The Effect of Disintegrin–Metalloproteinase ADAM9 in Gastric Cancer Progression

Kim, Jeong‐Min; Jeung, Hei Cheul; Rha, Sun Young; Yu, Eui-Young; Kim, Tae Soo; Shin, Young June; Zhang, Xianglan; Park, Kyu Hyun; Park, Seung Woo; Chung, Hyun Cheol; Powis, Garth

doi:10.1158/1535-7163.mct-13-1001

Cited by 38 publications

(35 citation statements)

References 22 publications

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“…In this study, a significant increase in ADAM9 protein expression in OSCC tissues, compared with in normal oral tissues, was demonstrated by immunohistochemistry, a finding that agrees with the results of other prior studies, which demonstrated ADAM9 protein overexpression in various types of cancer (9,15,17,18,(20)(21)(22)(23)25,26). Though particularly in squamous cell carcinoma, ADAM9 protein overexpression is also present in cancer of the cervix, the esophagus, the pharynx, the larynx, and the skin around the head and neck region (9,21,25,26).…”

Section: Discussionsupporting

confidence: 92%

“…Recently, studies have proposed the usage of ADAM9 as a prognostic or a therapeutic marker in various types of cancer. One example is a study conducted using high and low ADAM9-expressing gastric cancer cell lines (15). It was observed that monoclonal antibodies, or small interfering RNA, specifically targeted against ADAM9 could reduce cell proliferation and invasion in high ADAM9-expressing cell lines but not in low ADAM9-expressing cell lines (15).…”

Section: Discussionmentioning

confidence: 99%

“…One example is a study conducted using high and low ADAM9-expressing gastric cancer cell lines (15). It was observed that monoclonal antibodies, or small interfering RNA, specifically targeted against ADAM9 could reduce cell proliferation and invasion in high ADAM9-expressing cell lines but not in low ADAM9-expressing cell lines (15). Therefore, it is reasonable to assume that silencing ADAM9 expression could prove useful in decreasing aggressive behavior in high ADAM9-expressing oral cancer cell lines, which warrants further investigation.…”

Section: Discussionmentioning

confidence: 99%

“…ADAM9 possesses shedding and adhesive properties due to its metalloproteinase and disintegrin domains, respectively (13). Several specific substrates for ADAM9 have been reported, including heparin-binding epidermal growth factor (HB-EGF), β-amyloid precursor protein, fibronectin, β-casein, gelatin, tumor necrosis factor (TNF)-α, fibroblast growth factor, p75 TNF receptor, and c-kit ligand-1 (14,15). Therefore, ADAM9 can function in both physiological and pathological conditions.…”

Section: Introductionmentioning

confidence: 99%

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Overexpression of ADAM9 in oral squamous cell carcinoma

et al. 2017

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Abstract. Overexpression of a disintegrin and metalloproteinase 9 (ADAM9) has been shown in various types of cancer. Some studies have reported inconclusive findings regarding chromosomal aberrations in the ADAM9-containing region and ADAM9 expression in oral cancer. Therefore, in this study, ADAM9 protein expression was determined and compared between oral squamous cell carcinoma (OSCC) and normal oral tissues, and between oral cancer cell lines and human oral keratinocytes (HOKs). In total, 34 OSCC and 10 healthy paraffin-embedded tissue sections were probed with an anti-ADAM9 antibody, and the immunohistochemical score was determined by multiplying the percentage of positively stained cells with the intensity score. Four different oral cancer and eight independent HOK cell lines were cultured, and the expression of membrane ADAM9 and active ADAM9 at 84 kDa in these cell lines was assayed by flow cytometry and western blot hybridization, respectively. The results showed that the median immunohistochemical score of ADAM9 expression in OSCC tissues was significantly greater than that in normal tissues (P<0.001). Furthermore, among OSCC cases, intense staining of ADAM9 expression was detected in well-differentiated and in moderately-differentiated OSCC; ADAM9 expression was also correlated with an increased degree of cell differentiation (r=0.557; P=0.001). Expression of membrane ADAM9 was present in 3/4 cancer cell lines. Expression of active ADAM9 varied among all the tested cell lines, but significantly higher ADAM9 expression was present in certain cancer cell lines than those in HOKs (P<0.05). In summary, ADAM9 expression is enhanced in OSCC and oral cancer cell lines, suggesting its role in the pathogenesis of oral cancer. Similar to the overexpression of ADAM9 in well-differentiated prostate cancer, high degrees of ADAM9 expression have also been observed in well-differentiated OSCC.

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Section: Discussionsupporting

confidence: 92%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Overexpression of ADAM9 in oral squamous cell carcinoma

et al. 2017

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“…In addition to the specific ADAMs discussed above, limited evidence suggests that ADAM9, 97,98 ADAM12, 99,100…”

Section: Other Adams Implicated Cancermentioning

confidence: 99%

The ADAMs family of proteases as targets for the treatment of cancer

Mullooly

McGowan

Crown

et al. 2016

Cancer Biology & Therapy

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The ADAMs (a disintegrin and metalloproteases) are transmembrane multidomain proteins implicated in multiple biological processes including proteolysis, cell adhesion, cell fusion, cell proliferation and cell migration. Of these varied activities, the best studied is their role in proteolysis. However, of the 22 ADAMs believed to be functional in humans, only approximately a half possess matrix metalloproteinase (MMP)-like protease activity. In contrast to MMPs which are mostly implicated in the degradation of extracellular matrix proteins, the main ADAM substrates are the ectodomains of type I and type II transmembrane proteins. These include growth factor/cytokine precursors, growth factor/cytokine receptors and adhesion proteins. Recently, several different ADAMs, especially ADAM17, have been shown to play a role in the development and progression of multiple cancer types. Consistent with this role in cancer, targeting ADAM17 with either low molecular weight inhibitors or monoclonal antibodies was shown to have anticancer activity in multiple preclinical systems. Although early phase clinical trials have shown no serious side effects with a dual ADAM10/17 low molecular weight inhibitor, the consequences of long-term treatment with these agents is unknown. Furthermore, efficacy in clinical trials remains to be shown.

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ADAM9 contributes to vascular invasion in pancreatic ductal adenocarcinoma

et al. 2019

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A disintegrin and a metalloprotease (ADAM)‐9 is a metzincin cell‐surface protease with strongly elevated expression in solid tumors, including pancreatic ductal adenocarcinoma (PDAC). In this study, we performed immunohistochemistry (IHC) of a tissue microarray (TMA) to examine the expression of ADAM9 in a cohort of >100 clinically annotated PDAC cases. We report that ADAM9 is prominently expressed by PDAC tumor cells, and increased ADAM9 expression levels correlate with poor tumor grading (P = 0.027) and the presence of vasculature invasion (P = 0.017). We employed gene expression silencing to generate a loss‐of‐function system for ADAM9 in two established PDAC cell lines. In vitro analysis showed that loss of ADAM9 does not impede cellular proliferation and invasiveness in basement membrane. However, ADAM9 plays a crucial role in mediating cell migration and adhesion to extracellular matrix substrates such as fibronectin, tenascin, and vitronectin. This effect appears to depend on its catalytic activity. In addition, ADAM9 facilitates anchorage‐independent growth. In AsPC1 cells, but not in MiaPaCa‐2 cells, we noted a pronounced yet heterogeneous impact of ADAM9 on the abundance of various integrins, a process that we characterized as post‐translational regulation. Sprout formation of human umbilical vein endothelial cells (HUVECs) is promoted by ADAM9, as examined by transfer of cancer cell conditioned medium; this finding further supports a pro‐angiogenic role of ADAM9 expressed by PDAC cancer cells. Immunoblotting analysis of cancer cell conditioned medium highlighted that ADAM9 regulates the levels of angiogenic factors, including shed heparin‐binding EGF‐like growth factor (HB‐EGF). Finally, we carried out orthotopic seeding of either wild‐type AsPC‐1 cells or AsPC‐1 cells with silenced ADAM9 expression into murine pancreas. In this in vivo setting, ADAM9 was also found to foster angiogenesis without an impact on tumor cell proliferation. In summary, our results characterize ADAM9 as an important regulator in PDAC tumor biology with a strong pro‐angiogenic impact.

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The Effect of Disintegrin–Metalloproteinase ADAM9 in Gastric Cancer Progression

Cited by 38 publications

References 22 publications

Overexpression of ADAM9 in oral squamous cell carcinoma

Overexpression of ADAM9 in oral squamous cell carcinoma

The ADAMs family of proteases as targets for the treatment of cancer

ADAM9 contributes to vascular invasion in pancreatic ductal adenocarcinoma

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