ADAM17 is a Tumor Promoter and Therapeutic Target in Western Diet-associated Colon Cancer.
ADAM17 is a Tumor Promoter and Therapeutic Target in Western Diet-associated Colon Cancer.
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DOI：
10.1158/1078-0432.ccr-15-3140
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发表时间：
2017-01-15
期刊：
影响因子：
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通讯作者：
Bissonnette M
中科院分区：
文献类型：
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作者：
Mustafi R;Dougherty U;Mustafi D;Ayaloglu-Butun F;Fletcher M;Adhikari S;Sadiq F;Meckel K;Haider HI;Khalil A;Pekow J;Konda V;Joseph L;Hart J;Fichera A;Li YC;Bissonnette M
表皮生长因子受体（EGFR）是通过西方饮食（WD）促进肿瘤所必需的。金属蛋白酶ADAM 17通过释放pro-EGFR配体激活EGFR。ADAM 17受G蛋白偶联受体（包括CXCR 4）调节。在这里，我们研究了CXCR 4-ADAM 17串扰，并检查了ADAM 17在肿瘤发生中的作用。我们使用CXCR 4抑制剂AMD 3100和ADAM 17抑制剂BMS 566394来评估结肠癌细胞中CXCR 4-ADAM 17的串扰。我们比较了CXCR 4配体、CXCL 2和ADAM 17在喂食WD和标准饮食的小鼠中的表达。另外，小鼠接受马立马司他（一种广谱ADAM 17抑制剂）或AMD 3100处理，以评估ADAM 17和CXCR 4对EGFR的激活作用。使用Apc突变型Min小鼠，我们研究了ADAM 17/10抑制剂INCB 3619对肿瘤发生的影响。为了评估结肠细胞ADAM 17的作用，用氧化偶氮甲烷（AOM）处理具有ADAM 17条件性缺失的小鼠。还比较了来自原发性人结肠癌和邻近粘膜的结肠细胞中的ADAM 17表达。CXCL 12处理激活结肠癌细胞EGFR信号，CXCR 4或ADAM 17阻断剂降低了这种激活。在体内，WD增加基质细胞中的CXCL 12和结肠细胞中的TGFα。Marimastat或AMD 3100导致EGFR信号降低>50%（p<0.05）。在Min小鼠中，INCB 3619降低了腺瘤中的EGFR信号并抑制了肠道肿瘤多样性（p<0.05）。在AOM模型中，结肠细胞ADAM 17缺失减少EGFR信号和结肠肿瘤发展（p<0.05）。最后，ADAM 17在人恶性结肠细胞中上调>2.5倍。ADAM 17是一种WD诱导酶，由CXCL 12-CXCR 4信号转导激活，提示途径：西方饮食-> CXCL 12-> CXCR 4-> ADAM 17->TGFα->EGFR。ADAM 17可能是化学预防策略中的药物靶点。
Epidermal growth factor receptors (EGFR) are required for tumor promotion by Western diet (WD). 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 expression of CXCR4 ligand, CXCL2, and ADAM17 in mice fed WD 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 effects of ADAM17/10 inhibitor INCB3619 on tumorigenesis. To assess 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, WD 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 up-regulated >2.5-fold in human malignant colonocytes. ADAM17 is a WD-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.