A Disintegrin and Metalloproteinase Domain-9: A Novel Proteinase Culprit with Multifarious Contributions to Chronic Obstructive Pulmonary Disease

Wang, Xiaoyun; Polverino, Francesca; Rojas, Joselyn; Zhang, Duo; Sánchez, José; Yambayev, Ilyas; Lindqvist, Eva; Virtala, Robert; Djukanović, Ratko; Davies, Donna E.; Wilson, Susan R.; O’Donnell, Rory; Cunoosamy, Danen; Hazon, Petra; Higham, Andrew; Singh, Dave; Olsson, Henric; Owen, Caroline A.

doi:10.1164/rccm.201711-2300oc

Cited by 25 publications

(26 citation statements)

References 50 publications

(60 reference statements)

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“…Furthermore, it became evident that a lack of ADAM9 leads to retinal degeneration in mice and cone‐rod dystrophy in humans, respectively (Parry et al ., ). A recent study demonstrates involvement of ADAM9 in chronic obstructive pulmonary disease (Wang et al ., ). Functional studies focusing on the role of ADAM9 in tumor biology are scarce.…”

Section: Introductionmentioning

confidence: 97%

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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Section: Introductionmentioning

confidence: 97%

ADAM9 contributes to vascular invasion in pancreatic ductal adenocarcinoma

et al. 2019

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“…The role of ADAM9 in COPD has been shown to involve emphysema development and airway disease in mice. Therefore, targeting ADAM9 might be a therapeutic choice for COPD patients [ 13 ].…”

Section: Adam9 In Infectious and Inflammatory Diseasesmentioning

confidence: 99%

“…It is widely expressed in human tissues, and shows an abundant increase in pathological conditions [ 11 ]. ADAM9 expression is detected in multiple cell types, including monocytes [ 12 ], macrophages [ 13 ], neutrophils [ 14 ], keratinocytes [ 15 ], and fibroblasts [ 16 ]; and in multiple tissues, including lung [ 17 ], colon [ 18 ], kidney [ 19 ], vascular smooth muscle [ 20 , 21 ], nervous system [ 1 , 22 ], reproductive system [ 23 ], and secretary organs [ 24 ]. This indicates that ADAM9 is involved in a multitude of biological functions as well as pathophysiological conditions, such as inflammation and tumorigenesis [ 25 , 26 ].…”

Section: Introductionmentioning

confidence: 99%

“…In inflammation, ADAM9 contributes to monocyte fusion, mediating the conversion of monocytes-macrophages to multinucleated giant cells (MGCs) as a response to foreign bodies or bacteria; the resulting granulomatous lesions help to isolate the pathogens and also enhance phagocytotic activity [ 12 ]. ADAM9 also stimulates the inflammatory process through polymorphonuclear leukocytes, macrophages, and epithelial cells in some inflammatory diseases, such as acute lung injury or chronic obstructive pulmonary disease (COPD) [ 11 , 13 , 14 , 27 ]. ADAM9 is also expressed in the epidermis, where it delays wound healing by increasing collagen XVII shedding and matrix metalloproteinase-9 (MMP-9) secretion to decrease keratinocyte migration [ 28 ].…”

Section: Introductionmentioning

confidence: 99%

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An Overview of ADAM9: Structure, Activation, and Regulation in Human Diseases

Chou

Huang

Kuo

et al. 2020

IJMS

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ADAM9 (A disintegrin and a metalloprotease 9) is a membrane-anchored protein that participates in a variety of physiological functions, primarily through the disintegrin domain for adhesion and the metalloprotease domain for ectodomain shedding of a wide variety of cell surface proteins. ADAM9 influences the developmental process, inflammation, and degenerative diseases. Recently, increasing evidence has shown that ADAM9 plays an important role in tumor biology. Overexpression of ADAM9 has been found in several cancer types and is correlated with tumor aggressiveness and poor prognosis. In addition, through either proteolytic or non-proteolytic pathways, ADAM9 promotes tumor progression, therapeutic resistance, and metastasis of cancers. Therefore, comprehensively understanding the mechanism of ADAM9 is crucial for the development of therapeutic anti-cancer strategies. In this review, we summarize the current understanding of ADAM9 in biological function, pathophysiological diseases, and various cancers. Recent advances in therapeutic strategies using ADAM9-related pathways are presented as well.

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“…ADAM8 induced epidermal growth factor receptor shedding from airway epithelial cells, leading to decreased mucin gene expression (11,12). In contrast, Wang and colleagues reported higher ADAM9 expression in airway epithelia from patients with COPD than from nonsmokers and smokers without COPD (14). Furthermore, ADAM9 knockout mice exposed to cigarette smoke were protected from developing small airway fibrosis and emphysema (13,14).…”

Section: Protease-antiprotease Balancementioning

confidence: 99%