ADAM17 is a Tumor Promoter and Therapeutic Target in Western Diet–associated Colon Cancer

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.

Role of ADAM17 as a regulatory checkpoint of CD16A in NK cells and as a potential target for cancer immunotherapy

“…Blocking ADAM17 may decrease the inhibitory effects of soluble NKG2D ligands and increase NKG2D binding to its ligands on tumor cells. In addition, ADAM17 has been shown to be overexpressed in cancer cells and cause their release of EGFR ligands and adhesion molecules that promote growth and metastasis . Taken together, blocking ADAM17 activity may impair tumor cell growth and survival in various direct and indirect manners.…”

“…There have been broad efforts to develop ADAM17 inhibitors, with a particular focus on preventing tumor cell growth and spread . Initial efforts were on the development of selective small‐molecule inhibitors.…”

Role of ADAM10 in intestinal crypt homeostasis and tumorigenesis

“…One possible explanation for this striking result is that ADAM10-deficient Lgr5+ CBCs do not survive to undergo APC-mediated transformation. Interestingly, in a recent APC Min loss-of-heterozygosity adenoma study, the dual ADAM10/17 inhibitor INCB3619 inhibited intestinal tumor multiplicity and reduced EGFR signaling in adenomas [118]. In future studies, it will be important to examine the effects of ADAM10 inhibition in both established mouse adenomas and colitis-associated tumor models…”

MicroRNA‐224, negatively regulated by c‐jun, inhibits growth and epithelial‐to‐mesenchymal transition phenotype via targeting ADAM17 in oral squamous cell carcinoma

“…12 Abnormal expression of ADAM17 is usually found in a series of cancer, such as ovarian cancer, colon cancer, breast cancer and OSCC. [13][14][15] ADAM17 can be a novel therapeutic target for these cancers.We revealed that miR-224 was down-regulated in OSCC tissues and cell lines. We also demonstrated that miR-224 decreased growth and invasion in OSCC via targeting the ADAM17 protein.…”

“…12 Abnormal expression of ADAM17 is usually found in a series of cancer, such as ovarian cancer, colon cancer, breast cancer and OSCC. [13][14][15] ADAM17 can be a novel therapeutic target for these cancers.…”