ADAM-Mediated Signalling Pathways in Gastrointestinal Cancer Formation

Schumacher, Neele; Rose-John, Stefan; Schmidt-Arras, Dirk

doi:10.3390/ijms21145133

Cited by 17 publications

(18 citation statements)

References 130 publications

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“…Another group of cell surface metalloproteases, the ADAMs (A disintegrin and metalloproteases), is largely implicated in the shedding of protein ectodomain and paracrine signal transduction. Notably, ADAM10 and ADAM17 (TACE) play roles in gastroenterological tumors, contributing to different processes, such as a reduction in DNA damage repair, tumor growth, vascularization, and in the control of inflammatory responses in the intestine [ 90 , 91 , 92 ]. These two membrane-bound ADAM proteases can mediate the cleavage of mPD-L1 and release sPD-L1, as a 37-kDa N-terminal PD-L1 fragment, in breast cancer cell lines.…”

Section: Generation Of Soluble Pd-l1: Proteolysis and Alternative Splicingmentioning

confidence: 99%

Soluble Programmed Death Ligand-1 (sPD-L1): A Pool of Circulating Proteins Implicated in Health and Diseases

Bailly

Thuru

Quesnel

2021

Cancers

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Upon T-cell receptor stimulation, the Programmed cell Death-1 receptor (PD-1) expressed on T-cells can interact with its ligand PD-L1 expressed at the surface of cancer cells or antigen-presenting cells. Monoclonal antibodies targeting PD-1 or PD-L1 are routinely used for the treatment of cancers, but their clinical efficacy varies largely across the variety of tumor types. A part of the variability is linked to the existence of several forms of PD-L1, either expressed on the plasma membrane (mPD-L1), at the surface of secreted cellular exosomes (exoPD-L1), in cell nuclei (nPD-L1), or as a circulating, soluble protein (sPD-L1). Here, we have reviewed the different origins and roles of sPD-L1 in humans to highlight the biochemical and functional heterogeneity of the soluble protein. sPD-L1 isoforms can be generated essentially by two non-exclusive processes: (i) proteolysis of m/exoPD-L1 by metalloproteases, such as metalloproteinases (MMP) and A disintegrin and metalloproteases (ADAM), which are capable of shedding membrane PD-L1 to release an active soluble form, and (ii) the alternative splicing of PD-L1 pre-mRNA, leading in some cases to the release of sPD-L1 protein isoforms lacking the transmembrane domain. The expression and secretion of sPD-L1 have been observed in a large variety of pathologies, well beyond cancer, notably in different pulmonary diseases, chronic inflammatory and autoimmune disorders, and viral diseases. The expression and role of sPD-L1 during pregnancy are also evoked. The structural heterogeneity of sPD-L1 proteins, and associated functional/cellular plurality, should be kept in mind when considering sPD-L1 as a biomarker or as a drug target. The membrane, exosomal and soluble forms of PD-L1 are all integral parts of the highly dynamic PD-1/PD-L1 signaling pathway, essential for immune-tolerance or immune-escape.

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Section: Generation Of Soluble Pd-l1: Proteolysis and Alternative Splicingmentioning

confidence: 99%

Soluble Programmed Death Ligand-1 (sPD-L1): A Pool of Circulating Proteins Implicated in Health and Diseases

Bailly

Thuru

Quesnel

2021

Cancers

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“…Among others, this comprises soluble factors like chemokines and cytokines, growth factors, adhesion molecules, and receptors that have also been described to be released as soluble forms by ectodomain shedding [ 22 , 23 ]. ADAM17, which is at the focus of this study, has been demonstrated as a key sheddase controlling ectodomain cleavage of various substrates involved in metastasis, tumor progression, and therapy resistance [ 9 , 24 ].…”

Section: Discussionmentioning

confidence: 99%

Regulation of Platelet-Derived ADAM17: A Biomarker Approach for Breast Cancer?

Zhou¹,

Kropp

Hinterleitner³

et al. 2021

Diagnostics

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Tumor progression and metastasis are critically dependent on the tumor microenvironment. A disintegrin and metalloproteinase 17 (ADAM17) is associated with shedding of several substrates involved in tumor progression and known to be expressed by platelets of healthy donors and patients with solid tumors. Here, we report that platelet-derived ADAM17 (pADAM17) is regulated upon platelet activation of breast cancer patients, but not of healthy individuals. The observed downregulation of pADAM17 on platelets of cancer patients correlated with clinical parameters related to tumor progression including tumor stage and the occurrence of metastasis. Our data identify an association between platelet activation, modulation of platelet-derived ADAM17, and metastasis. In conclusion, we demonstrate that further development of pADAM17 as a liquid biomarker is warranted for monitoring disease progression in breast cancer.

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“…The ectodomain shedding by ADAM proteases is perceived as a prerequisite for the release of intracellular receptor domains (ICD) upon γ-secretase cleavage [8]. A role for γ-secretase in TNF mediated cell death induction in MCF-7 cells has been reported [7].…”

Section: Pharmacological Inhibition Of γ-Secretase Does Not Alter Tnf-r1 Mediated Cell Death Inductionmentioning

confidence: 99%

“…In general, it is assumed that extracellular cleavage by proteases of the A disintegrin and metalloproteinase enzyme family (i.e., ADAM17 or ADAM10) precedes RIP. While ADAM10 activity appears to be constitutive, ADAM17 can be activated (i.e., by phorbol myristate acetate, PMA) [8]. In human umbilical vein endothelial cells (HUVEC) cells, ADAM17 activity was required and modulated by extracellular sphingomyelinase for apoptosis induction [9].…”

Section: Introductionmentioning

confidence: 99%

Roles for ADAM17 in TNF-R1 Mediated Cell Death and Survival in Human U937 and Jurkat Cells

Fritsch

Frankenheim

Marischen

et al. 2021

Cells

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Signaling via death receptor family members such as TNF-R1 mediates pleiotropic biological outcomes ranging from inflammation and proliferation to cell death. Pro-survival signaling is mediated via TNF-R1 complex I at the cellular plasma membrane. Cell death induction requires complex IIa/b or necrosome formation, which occurs in the cytoplasm. In many cell types, full apoptotic or necroptotic cell death induction requires the internalization of TNF-R1 and receptosome formation to properly relay the signal inside the cell. We interrogated the role of the enzyme A disintegrin and metalloprotease 17 (ADAM17)/TACE (TNF-α converting enzyme) in death receptor signaling in human hematopoietic cells, using pharmacological inhibition and genetic ablation. We show that in U937 and Jurkat cells the absence of ADAM17 does not abrogate, but rather increases TNF mediated cell death. Likewise, cell death triggered via DR3 is enhanced in U937 cells lacking ADAM17. We identified ADAM17 as the key molecule that fine-tunes death receptor signaling. A better understanding of cell fate decisions made via the receptors of the TNF-R1 superfamily may enable us, in the future, to more efficiently treat infectious and inflammatory diseases or cancer.

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ADAM-Mediated Signalling Pathways in Gastrointestinal Cancer Formation

Cited by 17 publications

References 130 publications

Soluble Programmed Death Ligand-1 (sPD-L1): A Pool of Circulating Proteins Implicated in Health and Diseases

Soluble Programmed Death Ligand-1 (sPD-L1): A Pool of Circulating Proteins Implicated in Health and Diseases

Regulation of Platelet-Derived ADAM17: A Biomarker Approach for Breast Cancer?

Roles for ADAM17 in TNF-R1 Mediated Cell Death and Survival in Human U937 and Jurkat Cells

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