated with azoxymethane (AOM). ADAM17 expression was also compared in colonocytes from primary human colon cancers and adjacent mucosa.
CXCL12 treatment activated colon cancer cell EGFR signals, and CXCR4 or ADAM17 blockade reduced this activation. In vivo, Western diet increased CXCL12 in stromal cells and TGFα in colonocytes. Marimastat or AMD3100 caused >50% reduction in EGFR signals (P < 0.05). In Min mice, INCB3619 reduced EGFR signals in adenomas and inhibited intestinal tumor multiplicity (P < 0.05). In the AOM model, colonocyte ADAM17 deletion reduced EGFR signals and colonic tumor development (P < 0.05). Finally, ADAM17 was upregulated >2.5-fold in human malignant colonocytes.
ADAM17 is a Western diet-inducible enzyme activated by CXCL12-CXCR4 signaling, suggesting the pathway: Western diet→CXCL12→CXCR4→ADAM17→TGFα→EGFR. ADAM17 might serve as a druggable target in chemoprevention strategies. Clin Cancer Res; 23(2); 549-61. ©2016 AACR.
西方饮食促进肿瘤生长需要表皮生长因子受体（EGFR）。金属蛋白酶ADAM17通过释放前体EGFR配体来激活EGFR。ADAM17受包括CXCR4在内的G蛋白偶联受体调节。在此，我们研究了CXCR4-ADAM17的相互作用，并探讨了ADAM17在肿瘤发生中的作用。
我们使用CXCR4抑制剂AMD3100和ADAM17抑制剂BMS566394来评估结肠癌细胞中CXCR4-ADAM17的相互作用。我们比较了喂食西方饮食与标准饮食的小鼠中CXCR4配体CXCL2和ADAM17的表达。另外，用广谱ADAM17抑制剂马里司他或AMD3100处理小鼠，以评估ADAM17和CXCR4对EGFR的激活作用。使用Apc突变的Min小鼠，我们研究了ADAM17/10抑制剂INCB3619对肿瘤发生的影响。为了评估结肠细胞ADAM17的作用，用偶氮甲烷（AOM）处理具有ADAM17条件性缺失的小鼠。还比较了原发性人类结肠癌和相邻黏膜中结肠细胞的ADAM17表达。
CXCL12处理激活了结肠癌细胞EGFR信号，而CXCR4或ADAM17阻断则降低了这种激活。在体内，西方饮食增加了基质细胞中CXCL12和结肠细胞中TGFα的含量。马里司他或AMD3100使EGFR信号降低>50%（P<0.05）。在Min小鼠中，INCB3619降低了腺瘤中的EGFR信号并抑制了肠道肿瘤的多发性（P<0.05）。在AOM模型中，结肠细胞ADAM17缺失降低了EGFR信号和结肠肿瘤的发生（P<0.05）。最后，ADAM17在人类恶性结肠细胞中上调>2.5倍。
ADAM17是一种由CXCL12-CXCR4信号激活的西方饮食诱导酶，提示以下途径：西方饮食→CXCL12→CXCR4→ADAM17→TGFα→EGFR。ADAM17可能是化学预防策略中一个可成药的靶点。《临床癌症研究》；23(2)；549 - 61。©2016美国癌症研究协会。
