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Peking University-Juntendo University Joint Symposium on Cancer Research and Treatment ADAM28 (A Disintegrin and Metalloproteinase 28) in Cancer Cell Proliferation and Progression

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Peking University-Juntendo University Joint Symposium on Cancer Research and Treatment ADAM28 (A Disintegrin and Metalloproteinase 28) in Cancer Cell Proliferation and Progression Whatʼs New from Juntendo University, Tokyo Juntendo Medical Journal 2017. 63(5), 322-325 Peking University - Juntendo University Joint Symposium on Cancer Research and Treatment ADAM28 (a Disintegrin and Metalloproteinase 28) in Cancer Cell Proliferation and Progression YASUNORI OKADA＊ ＊Department of Pathophysiology for Locomotive and Neoplastic Diseases, Juntendo University Graduate School of Medicine, Tokyo, Japan A disintegrinandmetalloproteinase 28 (ADAM28) is overexpressedpredominantlyby carcinoma cells in more than 70% of the non-small cell lung carcinomas, showing positive correlations with carcinoma cell proliferation and metastasis. ADAM28 cleaves insulin-like growth factor binding protein-3 (IGFBP-3) in the IGF-I/IGFBP-3 complex, leading to stimulation of cell proliferation by intact IGF-I released from the complex. ADAM28 also degrades von Willebrand factor (VWF), which induces apoptosis in human carcinoma cell lines with negligible ADAM28 expression, andthe VWF digestionby ADAM28-expressing carcinoma cells facilitates them to escape from VWF-induced apoptosis, resulting in promotion of metastasis. We have developed human antibodies against ADAM28 andshown that one of them significantly inhibits tumor growth andmetastasis using lung adenocarcinoma cells. Our data suggest that ADAM28 may be a new molecular target for therapy of the patients with ADAM28-expressing non-small cell lung carcinoma. Key words: a disintegrin and metalloproteinase 28 (ADAM28), cell proliferation, invasion, metastasis, human antibody inhibitor Introduction human cancers 2). However, development of the synthetic inhibitors of MMPs andtheir application Cancer cell proliferation andprogression are for treatment of the cancer patients failed 3). modulated by proteolytic cleavage of tissue micro- On the other hand, members of the ADAM (a environmental factors such as extracellular matrix disintegrin and metalloproteinase) gene family, (ECM), growth factors andcytokines, receptors another family belonging to the metzincin gene andcell adhesionmolecules. Matrix metalloprotei- family, have recently attractedattention, since they nases (MMPs) in the metzincin gene family play an are implicatedin various pathophysiological events important role in the modulation through degrada- such as morphogenesis, inflammation andcancers by tion of ECM and/or non-ECM molecules in human proteolytic processing of transmembrane proteins, malignant tumors, leading to promotion of cancer cleavage of secretedfactors andmodulationof cell cell invasion andmetastasis 1)-3). When focusedon adhesion and signaling events 4)-6) (Table-1). ADAM carcinoma cell-derived MMPs, MMP-2 activated members are composed of common domains includ- by membrane-type 1 MMP andMMP-7 anchored ing propeptide, metalloproteinase, disintegrin-like, to cell membranes by CD151 are known to be cysteine-rich, epidermal growth factor (EGF)-like, important in cancer cell invasion andmetastases in transmembrane andcytoplasmic domains 5) 7). They Yasunori Okada Department of Pathophysiology for Locomotive and Neoplastic Diseases, Juntendo University Graduate School of Medicine 2-1-1 Hongo, Bunkyo-ku, Tokyo 113-8421, Japan TEL: +81-3-5800-7531 FAX: +81-3-5800-7532 E-mail: [email protected] 〔Received Dec. 24, 2016〕〔AcceptedJan. 23, 2017〕 Copyright © 2017 The Juntendo Medical Society. This is an open access article distributed under the terms of Creative Commons Attribution Li- cense (CC BY), which permits unrestricted use, distribution, and reproduction in any medium, provided the original source is properly credited. doi: 10.14789/jmj.63.322 322 Table-1 The human ADAM gene family ADAM Other names Proteinase-type (P) or Potential functions Substrates Integrin-binding Sites of expression non-proteinase type (NP) andsplice variants (isoforms) ADAM2 PH-30β, Fertilin-β NP Sperm/egg binding/fusion α4β1, α6β1, α9β1 Testis ADAM7 EAP I, GP-83 NP α4β1, α4β7, α9β1 Testis, erythrocyte ADAM8 MS2 (CD156) P Shaddase, neutrophil CD23, proTNFα, RANKL Macrophage, neutrophil infiltration ADAM9 MDC9, MCMP, P, Secreted form Shaddase, cell migration ProHB-EGF, TNF-p75 receptor, α2β1, α6β1, α6β4, α9β1, Various tissues Meltrin-γ APP, fibronectin, gelatin αVβ5 ADAM10 MDAM, P Sheddase, development, ProTNF-α, collagen IV, gelatin, Kidney, brain, chondrocyte Kuzbanian angiogenesis Myelin basic protein, Delta, APP, L1, CD44, proHB-EGF, Notch, Delta-like 1, Jagged, N-cadherin, E-cadherin, VE-cadherin, Ephrin A2, Ephrin A5 FASL, IL6R Juntendo Medical Journal 63(5), 2017 ADAM11 MDC NP, Secretedform Tumor suppressor gene? Brain ADAM12 Meltrin-α, MCMP, P, Secreted form Sheddase, myogenesis, ProHB-EGF, IGFBP-3 and5, α4β1, α7β1, α9β1 Osteoblast, muscle, MLTN, MLTNA adipogenesis proepiregulin collagen IV, chondrocyte, placenta gelatin, fibronectin ADAM15 Metargidin, MDC15, P, Cytoplasmic form Arteriosclerosis, angiogenesis Collagen IV, gelatin αVβ3, α4β1, α5β1, α9β1 Smooth muscle cell, chondrocyte, endo- AD56, CR II-7 thelial cell, osteoclast, synovial cells ADAM17 TACE, cSVP P Sheddase, heart development ProTNF-α, proTGF-α, α5β1 Macrophage, various tissues TNF-p75 receptor, ErbB4, TRANCE, proHB-EGF, proamphiregulin, proepiregulin, APP, IL6R, CD44, L-selectin ADAM18 ADAM27, NP Testis tMDC III ADAM19 Meltrin-β, FKSG34 P, N-terminal form Sheddase, formation of neuron Proneuregulin, RANKL α4β1, α5β1 Various tissues andcardiovascularorgans ADAM20 P Formation of sperm Testis ADAM21 ADAM31 P Testis ADAM22 MDC2 NP, Cytoplasmic form Brain ADAM23 MDC3 NP αVβ3 Brain, heart ADAM28 e-MDC II, MDC-Lm, P, Secretedform Growth factor metabolism Myelin basic protein, IGFBP-3, α4β1, α4β7, α9β1 Testis, lung, lymphocyte, gstrointestinal MDC-Ls CD23, von Willebrandfactor system, pancreas, pituitary gland ADAM29 svph 1 NP Testis ADAM30 svph 4 P Testis ADAM32 AJ131563 NP Testis ADAM33 P Genetically relatedto bronchial asthma APP, KL-1, insulin B chain α4β1, α5β1, α9β1 Lung (flbroblast, smooth muscle). uterus ADAMDEC1 P Lymphatic system, gastrointestinal system Abbreviations: HB-EGF, heparin-binding epidermal growth factor; APP, amyloid precursor protein; TNF, tumor necrosis factor; RANKL, receptor activator of nuclear facto κB ligand; IGFBP-3, insulin-like growth factor binding protein-3; TGF, transforming growth factor; TRANCE, TNF-related activation induced cytokine; IL6R, interleukin-6 receptor; KL-1, Kit-ligand-1. 323 Okada: ADAM28 in cancer cell proliferation and progression include 21 members, among which 13 members are serum levels of ADAM28, andfoundthat the level is proteinase-type ADAMs (Table-1). Many mem- significantly higher in the patients than in the brane proteins including growth factors such as EGF, control normal subjects 9). The levels were signifi- heparin-binding EGF, transforming growth factor-α cantly increasedwith advancesof tumor stage, and andcytokines such as tumor necrosis factor- α significantly higher in the patients with recurrent (TNF-α) are synthesizedas precursors andactivated carcinoma or lymph node metastasis. When the by processing with proteinases. In addition, a number proportion of ADAM28-immunostainedcarcinoma of cell surface receptors including TNF-α receptor-I, cells to total carcinoma cells (immunoreactivity) in TNF-α receptor-II, CD44, L-selectin andErb4/HER4 the adenocarcinomas with a tumor size of ≤20 mm undergo cleavage near the transmembrane domain, a in diameter was compared with the 7-year survival process called ectodomain shedding 4). In both cases, of the patients, disease-free and overall survivals ADAMs play a major role. ADAM members have cell were significantly lower in the ADAM28 high- adhesion properties by interaction with integrins and expressing group than in the low-expressing other proteins such as syndecans and fibronectin, group 9). These data suggest that the serological which may be involvedin cancer cell motility, invasion and/or histological assessment of ADAM28 may be andmetastasis. Thus, ADAMs are expectedto play diagnostic and prognostic markers for non-small roles in cancer cell proliferation andprogression cell lung carcinoma patients. through proteolytic and/or non-proteolytic modula- To examine the regulation mechanisms of tion of membrane andsecretedproteins. ADAM28 gene expression, we investigatedthe expression of ADAM28 in Madin-Darby canine Expression of ADAM28 in human non-small cell kidney epithelial cells transformed by several lung carcinomas oncogenes, andfoundthat v-src transformants selectively induce ADAM28 10). We also showedthat To study the expression of ADAM members, the the ADAM28 expression in human carcinoma cell mRNA expression of proteinase-type ADAM lines is correlatedwith phosphorylation of Src, and species including ADAM9, 10, 12, 15, 17, 19, 20, 21, demonstrated co-expression of ADAM28 and 28 and30 was examinedin human non-small cell phosphorylatedSrc in neoplastic cells of the lung, lung carcinomas 8). RT-PCR showedthat among the breast andcolon carcinomas. In both v-src trans- ADAM species examined, only ADAM28, which is formants andhuman ADAM28-expressing carci- composedof prototype membrane-type ADAM28m noma cell lines, activation of Src andits downstream andshort secreted-typeADAM28s, appearedto be MEK/ERK andPI3K/mTOR signaling pathways selectively expressedin all the carcinoma tissues. were essential to overexpression of ADAM28 10). Real-time quantitative PCR indicated that the relative expression levels of ADAM28m and Substrates and functions of ADAM28 ADAM28s are significantly more than 10-fold in carcinoma cell proliferation and metastasis higher
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