Abstract
Purpose: 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. Experimental Design: 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. Results: 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 TGFa 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. Conclusions: ADAM17 is a Western diet-inducible enzyme activated by CXCL12-CXCR4 signaling, suggesting the pathway: Western diet!CXCL12!CXCR4!ADAM17!TGFa!EGFR. ADAM17 might serve as a druggable target in chemoprevention strategies.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 549-561 |
| Number of pages | 13 |
| Journal | Clinical Cancer Research |
| Volume | 23 |
| Issue number | 2 |
| DOIs | |
| State | Published - Jan 15 2017 |
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ASJC Scopus subject areas
- Oncology
- Cancer Research
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ADAM17 is a tumor promoter and therapeutic target in western diet-Associated colon cancer. / 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.
In: Clinical Cancer Research, Vol. 23, No. 2, 15.01.2017, p. 549-561.Research output: Contribution to journal › Article
TY - JOUR
T1 - ADAM17 is a tumor promoter and therapeutic target in western diet-Associated colon cancer
AU - Mustafi, Reba
AU - Dougherty, Urszula
AU - Mustafi, Devkumar
AU - Ayaloglu-Butun, Fatma
AU - Fletcher, Michelle
AU - Adhikari, Sarbani
AU - Sadiq, Farhana
AU - Meckel, Katherine
AU - Haider, Haider I.
AU - Khalil, Abdurahman
AU - Pekow, Joel
AU - Konda, Vani
AU - Joseph, Loren
AU - Hart, John
AU - Fichera, Alessandro
AU - Li, Yan Chun
AU - Bissonnette, Marc
PY - 2017/1/15
Y1 - 2017/1/15
N2 - Purpose: 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. Experimental Design: 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. Results: 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 TGFa 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. Conclusions: ADAM17 is a Western diet-inducible enzyme activated by CXCL12-CXCR4 signaling, suggesting the pathway: Western diet!CXCL12!CXCR4!ADAM17!TGFa!EGFR. ADAM17 might serve as a druggable target in chemoprevention strategies.
AB - Purpose: 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. Experimental Design: 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. Results: 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 TGFa 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. Conclusions: ADAM17 is a Western diet-inducible enzyme activated by CXCL12-CXCR4 signaling, suggesting the pathway: Western diet!CXCL12!CXCR4!ADAM17!TGFa!EGFR. ADAM17 might serve as a druggable target in chemoprevention strategies.
UR - http://www.scopus.com/inward/record.url?scp=85011303875&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85011303875&partnerID=8YFLogxK
U2 - 10.1158/1078-0432.CCR-15-3140
DO - 10.1158/1078-0432.CCR-15-3140
M3 - Article
VL - 23
SP - 549
EP - 561
JO - Clinical Cancer Research
JF - Clinical Cancer Research
SN - 1078-0432
IS - 2
ER -