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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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Mustafi R, Dougherty U, Mustafi D, Ayaloglu-Butun F, Fletcher M, Adhikari S, Sadiq F, Meckel K, Haider HI, Khalil A, Pekow J, Konda VJ, Joseph L, Hart J, Fichera A, Li YC, Bissonnette M,


Mustafi R, Dougherty U, Mustafi D, Ayaloglu-Butun F, Fletcher M, Adhikari S, Sadiq F, Meckel K, Haider HI, Khalil A, Pekow J, Konda VJ, Joseph L, Hart J, Fichera A, Li YC, Bissonnette M, (click to view)

Mustafi R, Dougherty U, Mustafi D, Ayaloglu-Butun F, Fletcher M, Adhikari S, Sadiq F, Meckel K, Haider HI, Khalil A, Pekow J, Konda VJ, Joseph L, Hart J, Fichera A, Li YC, Bissonnette M,

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Clinical cancer research : an official journal of the American Association for Cancer Research 2016 8 3() pii

Abstract
PURPOSE
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.

EXPERIMENTAL DESIGN
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.

RESULTS
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.

CONCLUSIONS
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.

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