SEARCH

SEARCH BY CITATION

Abstract

  1. Top of page
  2. Abstract
  3. Members of the ADAM gene family
  4. Regulation of ADAM activity
  5. Expression and functions of ADAM in cancers
  6. Conclusions
  7. References

A disintegrin and metalloproteinases (ADAMs) are a new gene family of proteins with sequence similarity to the reprolysin family of snake venomases that share the metalloproteinase domain with matrix metalloproteinases (MMPs). They are structurally classified into two groups: the membrane-anchored ADAM and ADAM with thrombospondin motifs (ADAMTS). These molecules are involved in various biological events such as cell adhesion, cell fusion, cell migration, membrane protein shedding and proteolysis. Studies on the biochemical characteristics and biological functions of ADAMs are in progress, and accumulated lines of evidence have shown that some ADAMs are expressed in malignant tumors and participate in the pathology of cancers. The activities of ADAMs are regulated by gene expression, intracytoplasmic and pericellular regulation, activation of the zymogens and inhibition of activities by inhibitors. Many ADAM species, including ADAM8, ADAM9, ADAM10, ADAM12, ADAM15, ADAM17, ADAM19, ADAM28, ADAMTS1, ADAMTS4 and ADAMTS5, are expressed in human malignant tumors. Many of them are involved in the regulation of growth factor activities and integrin functions, leading to promotion of cell growth and invasion, although the precise mechanisms of these are not clear at the present time. In this article, we review recent information about ADAM family members and their implications for cancer cell proliferation and progression. (Cancer Sci 2007; 98: 621–628)

Abbreviations:  
ADAM

a disintegrin and metalloproteinase

ADAMTS

ADAM with thrombospondin motifs

ECM

extracellular matrix

EGF

epidermal growth factor

Foxm1

forkhead box m1

HB-EGF

heparin-binding epidermal growth factor

IC50

half maximal inhibitory concentration

IGF-I

insulin-like growth factor 1

IGFBP-3

insulin-like growth factor binding protein-3

MAPK

mitogen-activated protein kinase

MMP

matrix metalloproteinase

PKC

protein kinase C

PSGL-1

P-selectin glycoprotein ligand-1

RGD

Arg-Gly-Asp

TACE

TNF-α converting enzyme

TGF

transforming growth factor

TIMP

tissue inhibitor of metalloproteinases

TNF

tumor necrosis factor

TPA

12-O-tetradecanoylphorbol-13-acetate.

Modulation of tissue microenvironment through degradation of the ECM, processing of growth factors and activation of cell adhesion molecules is essential to cancer cell proliferation and progression. MMPs may play a central role in these processes, and elevated expression and activation of MMPs have been reported in many human cancer tissues.(1) Biochemical and clinicopathological analyses have suggested that the expression and activation of proMMP-2 by membrane-type 1 MMP and proMMP-7 anchored to cell membranes by CD151, a member of the tetraspanin family, are important in cancer cell invasion and metastasis in human malignant tumors.(2)

In recent years, however, members of the ADAM family of proteins, an MMP-related metalloproteinase family, have attracted attention, and functional analyses of ADAMs are ongoing. ADAMs are multifunctional proteins involved in the proteolytic processing of other transmembrane proteins, cell adhesion and cell signaling events. Many transmembrane proteins are processed by one or several proteolytic steps to the biologically active configuration. Examples include growth factors such as EGF, HB-EGF and TGF-α, and cytokines such as TNF-α, all of which are synthesized as precursors. In addition, there are a number of cell surface receptors that undergo cleavage near the transmembrane domain, a process called ectodomain shedding. These include TNF-α receptor-I, TNF-α receptor-II, CD44, L-selectin and Erb4/HER4. The soluble, released ectodomains of the receptors may be part of the downmodulation in response to ligand activation, or they may have a function of their own. It has become clear over the past few years that ADAMs play a major role in these processes.

Another function of ADAMs lies in their ability to act as ligands for integrins by competing with matrix proteins.(3) In addition, ADAMs have cell adhesion properties mediated by the interaction of their cysteine-rich domains with other proteins such as syndecans(4) and fibronectin.(5) The cytoplasmic tails of some ADAMs contain SH3-binding sites, which can potentially activate SH3 domain-containing signaling molecules such as src and grb.(3) Furthermore, recent studies have demonstrated that several ADAMs are highly expressed in cancer cells and cancer tissues. Although information about the functions of ADAMs in cancers is still limited, it is worth reviewing the biochemical and biological characteristics of ADAMs and their involvement in human cancer cell proliferation and progression according to the data of our group and other studies.

Members of the ADAM gene family

  1. Top of page
  2. Abstract
  3. Members of the ADAM gene family
  4. Regulation of ADAM activity
  5. Expression and functions of ADAM in cancers
  6. Conclusions
  7. References

There are two groups in the ADAM family: membrane-anchored ADAM (Table 1) and secreted-type ADAMTS (Table 2). ADAM members are composed of common domains including propeptide, metalloproteinase, disintegrin, cysteine-rich, EGF-like, transmembrane and cytoplasmic domains, whereas ADAMTS members contain thrombospondin motifs, cysteine-rich and spacer domains in addition to propeptide, metalloproteinase and disintegrin domains (Fig. 1). Several ADAM genes give rise to more than one protein due to differential splicing of mRNA. This causes the synthesis of secreted ADAM proteins, in addition to membrane-anchored forms, or variation in the length of the cytoplasmic tail of ADAM proteins.

Table 1. The a disintegrin and metalloproteinase (ADAM) gene family
ADAMOther namesTypeFunctions and featuresIntegrin-bindingLocalization
  1. APP, amyloid precursor protein; HB-EGF, heparin-binding epidermal growth factor; IGFBP-3, insulin-like growth factor binding protein-3; KL-1, Kit-ligand-1; N, non-proteinase type; P, proteinase type; TGF, transforming growth factor; TNF, tumor necrosis factor; TRANCE, TNF-related activation induced cytokine.

ADAM1PH-30α Fertillin-αNPSperm–egg binding and fusionα6β1 and α9β1Sperm
ADAM2PH-30β, Fertilin-βNPSperm–egg binding and fusionα4β1, α6β1 and α9β1Sperm
ADAM3Cyritestin, tMDC, CYRNNP α4β1, α6β1 and α9β1Sperm
ADAM4tMDC VNP  Testis
ADAM5tMDC IINP  Testis
ADAM6tMDC IVNP  Testis
ADAM7EAP I, GP-83NP α4β1, α4β7 and α9β1Testis
ADAM8MS2 (CD156)PNeutrophil infiltration, shedding of CD23 Macrophage, neutrophil
ADAM9MDC9, MCMP, Meltrin-γPShedding of HB-EGF, TNF-p75 receptor, cleavage of APP, digestion of fibronectin and gelatinα2β1, α6β1, α6β4, α9β1 and αVβ5Various tissues
ADAM10MDAM, KuzbanianPRelease of TNF-α, digestion of collagen IV, gelatin and myelin basic protein, cleavage of delta, APP, L1, and CD44, shedding of HB-EGF, presence of RRKR sequence  Kidney, brain, chondrocyte
ADAM11MDCNPTumor suppressor gene? Brain
ADAM12Meltrin-α, MCMP, MLTN, MLTNAPMuscle formation, presence of RRKR sequence, digestion of IGFBP-3 and 5, shedding of HB-EGF, digestion of collagen IV, gelatin and fibronectinα4β1, α7β1 and α9β1Osteoblast, muscle, chondrocyte, placenta
ADAM13xMDC13a, x ADAM13aNPMovement of neural crest Xenopus laevis
ADAM14ADM-1NP  Caenorhabditis elegans
ADAM15Metargidin, MDC15, AD56, CR II-7PExpression in arteriosclerosis, digestion of collagen IV and gelatinαVβ3, α5β1 and α9β1Smooth muscle cell, chondrocyte, endothelial cell, osteoclast
ADAM16xMDC16NP  Xenopus laevis
ADAM17TACE, cSVPPShedding of TNF-α, TGF-β, TNF-p75 receptor, ErbB4, TRANCE and HB-EGF, presence of RRKR sequence, cleavage of APP, Notch, L-selectin and CD44α5β1Macrophage, various tissues
ADAM18tMDC IIINP  Testis
ADAM19Meltrin-β, FKSG34PFormation of neuron, digestion of neuregulinα4β1 and α5β1Testis
ADAM20 PFormation of sperm Testis
ADAM21ADAM31P  Testis
ADAM22MDC2NP  Brain
ADAM23MDC3NP αVβ3Brain, heart
ADAM24Testinase-1NPSperm–egg binding and fusion Testis
ADAM25Testinase-2NP  Testis
ADAM26Testinase-3NP  Testis
ADAM27ADAM18, tMDCIIINP  Testis
ADAM28e-MDC II, MDC-Lm, MDC-LsPDigestion of myelin basic protein and IGFBP-3α4β1, α4β7 and α9β1Testis, lung, lymphocyte, pancreas, uterus
ADAM29svph 1NP  Testis
ADAM30svph 4P  Testis
ADAM32AJ131563NP  Testis
ADAM33 PMutation in bronchial asthma patients, cleavage of APP, KL-1 and insulin B chainα4β1, α5β1 and α9β1Lung (flbroblast, smooth muscle)
ADAM34Testinase-4NP  Testis
Table 2. The a disintegrin and metalloproteinase with thrombospondin motifs (ADAMTS) gene family
ADAMTSOther namesProteinase activityFunctions and biochemical featuresLocalization
ADAMTS 1C3-C5, METH1, KIAA1346+Binding to heparin, presence of RRKR sequence, digestion of aggrecan and versicanKidney, heart, cartilage
ADAMTS 2Procollagen N-proteinase, hPCPNI, PCINP+Processing of collagen I and II N-propeptidesSkin, tendon
ADAMTS 3KIAA 0366+Processing of collagen N-propeptidesBrain
ADAMTS 4KIAA0688, aggrecanase-1, ADMP-1+Digestion of aggrecan, brevican and versicanBrain, heart, cartilage
ADAMTS 5ADAMTS11, aggrecanase-2, ADMP-2+Digestion of aggrecanUterus, placenta, cartilage
ADAMTS 6   Placenta
ADAMTS 7   Various tissues
ADAMTS 8METH-2+Digestion of aggrecan, inhibition of angiogenesisLung, heart
ADAMTS 9KIAA1312+Digestion of aggrecanCartilage
ADAMTS 10
ADAMTS 12   Lung (fetus)
ADAMTS 13vWFCP, C9orf8+Cleavage of von Willebrand factorLiver, prostate, brain
ADAMTS 14 +Processing of collagen N-propeptidesBrain, uterus
ADAMTS 15 +Digestion of aggrecanLiver (fetus), kidney (fetus)
ADAMTS 16   Prostate, brain, uterus
ADAMTS 17FLJ32769, LOC123271  Prostate, brain, liver
ADAMTS 18ADAMTS21, HGNC:16662  Prostate, rain
ADAMTS 19   Lung (fetus)
ADAMTS 20   Brain, testis
image

Figure 1. Domain structures of a disintegrin and metalloproteinase (ADAM) and ADAM with thrombospondin motifs (ADAMTS). Members of the ADAM gene family are classified as membrane-anchored ADAM and secreted-type ADAMTS subgroups. CR, cysteine-rich domain; CT, cytosolic tail; Dis, disintegrin domain; E, epidermal growth factor-like domain; MP, metalloproteinase domain; Pro, propeptide domain; SP, spacer domain; TM, transmembrane domain; TS, thrombospondin-like domain.

Download figure to PowerPoint

According to differences in the active site sequence of the metalloproteinase domain, 60% of the members are non-proteolytic ADAM molecules, which are not discussed in this review. In contrast, active sites in the metalloproteinase domain of the proteinase-type ADAM molecules (ADAM8, -9, -10, -12, -15, -17, -19, -20, -21, -28, -30 and -33) contain a common HEXGHXXGXXHD sequence with a ‘Met-turn’, which is also present in the catalytic metalloproteinase domain of MMP members. For an up-to-date and authoritative list of all ADAMs, refer to the website of Dr Judith White at the University of Virginia (see http://www.people.virginia.edu/%7Ejw7g/Table_of_the_ADAMs.html). Among these ADAM proteins, proteinase activities have been demonstrated for ADAM8, -9, -10, -12, -15, -17, -19, -28 and -33 (Table 1). One of the major functions of ADAMs is shedding of membrane proteins. ADAM17 has been most extensively examined and is known to release soluble TNF-α from its membrane precursor, thus called TACE.(3) ADAM9, ADAM10 and ADAM17 can cleave amyloid precursor protein at the α-secretase processing site.(6) ADAM9 is implicated in the ectodomain shedding of membrane-anchored proHB-EGF.(7) ADAM12 also acts as a sheddase for proHB-EGF.(8) We have recently reported that ADAM28 cleaves IGFBP-3 at a site between the Arg97–Ala98 bond present in the central domain of this molecule.(9) Like MMPs, some ADAMs can also degrade ECM: ADAM10 cleaves type IV collagen,(10) ADAM12 digests gelatin, type IV collagen and fibronectin,(11) and ADAM15 cleaves type IV collagen and gelatin in vitro.(12)

The ADAMTS group comprises 19 members, all of which are proteinase type (Table 2). Information about their substrates and biological functions remains limited, but ADAMTS1, -2, -3, -4, -5, -8, -9 and -15 are ECM-degrading protein- ases. ADAMTS1, -4, -5, -8, -9 and -15 cleave specific Glu–X bonds (where X is most often Ala or Glu) of the core protein of aggrecan.(13,14) Due to their aggrecan-degrading activity, ADAMTS4 and ADAMTS5 are called aggrecanase-1 and aggrecanase-2, respectively,(15,16) and brevian and versican are also cleaved by ADAMTS4.(17,18) It is well known that ADAMTS 13 is a von Willebrand factor-cleaving proteinase, and its mutation causes thrombotic thrombocytopenic purpura.(19)

Regulation of ADAM activity

  1. Top of page
  2. Abstract
  3. Members of the ADAM gene family
  4. Regulation of ADAM activity
  5. Expression and functions of ADAM in cancers
  6. Conclusions
  7. References

ADAM activities can be regulated by several mechanisms, such as gene expression, intracytoplasmic and pericellular regulation, zymogen activation and inhibition by inhibitors, although the regulation mechanisms are not completely understood.

Gene expression.  The levels of ADAM17 mRNA expression show a 90% reduction in the lungs of knockout Foxm1 mice(20) indicating that foxm1, a transcription factor, may regulate the expression of ADAM17 in vivo. Expression of ADAM8 is induced via interferon-regulating factor 1 by treatment of the granular cells with TNF-α.(21) Sung et al. recently reported that intracellular reactive oxygen species and hydrogen peroxide, generated by cell stress, are inducers of ADAM9 expression.(22) In addition, the expression of ADAM12 is upregulated in hepatic stellate cells treated with TGF-β(23) and this effect is via phosphatidylinositol-3 kinase and MAPK kinase activities.

Intracytoplasmic and pericellular regulation.  The intracytoplasmic tails of most ADAM contain putative recognition motifs for signaling proteins and adaptors.(3) Thus, it is plausible that these proteins could participate in the regulation of metalloproteinase activity or subcellular localization of ADAM. TPA-induced ADAM activation has been widely established. In the TPA-stimulated processing of HB-EGF, PKCδ is involved.(7) PKCδ is considered to directly associate with and phosphorylate the cytoplasmic domain of ADAM9, and then HB-EGF shedding occurs. Similarly, TPA-stimulated shedding of the nerve growth factor receptor by ADAM17 appears to involve phosphorylation of the ADAM17 cytoplasmic tail.(24) Concerning subcellular localization of ADAM, PKCɛ is known to induce ADAM12 translocation to the cell surface depending on catalytic activity of PKCɛ.(25) In addition, extracellular signal-regulated kinase-dependent phosphorylation of Thr735 in ADAM17 molecules induces translocation of ADAM17 to the cell surface.(26) It is possible to speculate that modification of the intracytoplasmic tail domains of ADAMs causes their conformational changes, leading to activation of the ADAMs through cleavage of their prodomains. It is also possible that interaction with associated proteins relocates ADAMs to specialized regions of the membranes resulting in clustering of ADAM molecules, enabling them to interact with specific substrates. However, these possibilities remain to be elucidated by further work.

Zymogen activation.  Some ADAM members such as ADAM12 and ADAM17 have the furin-recognition site (RXXR sequence) at the end of the propeptide domain, and proprotein convertases such as furin can activate these proADAMs intracellularly.(27) ADAMTS4 is also activated intracellularly through processing of the propeptide by furin. However, the activation mechanism of other ADAMs without furin-recognition sites is not well known. We have reported that MMP-7 processes proADAM28 into the active form.(9) Although MMP-7 may not be only an activator for proADAM28, the data suggest a possible activation cascade of proADAMs by the action of MMPs. In addition to removal of the propeptide, secondary processing takes place and this may be important for some ADAMs to exhibit their full activity, especially in ADAMTS members. The C-terminal spacer region is cleaved with MT4-MMP(28) and truncation of the spacer region appears to result in full proteinase activity of ADAMTS4. The C-terminal fragment of ADAMTS4 is also reported to function as a competitor for the activity of the mature enzyme.(16) In addition, ADAMTS1 is cleaved within its spacer region by MMP-2, MMP-8 and MMP-15, leading to two distinct active forms.(29) However, it is not known whether these secondary cleavages are essential to many ADAM species. Thus, further studies are definitely needed to clarify the activation mechanism of ADAM species.

Inhibition of activities by inhibitors.  The activities of ADAMs can be inhibited by TIMPs, which were originally cloned as endogenous inhibitors of MMPs.(30) They are composed of four different members of 21–28 kDa with 40–50% sequence homology (i.e. TIMP-1, -2, -3 and -4). TIMP-1, -2, -3 and -4 all inhibit MMP activity by binding in a 1 : 1 molar ratio to form tight, non-covalent complexes, although TIMP-1 does not inhibit MT-MMPs efficiently.(30) In contrast to universal inhibition of MMPs by TIMPs, the activities of ADAMs are inhibited mainly by TIMP-3. TIMP-3 efficiently inhibits the activity of ADAM10,(31) ADAM12,(32) ADAM17,(31) ADAM28(9) and ADAM33,(33) as well as ADAMTS4 and ADAMTS5,(34) although some inhibitory activity of TIMP-1, TIMP-2 and TIMP-4 to ADAM10,(31) ADAM17,(6) ADAM28(9) and/or ADAM33(33) have also been reported. Based on the data of the constructed mutants of TIMP-3 that disrupt the interaction with MMP but not ADAM17, the inhibition mechanism of TIMP-3 for ADAM17 is considered to be different to that for MMP,(35) although the N-terminal subdomain of loops 1 through 3 is essential to the inhibition of both MMP and ADAM17. In contrast, ADAM8, ADAM9 and ADAM19 are not inhibited by any TIMP.(36,37) Because of the limited inhibitor activity to ADAM and tissue distribution of TIMP, it is plausible that besides TIMP, there must be inhibitor molecules to ADAM. Actually, our recent study demonstrated that ADAMTS4 is inhibited through interaction with fibronectin.(38) Further studies on inhibition mechanism of ADAM activities by new molecules are necessary.

Several synthetic inhibitors have been developed. The catalytic activity of ADAM8 and ADAM19 is sensitive to the hydroxamic acid-type inhibitor BB94 (Batimastat) (IC50 for ADAM8 = 50 nM), which was developed for inhibition of MMP.(37,39) The most efficient inhibitor compound for ADAM9 is CGS27023 (Kj = 1 nM).(40) Asakura et al.(8) have selected KB-R7785 as one of the most potent inhibitors for HB-EGF shedding by ADAM12 from over 2000 metalloproteinase inhibitors. KB-R7785 also completely inhibits ADAM28 activity at 1 µM.(9) Inhibitors selective to each ADAM member have been developed and the inhibitory activity of GI254023X to ADAM10 is more than 100-fold higher than that to ADAM17.(41) In addition, INCB3619 inhibits both ADAM17 and ADAM10 300-fold more efficiently (IC50 for ADAM17 = 14 nM and IC50 for ADAM10 = 22 nM) than ADAM9 and ADAM33.(42)

Expression and functions of ADAM in cancers

  1. Top of page
  2. Abstract
  3. Members of the ADAM gene family
  4. Regulation of ADAM activity
  5. Expression and functions of ADAM in cancers
  6. Conclusions
  7. References

There are many reports showing that members of the ADAM family are overexpressed in human cancers. These include the expression of ADAM8, ADAM9, ADAM10, ADAM12, ADAM15, ADAM17, ADAM19, ADAM28, ADAMTS1, ADAMTS4 and ADAMTS5 (Table 3). Although most of the reports describe the expression without functional analyses, expression and the possible roles of each ADAM species in cancers can be reviewed as follows.

Table 3. Expression of a disintegrin and metalloproteinases (ADAMs) in human cancers and their possible functions
ADAMMolecular weight (full length, kDa)Expression in cancersFunctions in cancersInhibitorsTIMP inhibition
  1. AR, amphiregulin; HB-EGF, heparin-binding epidermal growth factor; IGFBP-3, insulin-like growth factor binding protein-3; TGF, transforming growth factor; TIMP, tissue inhibitor of metalloproteinases.

ADAM888.7Lung,43 kidney,68 brain44Promotion of migrationBatimastat (BB94)None
ADAM9ADAM9: 90.5 ADAM9s: 72.3Breast,45 pancreas69 Stomach,50 skin,70 liver,71 lung48Promotion of cell adhesion and invasion, binding to integrins (α6β4 and α2β1)CGS 27023None
ADAM1084.1Oral cavity,49 stomach,72 ovary,51 uterine,51 colon,73 leukemia,74 prostate75L1 shedding, promotion of cell growth and migrationGI254023X, INCB3619TIMP-1, TIMP-3
ADAM12ADAM12m: 99.5 ADAM12s: 80.4Brain,54 breast,11 liver,23 stomach,50 colon55HB-EGF shedding, promotion of cell growthKB-R7785TIMP-3
ADAM1587.7Breast,58 prostate,76 stomach,50 lung57Promtion of cell growthNo studyNo study
ADAM1793Breast,58 ovary,77 kidney,68 colon,78 prostate79TGF-β shedding, promotion of cell growthINCB3619TIMP-2, TIMP-3
ADAM19105Brain,44 kidney68No studyBatimastat (BB94)None
ADAM28ADAM28m: 87 ADAM28s: 65Lung,62 breast,63 kidney68IGFBP-3 cleavage, promotion of cell growthKB-R7785TIMP-3, TIMP-4
ADAMTS1105Breast80HB-EGF and AR shedding, promotion of cell growth, survival and invasionNo studyNo study
ADAMTS490.2Brain66No studyNo studyTIMP-3
ADAMTS5101.7Brain67Brevican cleavage, promotion of invasionNo studyTIMP-3

ADAM8 (CD156/MS2).  Ishikawa et al. screened genes encoding transmembrane/secretory proteins that are upregulated in lung cancers by cDNA microarrys, and found that ADAM8 is specifically overexpressed in most cancer tissues and elevated in serum samples from the patients(43) (Table 3). They also showed that transfection of ADAM8 into tumor cells enhances the invasive activity. Overexpression of ADAM8 has also been reported in human renal cell carcinomas (Table 3). Furthermore, ADAM8 is highly regulated in human primary brain tumors such as astrocytomas, and the expression levels and activity are associated with invasiveness.(44) These reports suggest that ADAM8 is involved in tumor cell migration and invasion.

ADAM9 (MDC9, Meltrin γ).  ADAM9 is reportedly expressed in an active form at higher levels in breast cancers with lymph node metastasis than in those without metastasis, and correlates positively with HER-2/neu protein levels.(45) Similarly, ADAM9 is overexpressed in several cancers such as pancreatic cancer, stomach cancer, skin melanoma and hepatocellular carcinoma (Table 3). A recent experimental study using a mouse model has demonstrated that ADAM9 contributes to prostate carcinogenesis by cleaving EGF receptor ligands and the receptor for fibroblast growth factor.(46) ADAM9, secreted by activated stromal cells, is known to induce colon carcinoma cell invasion in vitro through binding to α6β4 and α2β1 integrins.(47) In addition, ADAM9 enhances cell adhesion and invasion of non-small cell lung carcinoma cells via modulation of α3β1 integrin and sensitivity to growth factors, and thus promotes brain metastasis of the carcinoma cells.(48) Therefore, it is suggested that ADAM9 plays a role in tumorigenesis, invasion and metastasis through modulation of growth factor activity and integrin function.

ADAM10 (Kuzbanian, MADM).  Overexpression of ADAM10 appears to promote the growth of oral squamous cell carcinoma and gastric carcinoma, as downregulation of its expression with antisense oligonucleotides or treatment with anti-ADAM10 antibodies reduces proliferation of the carcinoma cells.(49,50) ADAM10-mediated L1 release is reported to enhance tumor dissemination by increasing cell migration in ovarian and uterine carcinomas.(51) L1 is also involved in the motility and invasion of lymphoma, lung carcinoma and melanoma cells, where ADAM10 seems to be a major L1-sheddase in these tumor cell lines.(52,53) ADAM10 is also overexpressed in leukemia and prostate cancer (Table 3).

ADAM12 (Meltrin α, MCMP, MLTN).  Our group has examined the mRNA expression of 13 different ADAM species with putative metalloproteinase activity in human astrocytic tumors by reverse transcription–polymerase chain reaction, and found that ADAM12m is predominantly expressed in an active form in glioblastomas.(54) In that study, processing of proHB-EGF, a substrate of ADAM12m, was observed in glioblastoma tissues depending on ADAM12m expression levels, and was inhibited by treatment of the glioblastomas with ADAM inhibitor (KB-R7785), suggesting that ADAM12m plays a key role in the proliferation of glioblastoma cells through shedding of HB-EGF. The cysteine-rich domain of ADAM12 is known to support tumor cell adhesion through syndecans, which triggers signaling events and leads to β1 integrin-dependent cell spreading.(4,55) Roy et al. have disclosed that the ADAM12 levels in urine correlate with breast cancer progression, suggesting the possibility that ADAM12 may be a diagnostic marker for breast cancers and their progression.(11) They also report that ADAM12 cleaves various ECM molecules including gelatin, type IV collagen and fibronectin, suggesting a potential role for this enzyme in ECM digestion in cancer invasion and metastasis. ADAM12 expressed by carcinoma cells accelerates breast tumor progression through induction of stromal cell apotosis.(56) ADAM12 is also upregulated in cancers of stomach, liver and colon (Table 3). These data suggest that ADAM12 functions as a sheddase, adhesion molecule and ECM-degrading proteinase, and is involved in cancer progression.

ADAM15 (MDC15, Metargidin).  Lung carcinoma tissues and cell lines frequently express ADAM15, but the expression has no significant correlation with tumor stage or degree of differentiation.(57) Expression of ADAM15 is upregulated in various cancers of the breast, prostate, stomach and lung (Table 3), and treatment of carcinoma cell lines with anti-ADAM15 antibodies reduces cell proliferation.(50,58) However, the recombinant disintegrin domain of human ADAM15 is reported to be a potent intrinsic inhibitor of angiogenesis, tumor growth and metastasis.(59) Similarly, ADAM15 is shown to decrease integrin αvβ3/vitronectin-mediated ovarian cancer cell adhesion and motility in an RGD-dependent fashion.(60) Thus, the data on the role of ADAM15 in cancers are inconsistent.

ADAM17 (TACE).  ADAM17 is overexpressed in cancers of the breast, ovary, kidney, colon and prostate (Table 3). Interestingly, data showing that inhibition of ADAM17-mediated shedding of proTGF-α reduces the size of xenografts in nude mice suggest that ADAM17 is a target for tumorigenesis.(61) Treatment of breast cancer cell lines with anti-ADAM17 antibodies leads to a decrease in cell proliferation.(58)

ADAM19 (Meltrin β, FKSG34).  ADAM19 is highly expressed in human primary brain tumors (Table 3), and the expression and activity are associated with invasiveness.(44) ADAM19 is also highly expressed in renal cell carcinomas (Table 3), but the functions of ADAM19 in cancers remain to be elucidated.

ADAM28 (MDC-Lm, MDC-Ls).  We have recently reported that among the 11 different ADAM species with putative metalloproteinase activity, membrane-anchored ADAM28m and secreted-type ADAM28s are expressed predominantly in non-small cell lung carcinomas, showing positive correlations with cancer cell proliferation and lymph node metastasis.(62) In addition, we have demonstrated that both ADAM28m and ADAM28s are selectively overexpressed by carcinoma cells in human invasive breast carcinomas.(63) In that study, our in vitro and in vivo experiments have shown that inhibition or downregulation of ADAM28 activity by an ADAM inhibitor or ADAM28 small interfering RNA attenuates cell proliferation and IGF-I-induced cell signaling through decreased IGFBP-3 degradation. Based on these data, ADAM28 is considered to promote breast carcinoma cell proliferation through enhanced bioavailability of IGF-I (Fig. 2). Our preliminary study using yeast two-hybrid screening has shown that ADAM28s binds to PSGL-1 and promotes leukocyte rolling adhesion on endothelial cells (Shimoda H, Okada Y, unpublished data). Because some prostate carcinoma cell lines express PSGL-1,(64) studies on the role of ADAM28s in cancer metastasis through interaction with PSGL-1 are now under way in our laboratory. The mRNA expression level of ADAM28 is also increased in renal cell carcinomas (Table 3). ADAM28 may play a key role in cancer cell proliferation and metastasis.

image

Figure 2. Prospective role of a disintegrin and metalloproteinases (ADAMs) in breast carcinoma cell proliferation. ADAM28s and ADAM28m are overexpressed as active forms in breast carcinoma cells. ADAM28 cleaves insulin-like growth factor binding protein-3 (IGFBP-3) and releases insulin-like growth factor-I (IGF-I) through the IGF-I–IGFBP-3 complex. IGF-I induces cell proliferation through phosphorylation of the IGF type I receptor (IGF-IR) and extracellular signal-regulated kinase 1/2 (ERK1/2). Note that IGFBP-3 cleavage can be inhibited by treatment with anti-ADAM28 antibody or an ADAM inhibitor, KB-R7785, as well as ADAM28 small interfering RNA (siRNA).

Download figure to PowerPoint

ADAMTS1 (METH1, KIAA1346).  Liu et al. have reported that full-length ADAMTS1 promotes pulmonary metastasis of murine mammary carcinoma (TA3) and Lewis lung carcinoma cells by stimulating tumor cell proliferation, survival and invasion, and tumor angiogenesis through shedding of HB-EGF and amphiregulin precursors.(65) However, they have suggested that ADAMTS1 fragments are likely to inhibit tumor metastasis by negatively regulating HB-EGF and amphiregulin. ADAMTS1 is also highly upregulated in breast cancers with elevated metastatic activity (Table 3).

ADAMTS4 and ADAMTS5 (aggrecanase-1 and aggrecanase-2).  ADAMTS4 and ADAMTS5 are upregulated in proliferating glioblastoma cells and these proteinases may contribute to their invasive potential.(66) In addition, our study has demonstrated that ADAMTS5 is overexpressed in glioblastomas and cleaves brevican,(67) suggesting that ADAMTS5 may play a role in glioma cell invasion.

Conclusions

  1. Top of page
  2. Abstract
  3. Members of the ADAM gene family
  4. Regulation of ADAM activity
  5. Expression and functions of ADAM in cancers
  6. Conclusions
  7. References

In this article, we have reviewed the characteristics of ADAMs, regulation of their activity and their involvement in cancer cell proliferation and progression. Figure 3 summarizes recent information about ADAM in cancer biology. First, ADAMs are synthesized as inactive proADAMs, which may be activated by the action of furin or MMPs or by other unknown pathways. Second, a main role of ADAMs is shedding of growth factors such as TGF-α and HB-EGF, and this processing may alter signaling on the surfaces of cancer cells, resulting in enhanced cell proliferation by autocrine and paracrine mechanism. In addition, sheddase activity of ADAMs may be regulated by cell signaling such as through the PKC and MAPK pathway. Third, ADAMs function as adhesion molecules through binding to integrins or syndecans via their disintegrin and cysteine-rich domains, which might help the cell to digest the substrates. Fourth, ADAMs may indirectly regulate cell proliferation signals through integrins. Fifth, the role of ADAMs in cancer development and metastasis may be linked to their proteinase activity to other unknown membrane-anchored molecules, which may be cytokines, chemokines and their receptors. Like MMPs, ADAMs can cleave ECM molecules and thus cancer cells invade readily and adhere to new locations to establish a secondary site of growth. However, there are still many unanswered questions about the regulation and function of ADAMs. The development of cancer models such as transgenic mice overexpressing ADAM species or selective inhibitors for each ADAM will help to determine the role of ADAMs in carcinogenesis and cancer progression in vivo.

image

Figure 3. An overview of a disintegrin and metalloproteinases (ADAM) in cancer biology. Five different pathways may be involved in ADAM-mediated cancer cell proliferation and progression. (1) ProADAMs are activated by furin or matrix metalloproteinases (MMPs). (2) Sheddase activity of ADAMs is stimulated by external factors (e.g. 12-O-tetradecanoylphorbol-13-acetate [TPA]), leading to shedding of cell surface ligands such as heparin-binding-epidermal growth factor (HP-EGF) and transforming growth factor (TGF)-α. This process perhaps involves protein kinase C (PKC) and mitogen-activated protein kinase (MAPK) pathways. Then, soluble growth factors such as HP-EGF activate epidermal growth factor receptor on the cells in autocrine and paracrine manners. (3) The interaction of the disintegrin and cysteine-rich domains of ADAM with integrins or syndecans on the cells may help them to cleave the substrates (e.g. extracellular matrix [ECM]). (4) ADAMs modulate extracellular matrix–integrin interactions, and thus they can indirectly promote proliferation signals through integrins. (5) ADAM may process other undetermined membrane-anchored molecules such as chemokines, cytokines and their receptors, which are related to cancer cell proliferation and progression. CR, cysteine-rich domain; CT, cytosolic tail; Dis, disintegrin domain; E, epidermal growth factor-like domain; MP, metalloproteinase domain; Pro, propeptide domain; TM, transmembrane domain.

Download figure to PowerPoint

References

  1. Top of page
  2. Abstract
  3. Members of the ADAM gene family
  4. Regulation of ADAM activity
  5. Expression and functions of ADAM in cancers
  6. Conclusions
  7. References
  • 1
    Egeblad M, Werb Z. New functions for the matrix metalloproteinases in cancer progression. Nat Rev Cancer 2002; 2: 16174.
  • 2
    Shiomi T, Okada Y. MT1-MMP and MMP-7 in invasion and metastasis of human cancers. Cancer Metastasis Rev 2003; 22: 14552.
  • 3
    Seals DF, Courtneidge SA. The ADAMs family of metalloproteases: multidomain proteins with multiple functions. Genes Dev 2003; 17: 730.
  • 4
    Iba K, Albrechtsen R, Gilpin B et al. The cysteine-rich domain of human ADAM 12 supports cell adhesion through syndecans and triggers signaling events that lead to β1 integrin-dependent cell spreading. J Cell Biol 2000; 149: 114356.
  • 5
    Gaultier A, Cousin H, Darribere T, Alfandari D. ADAM13 disintegrin and cysteine-rich domains bind to the second heparin-binding domain of fibronectin. J Biol Chem 2000; 277: 23 336–44.
  • 6
    Huovila AP, Turner AJ, Pelto-Huikko M, Karkkainen I, Ortiz RM. Shedding light on ADAM metalloproteinases. Trends Biochem Sci 2005; 30: 41322.
  • 7
    Izumi Y, Hirata M, Hasuwa H et al. A metalloprotease-disintegrin, MDC9/meltrin-gamma/ADAM9 and PKCdelta are involved in TPA-induced ectodomain shedding of membrane-anchored heparin-binding EGF-like growth factor. EMBO J 1998; 17: 726072.
  • 8
    Asakura M, Kitakaze M, Takashima S et al. Cardiac hypertrophy is inhibited by antagonism of ADAM12 processing of HB-EGF: metalloproteinase inhibitors as a new therapy. Nat Med 2002; 8: 3540.
  • 9
    Mochizuki S, Shimoda M, Shiomi T, Fujii Y, Okada Y. ADAM28 is activated by MMP-7 (matrilysin-1) and cleaves insulin-like growth factor binding protein-3. Biochem Biophys Res Commun 2004; 315: 7984.
  • 10
    Millichip MI, Dallas DJ, Wu E, Dale S, McKie N. The metallo-disintegrin ADAM10 (MADM) from bovine kidney has type IV collagenase activity in vitro. Biochem Biophys Res Commun 1998; 245: 5948.
  • 11
    Roy R, Wewer UM, Zurakowski D, Pories SE, Moses MA. ADAM 12 cleaves extracellular matrix proteins and correlates with cancer status and stage. J Biol Chem 2004; 279: 51 323–30.
  • 12
    Martin J, Eynstone LV, Davies M, Williams JD, Steadman R. The role of ADAM 15 in glomerular mesangial cell migration. J Biol Chem 2002; 277: 33 683–9.
  • 13
    Russel DL, Doyle KM, Ochsner SA, Sandy JD, Richards JS. Processing and localization of ADAMTS-1 and proteolytic cleavage of versican during cumulus matrix expansion and ovulation. J Biol Chem 2003; 278: 42 330–9.
  • 14
    Somerville RP, Longpre JM, Jungers KA et al. Characterization of ADAMTS-9 and ADAMTS-20 as a distinct ADAMTS subfamily related to Caenorhabditis elegans GON-1. J Biol Chem 2003; 278: 950313.
  • 15
    Tortorella MD, Burn TC, Pratta MA et al. Purification and cloning of aggrecanase-1: a member of the ADAMTS family of proteins. Science 1999; 284: 16646.
  • 16
    Tortorella MD, Pratta M, Liu RQ et al. Sites of aggrecan cleavage by recombinant human aggrecanase-1 (ADAMTS-4). J Biol Chem 2000; 275: 18 566–73.
  • 17
    Sandy JD, Westling J, Kenagy RD et al. Versican V1 proteolysis in human aorta in vivo occurs at the Glu441–Ala442 bond, a site that is cleaved by recombinant ADAMTS-1 and ADAMTS-4. J Biol Chem 2001; 276: 13 372–8.
  • 18
    Nakamura H, Fujii Y, Inoki I et al. Brevican is degraded by matrix metalloproteinases and aggrecanase-1 (ADAMTS4) at different sites. J Biol Chem 2000; 275: 38 885–90.
  • 19
    Levy GG, Nichols WC, Lian EC et al. Mutations in a member of the ADAMTS gene family cause thrombotic thrombocytopenic purpura. Nature 2001; 413: 48894.
  • 20
    Kim IM, Ramakrishna S, Gusarova GA et al. The forkhead box m1 transcription factor is essential for embryonic development of pulmonary vasculature. J Biol Chem 2005; 280: 22 278–86.
  • 21
    Schlomann U, Rathke-Hartlieb S, Yamamoto S, Jockusch H, Bartsch JW. Tumor necrosis factor alpha induces a metalloprotease-disintegrin, ADAM8 (CD 156): implications for neuron–glia interactions during neurodegeneration. J Neurosci 2000; 20: 796471.
  • 22
    Sung SY, Kubo H, Shigemura K et al. Oxidative stress induces ADAM9 protein expression in human prostate cancer cells. Cancer Res 2006; 66: 951926.
  • 23
    Le Pabic H, Bonnier D, Wewer UM et al. ADAM12 in human liver cancers: TGF-β-regulated expression in stellate cells is associated with matrix remodeling. Hepatology 2003; 37: 105666.
  • 24
    Diaz-Rodriguez E, Montero JC, Esparis-Ogando A, Yuste L, Pandiella A. Extracellular signal-regulated kinase phosphorylates tumor necrosis factor α-converting enzyme at threonine 735: a potential role in regulated shedding. Mol Biol Cell 2002; 13: 203144.
  • 25
    Sundberg C, Thodeti CK, Kveiborg M et al. Regulation of ADAM12 cell-surface expression by protein kinase C epsilon. J Biol Chem 2004; 279: 51 601–11.
  • 26
    Soond S, Everson B, Riches DW, Murphy G. ERK-mediated phosphorylation of Thr735 in TNFα-converting enzyme and its potential role in TACE protein trafficking. J Cell Sci 2005; 118: 237180.
  • 27
    Loechel F, Gilpin BJ, Engvall E, Albrechtsen R, Wewer UM. Human ADAM 12 (meltrin alpha) is an active metalloprotease. J Biol Chem 1998; 273: 16 993–7.
  • 28
    Gao G, Plaas A, Thompson VP et al. ADAMTS4 (aggrecanase-1) activation on the cell surface involves C-terminal cleavage by glycosylphosphatidyl inositol-anchored membrane type 4-matrix metalloproteinase and binding of the activated proteinase to chondroitin sulfate and heparan sulfate on syndecan-1. J Biol Chem 2004; 279: 10 042–51.
  • 29
    Rodriguez-Manzaneque JC, Milchanowski AB, Dufour EK, Leduc R, Iruela-Arispe ML. Characterization of METH-1/ADAMTS1 processing reveals two distinct active forms. J Biol Chem 2004; 275: 33 471–9.
  • 30
    Baker AH, Edwards DR, Murphy G. Metalloproteinase inhibitors: biological actions and therapeutic opportunities. J Cell Sci 2002; 115: 371927.
  • 31
    Amour A, Knight CG, Webster A et al. The in vitro activity of ADAM-10 is inhibited by TIMP-1 and TIMP-3. FEBS Lett 2000; 473: 2759.
  • 32
    Loechel F, Fox JW, Murphy G, Albrechtsen R, Wewer UM. ADAM 12-S cleaves IGFBP-3 and IGFBP-5 and is inhibited by TIMP-3. Biochem Biophys Res Commun 2000; 278: 51115.
  • 33
    Zou J, Zhu F, Liu J et al. Catalytic activity of human ADAM33. J Biol Chem 2000; 279: 981830.
  • 34
    Kashiwagi M, Enghild JJ, Gendron C et al. Altered proteolytic activities of ADAMTS-4 expressed by C-terminal processing. J Biol Chem 2004; 279: 10 109–19.
  • 35
    Wei S, Kashiwagi M, Kota S et al. Reactive site mutations in tissue inhibitor of metalloproteinase-3 disrupt inhibition of matrix metalloproteinases but not tumor necrosis factor-alpha-converting enzyme. J Biol Chem 2004; 280: 32 877–82.
  • 36
    Amour A, Knight CG, English WR et al. The enzymatic activity of ADAM8 and ADAM9 is not regulated by TIMPs. FEBS Lett 2002; 524: 1548.
  • 37
    Chesneau V, Becherer JD, Zheng Y et al. Catalytic properties of ADAM19. J Biol Chem 2003; 278: 22 331–40.
  • 38
    Hashimoto G, Shimoda M, Okada Y. ADAMTS4 (aggrecanase-1) interaction with the C-terminal domain of fibronectin inhibits proteolysis of aggrecan. J Biol Chem 2004; 279: 32 483–91.
  • 39
    Schlomann U, Wildeboer D, Webster A et al. The metalloprotease disintegrin ADAM8. Processing by autocatalysis is required for proteolytic activity and cell adhesion. J Biol Chem 2002; 277: 48 210–19.
  • 40
    Roghani M, Becherer JD, Moss M et al. Metalloprotease-disintegrin MDC9: intracellular maturation and catalytic activity. J Biol Chem 1999; 274: 353140.
  • 41
    Ludwig A, Hundhausen C, Lambert MH et al. Metalloproteinase inhibitors for the disintegrin-like metalloproteinases ADAM10 and ADAM17 that differentially block constitutive and phorbol ester-inducible shedding of cell surface molecules. Comb Chem High Throughput Screen 2005; 8: 16171.
  • 42
    Zhou BB, Peyton M, He B et al. Targeting ADAM-mediated ligand cleavage to inhibit HER3 and EGFR pathways in non-small cell lung cancer. Cancer Cell 2006; 10: 3950.
  • 43
    Ishikawa N, Daigo Y, Yasui W et al. ADAM8 as a novel serological and histochemical marker for lung cancer. Clin Cancer Res 2006; 10: 836370.
  • 44
    Wildeboer D, Naus S, Amy Sang QX, Bartsch JW, Pagenstecher A. Metalloproteinase disintegrins ADAM8 and ADAM19 are highly regulated in human primary brain tumors and their expression levels and activities are associated with invasiveness. J Neuropathol Exp Neurol 2006; 65: 51627.
  • 45
    O'Shea C, McKie N, Buggy Y et al. Expression of ADAM-9 mRNA and protein in human breast cancer. Int J Cancer 2003; 105: 75461.
  • 46
    Peduto L, Reuter VE, Shaffer DR et al. Critical function for ADAM9 in mouse prostate cancer. Cancer Res 2005; 65: 931219.
  • 47
    Mazzocca A, Coppari R, De Franco R et al. A secreted form of ADAM9 promotes carcinoma invasion through tumor–stromal interactions. Cancer Res 2005; 65: 472838.
  • 48
    Shintani Y, Higashiyama S, Ohta M et al. Overexpression of ADAM9 in non-small cell lung cancer correlates with brain metastasis. Cancer Res 2004; 64: 41906.
  • 49
    Ko SY, Lin SC, Wong YK et al. Increase of disintergin metalloprotease 10 (ADAM10) expression in oral squamous cell carcinoma. Cancer Lett 2007; 245: 3343.
  • 50
    Carl-McGrath S, Lendeckel U, Ebert M, Roessner A, Rocken C. The disintegrin-metalloproteinases ADAM9, ADAM12, and ADAM15 are upregulated in gastric cancer. Int J Oncol 2005; 26: 1724.
  • 51
    Fogel M, Gutwein P, Mechtersheimer S et al. L1 expression as a predictor of progression and survival in patients with uterine and ovarian carcinomas. Lancet 2003; 362: 86975.
  • 52
    Gutwein P, Oleszewski M, Mechtersheimer S et al. Role of Src kinases in the ADAM-mediated release of L1 adhesion molecule from human tumor cells. J Biol Chem 2000; 275: 15 490–7.
  • 53
    Mechtersheimer S, Gutwein P, Agmon-Levin N et al. Ectodomain shedding of L1 adhesion molecule promotes cell migration by autocrine binding to integrins. J Cell Biol 2001; 155: 66173.
  • 54
    Kodama T, Ikeda E, Okada A et al. ADAM12 is selectively overexpressed in human glioblastomas and is associated with glioblastoma cell proliferation and shedding of heparin-binding epidermal growth factor. Am J Pathol 2004; 165: 174353.
  • 55
    Iba K, Albrechtsen R, Gilpin BJ, Loechel F, Wewer UM. Cysteine-rich domain of human ADAM 12 (meltrin alpha) supports tumor cell adhesion. Am J Pathol 1999; 154: 1489501.
  • 56
    Kveiborg M, Frohlich C, Albrechtsen R et al. A role for ADAM12 in breast tumor progression and stromal cell apoptosis. Cancer Res 2005; 65: 475461.
  • 57
    Schutz A, Hartig W, Wobus M et al. Expression of ADAM15 in lung carcinomas. Virchows Arch 2005; 446: 4219.
  • 58
    Lendeckel U, Kohl J, Arndt M et al. Increased expression of ADAM family members in human breast cancer and breast cancer cell lines. J Cancer Res Clin Oncol 2005; 131: 418.
  • 59
    Trochon-Joseph V, Martel-Renoir D, Mir LM et al. Evidence of antiangiogenic and antimetastatic activities of the recombinant disintegrin domain of metargidin. Cancer Res 2005; 64: 20629.
  • 60
    Beck V, Herold H, Benge A et al. ADAM15 decreases integrin αvβ3/vitronectin-mediated ovarian cancer cell adhesion and motility in an RGD-dependent fashion. Int J Biochem Cell Biol 2005; 37: 590603.
  • 61
    Borrell-Pages M, Rojo F, Albanell J, Baselga J, Arribas J. TACE is required for the activation of the EGFR by TGF-α in tumors. EMBO J 2005; 22: 111424.
  • 62
    Ohtsuka T, Shiomi T, Shimoda M et al. ADAM28 is overexpressed in human non-small cell lung carcinomas and correlates with cell proliferation and lymph node metastasis. Int J Cancer 2006; 118: 26373.
  • 63
    Mitsui Y, Mochizuki S, Kodama T et al. ADAM28 is overexpressed in human breast carcinomas: implications for carcinoma cell proliferation through cleavage of insulin-like growth factor binding protein-3. Cancer Res 2006; 66: 991320.
  • 64
    Dimitroff CJ, Descheny L, Trujillo N et al. Identification of leukocyte E-selectin ligands, P-selectin glycoprotein ligand-1 and E-selectin ligand-1, on human metastatic prostate tumor cells. Cancer Res 2005; 65: 575060.
  • 65
    Liu YJ, Xu Y, Yu Q. Full-length ADAMTS-1 and the ADAMTS-1 fragments display pro- and antimetastatic activity, respectively. Oncogene 2006; 25: 245267.
  • 66
    Held-Feindt J, Paredes EB, Blomer U et al. Matrix-degrading proteases ADAMTS4 and ADAMTS5 (disintegrins and metalloproteinases with thrombospondin motifs 4 and 5) are expressed in human glioblastomas. Int J Cancer 2006; 118: 5561.
  • 67
    Nakada M, Miyamori H, Kita D et al. Human glioblastomas overexpress ADAMTS-5 that degrades brevican. Acta Neuropathol (Berl) 2005; 110: 23946.
  • 68
    Roemer A, Schwettmann L, Jung M et al. Increased mRNA expression of ADAMs in renal cell carcinoma and their association with clinical outcome. Oncol Rep 2004; 11: 52936.
  • 69
    Grutzmann R, Luttges J, Sipos B et al. ADAM9 expression in pancreatic cancer is associated with tumor type and is a prognostic factor in ductal adenocarcinoma. Br J Cancer 2004; 90: 10538.
  • 70
    Zigrino P, Mauch C, Fox JW, Nischt R. ADAM9 expression and regulation in human skin melanoma and melanoma cell lines. Int J Cancer 2005; 116: 8539.
  • 71
    Tannapfel A, Anhalt K, Hausermann P et al. Identification of novel proteins associated with hepatocellular carcinomas using protein microarrays. J Pathol 2003; 201: 23849.
  • 72
    Yoshimura T, Tomita T, Dixon MF et al. ADAM (a disintegrin and metalloproteinase) messenger RNA expression in Helicobacter pylori-infected, normal, and neoplastic gastric mucosa. J Infect Dis 2002; 185: 33240.
  • 73
    Gavert N, Conacci-Sorrell M, Gast D et al. L1, a novel target of beta-catenin signaling, transforms cells and is expressed at the invasive front of colon cancers. J Cell Biol 2005; 168: 63342.
  • 74
    Wu E, Croucher PI, Mckie N. Expression of members of the novel membrane linked metalloproteinase family ADAM in cells derived from a range of haematological malignancies. Biochem Biophys Res Commun 1997; 235: 43742.
  • 75
    McCulloch DR, Akl P, Samaratunga H, Herington AC, Odorico DM. Expression of the disintegrin metalloproteinase, ADAM-10, in prostate cancer and its regulation by dihydrotestosterone, insulin-like growth factor I, and epidermal growth factor in the prostate cancer cell model LNCaP. Clin Cancer Res 2004; 10: 31423.
  • 76
    Kuefer R, Day KC, Kleer CG et al. ADAM15 disintegrin is associated with aggressive prostate and breast cancer diseases. Neoplasia 2006; 8: 31929.
  • 77
    Tanaka Y, Miyamoto S, Suzuki SO et al. Clinical significance of heparin-binding epidermal growth factor-like growth factor and a disintegrin and metalloproteinase 17 expression in human ovarian cancer. Clin Cancer Res 2005; 11: 478392.
  • 78
    Blanchot-Jossic F, Jarry A, Masson D et al. Up-regulated expression of ADAM17 in human colon carcinoma: Co-expression with EGFR in neoplastic and endothelial cells. J Pathol 2005; 207: 15663.
  • 79
    Karan D, Lin FC, Bryan M et al. Expression of ADAMs (a disintegrin and metalloprotease) and TIMP-3 (tissue inhibitor of metalloproteinase-3) in human prostatic adenocarcinomas. Int J Oncol 2003; 23: 136571.
  • 80
    Minn AJ, Kang Y, Serganova I et al. Distinct organ-specific metastatic potential of individual breast cancer cells and primary tumors. J Clin Invest 2005; 115: 4455.