ADAMs, cell migration and cancer

Arribas, Joaquı́n; Bech-Serra, Joan Josep; Santiago-Josefat, Belen

doi:10.1007/s10555-006-7889-6

Cited by 109 publications

(119 citation statements)

References 104 publications

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“…There are many reports showing that members of the ADAM family are differentially expressed in human tumors and are frequently associated with tumor progression and poor disease outcome (31,32); however, until recently, these studies were not accompanied by functional analyses (33)(34)(35). Here, we provide additional evidence for the involvement of ADAM family members in metastatic progression.…”

Section: Discussionmentioning

confidence: 63%

ADAM23 Negatively Modulates αvβ3 Integrin Activation during Metastasis

Verbisck

Costa

et al. 2009

Cancer Research

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The ADAM23 gene is frequently silenced in different types of tumors, and, in breast tumors, silencing is correlated with tumor progression, suggesting that it might be associated with the acquisition of a metastatic phenotype. ADAM23 exerts its function mainly through the disintegrin domain, because its metalloprotease domain is inactive. Analysis of ADAM23 binding to integrins has revealed a specific interaction with A v B 3 integrin mediated by the disintegrin domain. Altered expression of A v B 3 integrin has been observed in different types of tumors, and expression of this integrin in the activated form has been shown to promote metastasis formation. Here, we investigated the possibility that interaction between ADAM23 and A v B 3 integrin might negatively modulate A v B 3 activation during metastatic progression. ADAM23 expression was knocked down using short hairpin RNA in the MDA-MB-435 cell line, which has been extensively used as a model for A v B 3 integrin activation. Ablation of ADAM23 enhanced A v B 3 integrin activation by at least 2-to 4-fold and ADAM23 knockdown cells showed enhanced migration and adhesion to classic A v B 3 integrin ligands. Ablation of ADAM23 expression also enhanced pulmonary tumor cell arrest in immunodeficient mice. To complement our findings with clinical evidence, we showed that silencing of ADAM23 gene by DNA promoter hypermethylation in a collection of 94 primary breast tumors was significantly associated with lower distant metastases-free and disease-specific survivals and was an independent prognostic factor for poor disease outcome. Our results strongly support a functional role of ADAM23 during metastatic progression by negatively modulating A v B 3 integrin activation. [Cancer Res 2009;69(13):5546-52]

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Section: Discussionmentioning

confidence: 63%

ADAM23 Negatively Modulates αvβ3 Integrin Activation during Metastasis

Verbisck

Costa

et al. 2009

Cancer Research

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“…For example, a number of different ADAMs bind to integrins through the conserved sequence RX6DLPEF (6). In general, it seems that any integrin can bind to multiple ADAMs whereas, conversely, any ADAM can attach to several integrins (6,7).…”

Section: Structure Of Adamsmentioning

confidence: 99%

Role of ADAMs in Cancer Formation and Progression

Duffy

McKiernan

O’Donovan

et al. 2009

Clinical Cancer Research

198

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The ADAMs (a disintegrin and metalloproteinase) comprise a family of multidomain transmembrane and secreted proteins. One of their best-established roles is the release of biologically important ligands, such as tumor necrosis factor^a, epidermal growth factor, transforming growth factor^a, and amphiregulin. Because these ligands have been implicated in the formation and progression of tumors, it might be expected that the specific ADAMs involved in their release would also be involved in malignancy. Consistent with this hypothesis, emerging data from model systems suggest that ADAMs, such as ADAM-9, ADAM-12, ADAM-15, and ADAM-17, are causally involved in tumor formation/progression. In human cancer, specific ADAMs are upregulated, with levels generally correlating with parameters of tumor progression and poor outcome. In preclinical models, selective ADAM inhibitors against ADAM-10 and ADAM-17 have been shown to synergize with existing therapies in decreasing tumor growth.TheADAMs are thus a new family of potential targets for the treatment of cancer, especially malignancies that are dependent on human epidermal growth factor receptor ligands or tumor necrosis factor^a.

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“…In addition, concerns have been raised that some metalloproteases act as tumor suppressors (4,5). A more precise inhibition of specific metalloproteases and/or of the cleavage of specific disease-involved substrates could circumvent these problems.…”

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confidence: 99%

Epidermal Growth Factor (EGF) Ligand Release by Substrate-specific A Disintegrin and Metalloproteases (ADAMs) Involves Different Protein Kinase C (PKC) Isoenzymes Depending on the Stimulus

Dang

Dubbin

D'Aiello

et al. 2011

Journal of Biological Chemistry

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The dysregulation of EGF family ligand cleavage has severe consequences for the developing as well as the adult organism. Therefore, their production is highly regulated. The limiting step is the ectodomain cleavage of membrane-bound precursors by one of several a disintegrin and metalloprotease (ADAM) metalloproteases, and understanding the regulation of cleavage is an important goal of current research. We have previously reported that in mouse lung epithelial cells, the pro-EGF ligands TGF␣, neuregulin 1␤ (NRG), and heparinbinding EGF are differentially cleaved depending on the cleavage stimulus (Herrlich, A., Klinman, E., Fu, J., Sadegh, C., and Lodish, H. (2008) FASEB J.). In this study in mouse embryonic fibroblasts that lack different ADAMs, we show that induced cleavage of EGF ligands can involve the same substratespecific metalloprotease but does require different stimulus-dependent signaling pathways. Cleavage was stimulated by phorbol ester (12-O-tetradecanoylphorbol-13-acetate (TPA), a mimic of diacylglycerol and PKC activator), hypertonic stress, lysophosphatidic acid (LPA)-induced G protein-coupled receptor activation, or by ionomycin-induced intracellular calcium release. Although ADAMs showed substrate preference (ADAM17, TGF␣ and heparin-binding EGF; and ADAM9, NRG), substrate cleavage differed substantially with the stimulus, and cleavage of the same substrate depended on the presence of different, sometimes multiple, PKC isoforms. For instance, classical PKC was required for TPA-induced but not hypertonic stress-induced cleavage of all EGF family ligands. Inhibition of PKC enhanced NRG release upon TPA stimulation, but it blocked NRG release in response to hypertonic stress. Our results suggest a model in which substantial regulation of ectodomain cleavage occurs not only on the metalloprotease level but also on the level of the substrate or of a third protein.Metalloprotease-mediated ectodomain cleavage of transmembrane proteins such as EGF ligand precursors is involved in the regulation of many physiological signaling pathways, and its dysregulation can cause kidney disease, heart disease, and cancer (1, 2). For example, in the kidney, many of the deleterious effects of chronic exposure to the G-protein-coupled receptor (GPCR) 2 agonist angiotensin II are mediated by metalloproteinase (ADAM17)-dependent release of the EGF ligand TGF␣ and subsequent epidermal growth factor receptor activation. Angiotensin II is the main effector of the renin-angiotensin system and has important roles in the regulation of blood pressure and aldosterone secretion (3).Although several ADAM gene disruptions are lethal in the mouse, metalloprotease inhibitors have shown therapeutic potential; however, not unexpectedly, the essential role of ADAMs in normal physiology as well as the broad spectrum nature of currently available inhibitors are probably the cause for a number of their side effects. In addition, concerns have been raised that some metalloproteases act as tumor suppressors (4,5). A more precise inhibiti...

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ADAMs, cell migration and cancer

Cited by 109 publications

References 104 publications

ADAM23 Negatively Modulates αvβ3 Integrin Activation during Metastasis

ADAM23 Negatively Modulates αvβ3 Integrin Activation during Metastasis

Role of ADAMs in Cancer Formation and Progression

Epidermal Growth Factor (EGF) Ligand Release by Substrate-specific A Disintegrin and Metalloproteases (ADAMs) Involves Different Protein Kinase C (PKC) Isoenzymes Depending on the Stimulus

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