ADAM17 is a tumor promoter and therapeutic target in western diet-Associated colon cancer

Reba Mustafi, Urszula Dougherty, Devkumar Mustafi, Fatma Ayaloglu-Butun, Michelle Fletcher, Sarbani Adhikari, Farhana Sadiq, Katherine Meckel, Haider I. Haider, Abdurahman Khalil, Joel Pekow, Vani Konda, Loren Joseph, John Hart, Alessandro Fichera, Yan Chun Li, Marc Bissonnette*

*Corresponding author for this work

Research output: Contribution to journalArticle

16 Citations (Scopus)

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 languageEnglish (US)
Pages (from-to)549-561
Number of pages13
JournalClinical Cancer Research
Volume23
Issue number2
DOIs
StatePublished - Jan 15 2017

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Carcinogens
Colonic Neoplasms
Therapeutics
Western Diet
ADAM17 Protein
Carcinogenesis
Azoxymethane
Ligands
Chemoprevention
Metalloproteases
Stromal Cells
G-Protein-Coupled Receptors
ErbB Receptors
Mucous Membrane

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Mustafi, R., Dougherty, U., Mustafi, D., Ayaloglu-Butun, F., Fletcher, M., Adhikari, S., ... Bissonnette, M. (2017). ADAM17 is a tumor promoter and therapeutic target in western diet-Associated colon cancer. Clinical Cancer Research, 23(2), 549-561. https://doi.org/10.1158/1078-0432.CCR-15-3140
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. / ADAM17 is a tumor promoter and therapeutic target in western diet-Associated colon cancer. In: Clinical Cancer Research. 2017 ; Vol. 23, No. 2. pp. 549-561.
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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.",
author = "Reba Mustafi and Urszula Dougherty and Devkumar Mustafi and Fatma Ayaloglu-Butun and Michelle Fletcher and Sarbani Adhikari and Farhana Sadiq and Katherine Meckel and Haider, {Haider I.} and Abdurahman Khalil and Joel Pekow and Vani Konda and Loren Joseph and John Hart and Alessandro Fichera and Li, {Yan Chun} and Marc Bissonnette",
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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, V, Joseph, L, Hart, J, Fichera, A, Li, YC & Bissonnette, M 2017, 'ADAM17 is a tumor promoter and therapeutic target in western diet-Associated colon cancer', Clinical Cancer Research, vol. 23, no. 2, pp. 549-561. https://doi.org/10.1158/1078-0432.CCR-15-3140

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 journalArticle

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.

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