review article role of b cell development marker cd10 in...

Review ArticleRole of B Cell Development Marker CD10 inCancer Progression and Prognosis

Deepshikha Mishra1 Sunita Singh2 and Gopeshwar Narayan1

1Department of Molecular and Human Genetics Banaras Hindu University Varanasi 221 005 India2Department of Zoology Mahila Mahavidyalaya Banaras Hindu University Varanasi 221 005 India

Correspondence should be addressed to Gopeshwar Narayan gnarayanbhuacin

Received 29 July 2016 Revised 7 October 2016 Accepted 17 October 2016

Academic Editor Sharad S Singhal

Copyright copy 2016 Deepshikha Mishra et al This is an open access article distributed under the Creative Commons AttributionLicense which permits unrestricted use distribution and reproduction in any medium provided the original work is properlycited

The human CD10 antigen is a single pass type II transmembrane 100 kD cell surface glycoprotein belonging to peptidase M13family Identified in common acute lymphoblastic leukemia as a cancer specific antigen CD10 is a cell surface ectoenzyme widelyexpressed on different types of cells Earlier it was used only as a cell surface marker to identify and differentiate betweenhaematological malignancies Later reported to be present in various malignancies it is thought to play significant role in cancerdevelopment and progression Regulated expression of CD10 is necessary for angiogenesis and so forth However its expressionlevel is found to be deregulated in different cancers In some cancers it acts as tumor suppressor and inhibits tumor progressionwhereas in others it has tumor promoting tendency However its role in tumorigenesis remains unclear This review summarisesstructural features functions and probable role of CD10 in cancer development

1 Introduction

Cluster of differentiation CD10 neprilysin common acutelymphoblastic leukemia antigen (CALLA) neutral endopep-tidase (NEP) enkephalinase or EC 342411 is a 90ndash110 kDacell surface type II integral membrane protein of M13 family[1] NEP protein comprises of three domains a short cyto-plasmic N terminal domain a transmembrane hydrophobicdomain and a large extracellular domain having catalyticactivity [2] Phylogenetic analysis of zinc-metalloenzymesof M13 family shows two major subsites a comparativelyinvariant S11015840 subsite responsible for their strong preferencefor hydrophobic residues and variation rich S21015840 subsite a keydetermining factor for substrate specificity of M13 peptidases[3]

Common acute lymphoblastic leukemia antigen (CALLA)is expressed specifically in early lymphoid progenitor stagesshowing immature phenotype that suggests its role in lym-phoid cell development and differentiation It was originallyidentified to be present on acute lymphoblastic leukemic cells[4 5] and hence was called common acute lymphoblasticleukemia antigen albeit was later found to be expressed

in a variety of cells including prostate kidney intestineendometrium adrenal glands and lung Its presence onother cells suggests its varied biological role not restrictedspecifically to haematological malignancies It acts by cleav-ing amino side peptide bonds of the hydrophobic aminoacids causing inactivation of a range of physiologically activeneuropeptides CD10metabolises biologically active peptideslike bradykinin oxytocin atrial natriuretic factor substanceP bombesin endothelin-1 Leu- and Met-enkephalins neu-rotensin and so forth resulting in reduced concentrationsof functionally active neuropeptide for receptor ligand sig-nalling neurotransmitter levels modulation blood pressurecontrol reproduction and so forth [6 7] Figure 1 shows therole of CD10 in inactivating a broad range of physiologicallyactive peptides

Studies have shown the role of CD10 in Alzheimerrsquos dis-ease ageing cardiac disorders and some other diseases how-ever there is a scarcity of literature to establish a clear relationbetween CD10 and cancer development Various techniqueslike immunohistochemistry fine needle aspiration cytology(FNAC) staining and enzyme-linked immunosorbent assayare used for its detectionThe differential expression of CD10

Hindawi Publishing CorporationMolecular Biology InternationalVolume 2016 Article ID 4328697 9 pageshttpdxdoiorg10115520164328697

2 Molecular Biology International

Normal cellular microenvironment

Basement membrane

Stromal cells

Cleaved peptides

Normal cellsCD10 receptor

ECM

Normal cellsStromal cellsCD10 receptorExtracellular matrix

Figure 1 Role of neutral endopeptidaseCD10 in inactivatingmultiple physiologically active peptides like endothelin-1 bombesin bradykininLeu- and Met-enkephalins atrial natriuretic factor oxytocin neurotensin and bombesin-like peptides present in the normal cellularmicroenvironment

appears to be very interesting feature from a diagnostic pointof view which can be exploited further as a marker for goodand bad prognosis between different stages of cancer

This review is aimed at providing therapeutic and diag-nostic insights and further evaluates CD10 contribution incancer progression In addition this review also summarisesCD10 expression status in different tumors and its biologicalsignificance Herein we have summarised CD10 involve-ment and role in cancer progression We have studied theexpression of CD10 in different tumors to determine whetherit could serve as a progression marker for tumor and itsprognosis Finally we have reviewed its clinical correlationwith cancer progression and relevance as a cancer biomarker

2 Molecular and Structural Features ofCD10 (NEP)

Present on chromosome 3 at 3q252 cytogenetic band CD10(NEP) is present as a single copy of more than 45 kb CD10shows alternative splicing in the 51015840 untranslated region pro-ducing four different mRNA transcripts though the codingregion remains unaffected Biologically its main functionis to metabolise polypeptides of up to 30 amino acidspreferentially by cleaving peptides between hydrophobicresidues Three-dimensional secondary structural model ofCD10-enzyme shows presence of 400 residuesrsquo active site

located in a central pocket [8] having a glutamate-active(E646) site responsible for catalysis and two histidine-active(583HExxH687) sites responsible for cofactor zinc binding[9] It shows a highly conserved sequence homology withother species with only minor changes in amino acidsequences CD10 activity is inhibited by phosphoramidonwhich binds to its active enzymatic site Phosphoramidon isa metabolite isolated from Streptomyces initially identifiedas a thermolysin inhibitor [8] CD10 present on pre-B cellis transiently expressed during different stages in B cellmaturation stages and it disappears in mature B cells Thissuggests that CD10 might play a role in pre-B cell maturationand differentiation [10] Apart from pre-B cells it is expressedby endometrial stromal cells [11] liver [12] and stomach andcolon [13] cells

3 CD10 Expression in NormalB Cell Development

Timeof appearance anddisappearance of cell surfacemarkerscan be very helpful in tracing the events involved in thecourse of a cell development The mature and immature Bcells can be easily identified at the developmental stage bythe presence or absence of immunoglobulin which is not(or is poorly) present on the cell surface of the immature Bcells but is expressed later on the differentiated later stages

Molecular Biology International 3

A battery of other clusters of cell surface differentiationmarkers like CD10 CD19 CD20 CD21 CD24 CD34 andCD38 help in easy identification of stages in B cell develop-ment [14] Out of numerous CD markers CD10 is of primeimportance as it is a common lymphoid progenitor (CLP) ofearly stages of differentiation of B (E-B) stage [15] An increasein the expression of CD10 cell surface marker is found tobe directly proportional to the differentiation potential ofB cells and further represents developmental commitmentand progression [16] Expression of CD10 on cell surfacehas prime clinical importance as it can be easily quantifiedthrough flow cytometry A deregulated expression of CD10also plays a role in infant leukemias of early B developmentalstages [17] and can effectively serve as target for clinicalintervention and targeted drug designing CD10 expressionon immature B cell surface is critical for its developmenthowever now it is found to be expressed by a variety ofother cell types CD10 was found to react with majority ofnon-T-cell ALL patients and not with normal hematopoieticcells [18] hence it is widely used for distinguishing mostcases of ALL from other hematologic malignancies CD10is commonly used in the flow cytometric diagnosis andmonitoring of haematological malignancies of B cell originmature and blastic stage categorisation and further MRDdetection [19ndash21]

4 CD10 Expression in Cancers

The role of neprilysin also known as CD10 has been corre-lated with many cancers however their exact roles in tumorprogression and resistance are not well established Howevermajority of malignancies show an upregulated expressionof CD10 and its correlation with higher tumor stage andseverity hence it can be concluded that CD10 behave asdouble edge swords Stromal cells CD10 expression could beone of the reasons behind observed behaviour

CD10 expression is considered an adverse prognosticfactor in lung adenocarcinoma patients where hypoxic con-dition present in the microenvironment is considered oneof the key reasons behind CD10 upregulated expression inthe tumor stroma [22] Interestingly NF-120581B expression showsinverse correlation with CD10 expression and is consideredan adverse prognostic factor for relapse after radical prosta-tectomy in prostate cancer [23] Expression of CD10 surfaceantigen is correlated with therapeutic resistance by beingrefractory to drugs and radiation in head and neck squamouscell carcinoma (HNSCC) [24] A higher expression in theinvasive front in colorectal cancer tumor samples showsCD10involvement in cancer development and progression [25]The expression of CD10 in seminomas intratubular germ celltumor and in precursors of germ cell tumors and loss after dif-ferentiation can be used as important marker to differentiateseminoma and testicular tumor [26] Increased stromal CD10expression is significantly related with an increasing tumorgrade in breast cancer further its expression is also foundto be higher in unfavourable group [27] An increased levelof expression was found in patients with liver metastasis andadvanced cancer stages [28] A new study shows upregulationof CD10 expression by Twist1 and its direct correlation with

cell migration and anchorage-independent tumor growthin esophageal squamous cell carcinoma cells [29] It isalso widely expressed in well-differentiated to moderate topoorly differentiated samples in hepatocellular carcinomaand the canalicular staining can be exploited as a highlyspecific hepatocytic differentiation marker [30 31] It showsspecifically strong expression in basal cell carcinoma (BCC)with null expression in deeply infiltrative BCCs making ita diagnostically important marker [32] A more aggressivephenotype expression with higher malignant potential isassociated with CD10 expression in prostate cancer [33] Pan-creatic tumors showed differential expression of NEPCD10which was involved in tumor cell proliferation activity ofpancreatic cancer cells [34] Stromal CD10 expression wasstrongly correlated with higher tumor grade and estrogenreceptor negativity however no correlation was found withprogesterone receptors Her2 status lymph node tumor sizehistological subtype and so forth Further stromal cell CD10expression was also found to be associated with decreasedsurvival [35] Expression of CD10 showed significant correla-tion with high proliferative index tumor size andmetastasisfurther a membrane expression correlated with poor differ-entiation [36] In colorectal carcinoma CD10 expression iscorrelated with liver metastasis and can be used as goodpredictor [37] However in urothelial tumors cytoplasmicstaining was predominant with moderate to strong expres-sion in majority of neoplasms [38] CD10 overexpressionhas also been associated with colorectal cancer developmentand progression [39] In gastric cancer stromal cells CD10expression correlated with hallmark feature of cancer likeinvasion and metastasis [40] A specific pattern of increasingstromal CD10 expression in benign lesions and malignantphyllodes tumors suggests its usefulness in assessing tumor[41] In invasive breast cancer stromal expression of CD10highlights high grade estrogen receptor negativity and poorprognosis [42] and can be used as a predictor of diseaseoutcome [43] In melanomas CD10 protein expression leveldetected by immunohistochemistry was found to be morein advanced primary tumors and metastatic melanomasthan primary tumors [44] A differential expression patternwith an upregulated level of CD10 was found during theprocess of metastasis in melanomas of skin and can bediagnostically used to differentiate between primary andmetastatic melanomas [45] CD10 protein expression levelwas found to be decreased in poorly differentiated type ofhuman adenocarcinomabywestern blot analysis as comparedto normal epithelial cells of stomach and colon [13] On thecontrary its expression is not detected in normal thyroidtissue but is found to be highly expressed in follicular variantsof papillary thyroid cancer (PTC) [46] and advanced stagesof PTC [47] In the process of prostate cancer developmenta decreased or total loss of CD10 expression is an earlyand frequent event and differentiates hormone sensitive andrefractory cases [48] This CD10 loss is known to play criticalrole in the development of androgen-independent prostatecancer by using mitogenic neuropeptides as an alternativesource for cell proliferation in the place of androgen [49] Ahigh level of CD10 expression in primary tumor sample ofprostate cancer is significantly associated with larger size of


Table 1 CD10 expression status in different cancers

Cancer CD10 level Prognosis ReferencesProstate cancer Decreasedtotal loss of CD10 expression Androgen-independent progression [48 49]

Prostate cancer High level of CD10 Aggressive phenotype higher malignancyrate larger metastases early death [33 50]

Breast cancer Stromal CD10 expression Poor prognosis estrogen receptornegativity high grade [35 43]

Melanomas High CD10 expression Advanced stage higher metastasis [44 45]Follicular papillary thyroid cancer High CD10 expression Bad [46]Papillary thyroid cancer High CD10 expression Advanced stage [47]Adenocarcinoma of stomach and colon Decreased CD10 expression Poor differentiation [13]Head and neck squamous cell carcinoma Increased CD10 expression Therapeutic resistance [44]Colorectal cancer Increased CD10 expression Higher invasion [25]Colorectal cancer Serum CD10 expression Liver metastasis [28]

Esophageal squamous cell carcinoma Upregulated CD10 expression Poor disease-free survival and overallsurvival [29]

Pancreatic endocrine tumors Membranous expression of CD10Poor differentiation high proliferativeindex low microvascular density largetumor size metastasis poor survival

[36]

Cervical carcinoma Decreased CD10 expression Higher proliferation and invasion [52]Ovarian carcinoma Increased CD10 expression Suppressing progressive potential [53]

Gastric carcinoma Stromal cells CD10 expression Differentiated carcinoma high depth ofinvasion lymph node metastasis [40]

metastases early death [50] and aggressive phenotype witha higher malignancy rate [33] and can be effectively used forstratifying prostate cancer outcome A decreased expressionof CD10 is correlated with higher proliferation and invasionin breast cancer [51] Table 1 shows the correlation betweenCD10 expression level and its prognostic implications asreported in different cancers

Figure 2 shows the generalised model for cancer devel-opment using prostate cancer as an example Total loss ordecreases in CD10 expression promote peptide-mediatedaberrant cell proliferation by high amount of accumulatedpeptide concentrations

5 Probable Mechanism and Pathways

The CD10 also known as neprilysin primarily with itsenzymatic activity acts on multiple downstream target thismight contribute to the development of diseased state Oneof the most plausible explanations behind CD10 involvementin tumorigenesis is by the enhanced accumulation of peptidesthat are cleaved by CD10 which leads to the proliferation ofundifferentiated cells Secondly CD10 may also act via alter-ing signalling pathways associated While it targets outsidethe cell via its enzymatic activity it targets at intracellular levelby interacting with various signalling pathways It is knownfrom the available literature that CD10 inactivates a diverserange of physiologically active neuropeptides by cleavingamino terminal peptide bonds of hydrophobic amino acids[1] Thereby it clears physiologically active neuropeptidespresent in the microenvironment available for cell signallingSo it is expected that a decreased CD10 expression might

be responsible for tumor progression by presence of higherpeptide concentrations available for higher cell signalling intumormilieuwhichwill further facilitate tumor proliferationCD10 is known to behave as a tumor suppressor by inhibitingvarious events contributing to neoplastic progression Afew studies on prostate cancer show CD10 role as tumorsuppressor and involvement in cancer progression and thedevelopment however the exactmechanismunderlying is yetto be explored A decreased or loss of CD10 expression is afrequent and early event in prostate cancer development [49]It inhibits cell migration via protein-protein interaction withtyrosine phosphorylated Lyn kinase forming neprilysin-Lyn-phosphatidylinositol-3-kinase protein complex This com-plex blocks focal adhesion kinase and phosphatidylinositol-3-kinase interaction competitively inhibiting cell migration[54] It also inhibits tumorigenesis in prostate cancer viareducing FGF-2-mediated angiogenesis it negatively regu-lates angiogenesis by proteolytically inactivating fibroblastgrowth factor-2 [55 56] It also interacts with endogenousPTEN tumor suppressor recruiting it to cell membranewhich causes prolonged PTEN protein stability and phos-phatase activity This increased activity results in constitutivedownregulation of AKT [57] CD10-positive subpopulationin head and neck squamous cell carcinoma acquires can-cer stem cell (CSC) property and expresses higher levelof CSC marker OCT34 An elevated level of CD10 andOCT34 results in increased tendency to form tumors andspheres implicated in therapeutic resistance and refractoryHNSCC [24] MUC2 a glycoprotein forms insoluble pro-tective mucous barrier inside the gut lumen but its reducedexpression along with CD10 overexpression is reported to


Loss of CD10 as an early event

Bombesin

ET-1

Increased cell migration

Increasedcell survival

Increased level of substrates

Deregulation in CD10 enzymatic activity

Alteration in CD10

Prostate cancer Normal prostate

Neuropeptides mediated cell proliferation

(a)

(c)

(b)

Cancerous cell

Normal cell

CD10 receptor

Substrates

signalling

Aggressive prostatecancer

Figure 2 Prostate cancer model showing (a) normal prostate (b) early prostate cancer and (c) late stage aggressive prostate cancer Highamount of peptides accumulated in the cellular microenvironment facilitates neoplastic transformation and further progression Excessneuropeptides like bombesin and endothelin-1 (ET-1) as substrate deregulate multiple signalling pathways and make the cancer aggressiveand treatment refractory

play a role in development of and progression of colorectalcancer [39] In cervical [52] and ovarian carcinoma [53] adecreased CD10 expression promotes cancer progression Aloss of CD10 expression by DNA methylation of promoteris one of the factors causing lymphoid malignancies [58] asimilar mechanism can play a crucial role as an early eventin other malignancies also Some of the important signallingpathways involved in CD10 mediated cancer progression aresummarised in Table 2

6 CD10 Chemotherapy andDiagnostic Implications

Chemotherapy is known to modulate CD10 expression insome cancers In NALM-1 pre-B leukemic cell line doxoru-bicin and PMAdownregulatedCD10 expression [59] whereasprednisone significantly reduced CD10 and CD34 expression[60] Breast cancer stromal CD10 expression profile changeswith neoadjuvant anthracycline-based chemotherapy [61]


Table 2 Main signalling pathways involved in CD10 mediated malignancies

Cancer Signalling pathway Reference

Prostate cancer CD10-FAK kinase interaction [54]FGF-2-mediated angiogenesis [55 56]

Non-small cell lung cancer Hypoxia induced stromal CD10 upregulation [22]Head and neck squamous cell carcinoma Increased expression of OCT34 by CD10-positive population [24]Esophageal squamous cell carcinoma Twist1 mediated CD10 upregulation [29]Prostate cancer Decreased CD10 expression with high NF-120581B expression [23]Prostate cancer CD10 loss mediated Akt activation [57]Colorectal cancer CD10 overexpression with MUC2 reduced expression [39]Leukemias DNA methylation of promoter region of CD10 [58]

Further an expression level after chemotherapy correlates topoor clinical response and a decreased level shows completeor partial clinical response [27] also stromal CD10 expressionsignificantly correlated with increasing tumor grade mitoticrate ER negativity Her2neu positivity and worse prognosiswhich suggests its role as a routine prechemotherapy markerin breast carcinoma [35] In ovarian cancer CD10 overexpres-sion increased paclitaxel susceptibility and reduced tumori-genesis in vivo also [53] In head and neck squamous cell car-cinoma (HNSCC) CD10-positive cell population was foundto be more refractory to radiation and chemotherapeuticdrugs like cisplatin and fluorouracil than the CD10-negativepopulation Also CD10-positive population possessed cancerstem cell features and expressed a higher level of cancerstem cell markers OCT34 with enhanced tendency to formspheres in both in vitro and in vivo tumors which suggestsa cancer stem cell like proliferative property in these cancercells [24] Chemotherapeutic drug doxorubicin is knownto decrease the expression of CD10 [59] one of the mostplausible reasons behind it could be presence of significantbinding sites between doxorubicin and CD10 as shown bymolecular docking analysis [62]

CD10 qualifies to be of high diagnostic utility bybeing able to discriminate between hepatocellular carcinoma(HCC) and metastatic carcinoma of the liver [30] CD10expression is used as marker to diagnose follicular carcinomawith follicular variant of papillary thyroid carcinoma [46]However it cannot be used to differentiate between benignand malignant cases but shows strong positivity in papillarycarcinoma [63] It can also be used as an additionalmarker forthe diagnosis of renal malignancies [64] Its role is also impli-cated in differential diagnosis of renal cancer always negativegynecologic clear cell carcinoma types and metastatic clearcell carcinoma types [65] CD10marker is of high importancein endometrial stromal neoplasms and can be used in apanel with desmin and alpha-inhibin [66] Interestinglyendometrial mixed carcinoma cells expressing CD10 showlong survival [67] It is differentially expressed in small cellcarcinomas of the lung (SCLC) beingminimally expressed inbronchoalveolar and large cell carcinoma cell lines whereasit is highly expressed in squamous adenosquamous andadenocarcinoma cell lines [68] In totality CD10 serves as areliable and sensitivemarker of normal and cancerous tissues

7 Conclusion and Perspective

CD10 presence on epithelial cells as well as on surroundingstromal cells in tumor milieu might be a driving force incancer progression Enzymatically cleaved peptides can actvia autocrine or paracrine signalling favouring moleculardysregulation in the tumormicroenvironment A deregulatedCD10 expression by stromal cells and tumor cell may leadto cancer growth and progression disturbing the cell nor-mal microenvironment Its remarkable presence on differentcancerous cells might suggest its role as a good progressionmarker and can be used widely for differentiating betweentreatment favourable and adverse stages and can thereforelead to an important role in the category of tumor progressionmarker

The classical role of this cell surface enzyme is tohydrolyze different peptides involved in varied biological pro-cesses like tissue remodelling embryogenesis angiogenesisand so forth present in the extracellular matrix (ECM) Aregulated CD10 expression by epithelial and stromal cellsis necessary for proper homeostasis maintenance in thematrix and deregulation of this balance results in cancer andAlzheimerrsquos disease by accumulating in the cell microenvi-ronment which results in generation of key factors contribut-ing or inhibiting deregulated cell proliferation angiogenesisand migration Besides their role as peptide degraders CD10interact elegantly with the intracellular signalling pathwayslike PI3-K pathway Fak-Src pathway and so forth and thiscommunication activates downstream molecules

Our knowledge about diverse roles of CD10 in the cancermicroenvironment is expanding after improved understand-ing of the CD10 signalling behind cancer progression andresistance However the differential expression of CD10in cancer and varied outcomes remain a problem Futurestudies onmeta-analysis ofCD10 expressionwill be extremelyhelpful

In conclusion CD10 can be a very useful progressionmarker and an attractivemolecular target for targeted therapydesigning Its routine expression analysis along with othermarkers might be very helpful in cancer diagnosis andtreatment response Even though its expression in some casesis related with better treatment response CD10 expressionis biased towards cancer proliferation and progression This


behaviour suggests that CD10 behaves as dual edge swordand depending upon the peptides present in tumor microen-vironment modulates cancer progression accordingly Thisreview explores the role of CD10 in cancer detection andprognosis and its utility as an important marker for a betterdetection when used with other progression markers How-ever its dual nature warrants more detailed and extensiveinvestigations in this field

Competing Interests

The authors declare no competing interests

Acknowledgments

The authors thankfully acknowledge junior and seniorresearch fellowship from the Department of BiotechnologyGovernment of India to Deepshikha Mishra

References

[1] E G Erdos and R A Skidgel ldquoNeutral endopeptidase 2411(enkephalinase) and related regulators of peptide hormonesrdquoFASEB Journal vol 3 no 2 pp 145ndash151 1989

[2] M Sumitomo R Shen and D M Nanus ldquoInvolvement ofneutral endopeptidase in neoplastic progressionrdquo Biochimica etBiophysica Acta (BBA)mdashProteins and Proteomics vol 1751 no1 pp 52ndash59 2005

[3] N D Bland J W Pinney J E Thomas A J Turner and RE Isaac ldquoBioinformatic analysis of the neprilysin (M13) familyof peptidases reveals complex evolutionary and functionalrelationshipsrdquoBMCEvolutionary Biology vol 8 article 16 2008

[4] M FGreavesG BrownNT Rapson andTA Lister ldquoAntiserato acute lymphoblastic leukemia cellsrdquoClinical Immunology andImmunopathology vol 4 no 1 pp 67ndash84 1975

[5] J Ritz J M Pesando J Notis-McConarty H Lazarus andS F Schlossman ldquoA monoclonal antibody to human acutelymphoblastic leukaemia antigenrdquoNature vol 283 no 5747 pp583ndash585 1980

[6] M A Shipp G E Tarr C-Y Chen et al ldquoCD10neutralendopeptidase 2411 hydrolyzes bombesin-like peptides andregulates the growth of small cell carcinomas of the lungrdquoProceedings of the National Academy of Sciences of the UnitedStates of America vol 88 no 23 pp 10662ndash10666 1991

[7] M A Shipp and A T Look ldquoHematopoietic differentiationantigens that are membrane-associated enzymes cutting is thekeyrdquo Blood vol 82 no 4 pp 1052ndash1070 1993

[8] C Oefner A DrsquoArcy M Hennig F K Winkler and G E DaleldquoStructure of human neutral endopeptidase (neprilysin) com-plexed with phosphoramidonrdquo Journal of Molecular Biologyvol 296 no 2 pp 341ndash349 2000

[9] C Marie-Claire G Tiraboschi E Ruffet N Inguimbert M-C Fournie-Zaluski and B P Roques ldquoExploration of the Srsquo1subsite of neprilysin a joined molecular modeling and site-directed mutagenesis studyrdquo Proteins Structure Function andGenetics vol 39 no 4 pp 365ndash371 2000

[10] M C Bene ldquoImmunophenotyping of acute leukaemiasrdquoImmunology Letters vol 98 no 1 pp 9ndash21 2005

[11] K Imai H Kanzaki H Fujiwara et al ldquoExpression ofaminopeptidase N and neutral endopeptidase on the endome-trial stromal cells in endometriosis and adenomyosisrdquo HumanReproduction vol 7 no 9 pp 1326ndash1328 1992

[12] S L Loke C Y Leung K Y Chiu W L Yau K N Cheungand L Ma ldquoLocalisation of CD10 to biliary canaliculi byimmunoelectron microscopical examinationrdquo Journal of Clin-ical Pathology vol 43 no 8 pp 654ndash656 1990

[13] Y Sato F Itoh Y Hinoda et al ldquoExpression of CD10neutralendopeptidase in normal and malignant tissues of the humanstomach and colonrdquo Journal of Gastroenterology vol 31 no 1pp 12ndash17 1996

[14] A M Vale and H W Schroeder Jr ldquoClinical consequences ofdefects in B-cell developmentrdquo Journal of Allergy and ClinicalImmunology vol 125 no 4 pp 778ndash787 2010

[15] M E Hystad J H Myklebust T H Boslash et al ldquoCharacterizationof early stages of human B cell development by gene expressionprofilingrdquo Journal of Immunology vol 182 no 9 p 5882 2009

[16] M Ichii K Oritani T Yokota et al ldquoThe density of CD10corresponds to commitment and progression in the human Blymphoid lineagerdquo PLoS ONE vol 5 no 9 Article ID e129542010

[17] E Sanz N Munoz-A J Monserrat et al ldquoOrdering humanCD34+CD10minusCD19+ prepro-B-cell and CD19minus common lym-phoid progenitor stages in two pro-B-cell development path-waysrdquo Proceedings of the National Academy of Sciences of theUnited States of America vol 107 no 13 pp 5925ndash5930 2010

[18] J M Pesando J Ritz and H Lazarus ldquoLeukemia-associatedantigens in ALLrdquo Blood vol 54 no 6 pp 1240ndash1248 1979

[19] M J Borowitz M Devidas S P Hunger et al ldquoClinicalsignificance of minimal residual disease in childhood acutelymphoblastic leukemia and its relationship to other prognosticfactors A Childrenrsquos Oncology Group Studyrdquo Blood vol 111 no12 pp 5477ndash5485 2008

[20] F E Craig andKA Foon ldquoFlow cytometric immunophenotyp-ing for hematologic neoplasmsrdquo Blood vol 111 no 8 pp 3941ndash3967 2008

[21] B LWoodM Arroz D Barnett et al ldquo2006 Bethesda Interna-tional Consensus recommendations on the immunophenotypicanalysis of hematolymphoid neoplasia by flow cytometry opti-mal reagents and reporting for the flow cytometric diagnosis ofhematopoietic neoplasiardquo Cytometry Part B-Clinical Cytometryvol 72 supplement 1 pp S14ndashS22 2007

[22] K Leithner CWohlkoenig E Stacher et al ldquoHypoxia increasesmembrane metallo-endopeptidase expression in a novel lungcancer ex vivomodelmdashrole of tumor stroma cellsrdquoBMCCancervol 14 no 1 article 40 2014

[23] I A Voutsadakis P J Vlachostergios D D Daliani et al ldquoCD10is inversely associated with nuclear factor-kappa B and predictsbiochemical recurrence after radical prostatectomyrdquo UrologiaInternationalis vol 88 no 2 pp 158ndash164 2012

[24] T Fukusumi H Ishii M Konno et al ldquoCD10 as a novel markerof therapeutic resistance and cancer stem cells in head and necksquamous cell carcinomardquo British Journal of Cancer vol 111 no3 pp 506ndash514 2014

[25] T J Jang J B Park and J I Lee ldquoThe expression of CD10and CD15 is progressively increased during colorectal cancerdevelopmentrdquo Korean Journal of Pathology vol 47 no 4 pp340ndash347 2013

[26] RDel Sordo S Ascani G Bellezza I FerriM Sbaraglia andASidoni ldquoCD10 is frequently expressed in classical seminomasrdquoHistology and Histopathology vol 29 no 1 pp 101ndash106 2014


[27] S H Jana B M Jha C Patel D Jana and A AgarwalldquoCD10-A new prognostic stromal marker in breast carcinomaits utility limitations and role in breast cancer pathogenesisrdquoIndian Journal of Pathology and Microbiology vol 57 no 4 pp530ndash536 2014

[28] T Sasaki H Kuniyasu Y Luo et al ldquoSerum CD10 is associatedwith liver metastasis in colorectal cancerrdquo Journal of SurgicalResearch vol 192 no 2 pp 390ndash394 2014

[29] K-W Lee C O Sung J H Kim et al ldquoCD10 expressionis enhanced by Twist1 and associated with poor prognosis inesophageal squamous cell carcinoma with facilitating tumori-genicity in vitro and in vivordquo International Journal of Cancervol 136 no 2 pp 310ndash321 2015

[30] A Ahuja N Gupta N Kalra R Srinivasan Y Chawla and ARajwanshi ldquoRole of CD10 immunochemistry in differentiatinghepatocellular carcinoma from metastatic carcinoma of theliverrdquo Cytopathology vol 19 no 4 pp 229ndash235 2008

[31] N Borscheri A Roessner and C Rocken ldquoCanalicularimmunostaining of neprilysin (CD10) as a diagnostic markerfor hepatocellular carcinomasrdquo American Journal of SurgicalPathology vol 25 no 10 pp 1297ndash1303 2001

[32] J Wagoner C Keehn and M B Morgan ldquoCD-10 immunos-taining differentiates superficial basal cell carcinoma fromcutaneous squamous cell carcinomardquo American Journal ofDermatopathology vol 29 no 6 pp 555ndash558 2007

[33] M A DallrsquoEra L D True A F Siegel M P Porter T MSherertz and A Y Liu ldquoDifferential expression of CD10 inprostate cancer and its clinical implicationrdquo BMC Urology vol7 article 3 2007

[34] M Erhuma M Kobel T Mustafa et al ldquoExpression of neutralendopeptidase (NEPCD10) on pancreatic tumor cell linespancreatitis and pancreatic tumor tissuesrdquo International Journalof Cancer vol 120 no 11 pp 2393ndash2400 2007

[35] N A Makretsov M Hayes B A Carter S Dabiri C B Gilksand D G Huntsman ldquoStromal CD10 expression in invasivebreast carcinoma correlates with poor prognosis estrogenreceptor negativity and high graderdquoModern Pathology vol 20no 1 pp 84ndash89 2007

[36] L Deschamps A Handra-Luca D OrsquoToole et al ldquoCD10expression in pancreatic endocrine tumors correlation withprognostic factors and survivalrdquo Human Pathology vol 37 no7 pp 802ndash808 2006

[37] Y Fujimoto Y Nakanishi S Sekine et al ldquoCD10 expression incolorectal carcinoma correlates with liver metastasisrdquo Diseasesof the Colon and Rectum vol 48 no 10 pp 1883ndash1889 2005

[38] R Murali and W Delprado ldquoCD10 immunohistochemicalstaining in urothelial neoplasmsrdquo American Journal of ClinicalPathology vol 124 no 3 pp 371ndash379 2005

[39] T Iwase R Kushima K-I Mukaisho S Mitsufuji T Okanoueand T Hattori ldquoOverexpression of CD10 and reduced MUC2expression correlate with the development and progression ofcolorectal neoplasmsrdquo Pathology Research and Practice vol 201no 2 pp 83ndash91 2005

[40] W B Huang X J Zhou J Y Chen et al ldquoCD10-positivestromal cells in gastric carcinoma correlationwith invasion andmetastasisrdquo Japanese Journal of Clinical Oncology vol 35 no 5pp 245ndash250 2005

[41] G M Tse A K Tsang T C Putti et al ldquoStromal CD10 expres-sion in mammary fibroadenomas and phyllodes tumoursrdquoJournal of Clinical Pathology vol 58 no 2 pp 185ndash189 2005

[42] N A Makretsov M Hayes B A Carter S Dabiri C B Gilksand D G Huntsman ldquoStromal CD10 expression in invasive

breast carcinoma correlates with poor prognosis estrogenreceptor negativity and high graderdquoModern Pathology vol 20no 1 pp 84ndash89 2007

[43] K Iwaya H Ogawa M Izumi M Kuroda and K MukaildquoStromal expression of CD10 in invasive breast carcinoma anew predictor of clinical outcomerdquo Virchows Archiv vol 440no 6 pp 589ndash593 2002

[44] N Bilalovic B Sandstad R Golouh J M Nesland I Selakand E E Torlakovic ldquoCD10 protein expression in tumor andstromal cells of malignant melanoma is associated with tumorprogressionrdquo Modern Pathology vol 17 no 10 pp 1251ndash12582004

[45] J Kanitakis D Narvaez and A Claudy ldquoDifferential expres-sion of the CD10 antigen (neutral endopeptidase) in primaryversus metastatic malignant melanomas of the skinrdquoMelanomaResearch vol 12 no 3 pp 241ndash244 2002

[46] C Tomoda R Kushima E Takeuti K-I Mukaisho T Hattoriand H Kitano ldquoCD10 expression is useful in the diagnosis offollicular carcinoma and follicular variant of papillary thyroidcarcinomardquoThyroid vol 13 no 3 pp 291ndash295 2003

[47] M Mokhtari and F Ameri ldquoDiagnostic value of CD-10 markerin differentiating of papillary thyroid carcinoma from benignthyroid lesionsrdquo Advanced Biomedical Research vol 3 article206 2014

[48] C N Papandreou B Usmani Y Geng et al ldquoNeutral endopep-tidase 2411 loss inmetastatic humanprostate cancer contributesto androgen-independent progressionrdquoNatureMedicine vol 4no 1 pp 50ndash57 1998

[49] S J Freedland D B Seligson A Y Liu et al ldquoLoss of CD10(neutral endopeptidase) is a frequent and early event in humanprostate cancerrdquo Prostate vol 55 no 1 pp 71ndash80 2003

[50] A Fleischmann C Rocha N Saxer-Sekulic I Zlobec GSauter and G N Thalmann ldquoHigh CD10 expression in lymphnode metastases from surgically treated prostate cancer inde-pendently predicts early deathrdquoVirchows Archiv vol 458 no 6pp 741ndash748 2011

[51] S Thomas R J Babu K Agarwal et al ldquoEffect of neoadjuvantchemotherapy on stromal CD10 antigens in breast cancermdashapreliminary studyrdquo Indian Journal of Cancer vol 50 no 1 pp46ndash51 2013

[52] M Terauchi H Kajiyama K Shibata K Ino S Mizutani andF Kikkawa ldquoAnti-progressive effect of neutral endopeptidase2411 (NEPCD10) on cervical carcinoma in vitro and in vivordquoOncology vol 69 no 1 pp 52ndash62 2005

[53] H Kajiyama K Shibata M Terauchi et al ldquoNeutral endopep-tidase 2411CD10 suppresses progressive potential in ovariancarcinoma in vitro and in vivordquo Clinical Cancer Research vol11 no 5 pp 1798ndash1808 2005

[54] M Sumitomo R Shen M Walburg et al ldquoNeutral endopep-tidase inhibits prostate cancer cell migration by blocking focaladhesion kinase signalingrdquoThe Journal of Clinical Investigationvol 106 no 11 pp 1399ndash1407 2000

[55] A Horiguchi D Y T Chen O B Goodman et al ldquoNeu-tral endopeptidase inhibits prostate cancer tumorigenesis byreducing FGF-2-mediated angiogenesisrdquo Prostate Cancer andProstatic Diseases vol 11 no 1 pp 79ndash87 2008

[56] O B Goodman Jr M Febbraio R Simantov et al ldquoNeprilysininhibits angiogenesis via proteolysis of fibroblast growth factor-2rdquo Journal of Biological Chemistry vol 281 no 44 pp 33597ndash33605 2006


[57] M Sumitomo A Iwase R Zheng et al ldquoSynergy in tumorsuppression by direct interaction of neutral endopeptidase withPTENrdquo Cancer Cell vol 5 no 1 pp 67ndash78 2004

[58] K H Taylor J Liu J Guo J W Davis H Shi and C WCaldwell ldquoPromoter DNA methylation of CD10 in lymphoidmalignanciesrdquo Leukemia vol 20 no 10 pp 1910ndash1912 2006

[59] I Martin-Kleiner I Svoboda-Beusan and J Gabrilovac ldquoPMAand doxorubicin decrease viability MTT activity and expres-sion of CD10marker on NALM-1 leukemic cellsrdquo Immunophar-macology and Immunotoxicology vol 28 no 3 pp 411ndash4202006

[60] G Gaipa G Basso S Aliprandi et al ldquoPrednisone inducesimmunophenotypic modulation of CD10 and CD34 in non-apoptotic B-cell precursor acute lymphoblastic leukemia cellsrdquoCytometry Part B Clinical Cytometry vol 74 no 3 pp 150ndash1552008

[61] S Thomas R J Babu K Agarwal et al ldquoEffect of neoadjuvantchemotherapy on stromal CD10 antigens in breast cancermdashAPreliminary Studyrdquo Indian Journal of Cancer vol 50 no 1 pp46ndash51 2013

[62] D Mishra V K Singh S Singh and G Narayan ldquoMolecularmodelling-docking cell surface receptor CD10 target for dox-orubicinrdquo Online Journal of Bioinformatics vol 16 no 3 pp286ndash292 2015

[63] G Yegen M A Demir Y Ertan O A Nalbant and MTuncyurek ldquoCan CD10 be used as a diagnostic marker inthyroid pathologyrdquoVirchows Archiv vol 454 no 1 pp 101ndash1052009

[64] C Langner M Ratschek P Rehak L Schips and R ZigeunerldquoCD10 is a diagnostic and prognosticmarker in renalmalignan-ciesrdquo Histopathology vol 45 no 5 pp 460ndash467 2004

[65] J Ordi C Romagosa F A Tavassoli et al ldquoCD10 expression inepithelial tissues and tumors of the gynecologic tract a usefulmarker in the diagnosis of mesonephric trophoblastic andclear cell tumorsrdquo The American Journal of Surgical Pathologyvol 27 no 2 pp 178ndash186 2003

[66] W G McCluggage V P Sumathi and P Maxwell ldquoCD10is a sensitive and diagnostically useful immunohistochemicalmarker of normal endometrial stroma and of endometrialstromal neoplasmsrdquo Histopathology vol 39 no 3 pp 273ndash2782001

[67] K Uehara F Ikehara Y Tanabe et al ldquoCD10 expressionin the neuroendocrine carcinoma component of endometrialmixed carcinoma association with long survivalrdquo DiagnosticPathology vol 11 article 16 2016

[68] R K Ganju M Sunday D G Tsarwhas A Card and M AShipp ldquoCD10NEP in non-small cell lung carcinomas relation-ship to cellular proliferationrdquo Journal of Clinical Investigationvol 94 no 5 pp 1784ndash1791 1994

Submit your manuscripts athttpwwwhindawicom

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Anatomy Research International

PeptidesInternational Journal of


Hindawi Publishing Corporation httpwwwhindawicom

International Journal of

Volume 2014

Zoology


Molecular Biology International

GenomicsInternational Journal of


The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014


BioinformaticsAdvances in

Marine BiologyJournal of



Signal TransductionJournal of


BioMed Research International

Evolutionary BiologyInternational Journal of



Biochemistry Research International

ArchaeaHindawi Publishing Corporationhttpwwwhindawicom Volume 2014


Genetics Research International


Advances in

Virolog y

Hindawi Publishing Corporationhttpwwwhindawicom

Nucleic AcidsJournal of

Volume 2014

Stem CellsInternational



Enzyme Research



Microbiology


Normal cellular microenvironment

Basement membrane

Stromal cells

Cleaved peptides

Normal cellsCD10 receptor

ECM

Normal cellsStromal cellsCD10 receptorExtracellular matrix

Figure 1 Role of neutral endopeptidaseCD10 in inactivatingmultiple physiologically active peptides like endothelin-1 bombesin bradykininLeu- and Met-enkephalins atrial natriuretic factor oxytocin neurotensin and bombesin-like peptides present in the normal cellularmicroenvironment

appears to be very interesting feature from a diagnostic pointof view which can be exploited further as a marker for goodand bad prognosis between different stages of cancer

This review is aimed at providing therapeutic and diag-nostic insights and further evaluates CD10 contribution incancer progression In addition this review also summarisesCD10 expression status in different tumors and its biologicalsignificance Herein we have summarised CD10 involve-ment and role in cancer progression We have studied theexpression of CD10 in different tumors to determine whetherit could serve as a progression marker for tumor and itsprognosis Finally we have reviewed its clinical correlationwith cancer progression and relevance as a cancer biomarker

2 Molecular and Structural Features ofCD10 (NEP)

Present on chromosome 3 at 3q252 cytogenetic band CD10(NEP) is present as a single copy of more than 45 kb CD10shows alternative splicing in the 51015840 untranslated region pro-ducing four different mRNA transcripts though the codingregion remains unaffected Biologically its main functionis to metabolise polypeptides of up to 30 amino acidspreferentially by cleaving peptides between hydrophobicresidues Three-dimensional secondary structural model ofCD10-enzyme shows presence of 400 residuesrsquo active site

located in a central pocket [8] having a glutamate-active(E646) site responsible for catalysis and two histidine-active(583HExxH687) sites responsible for cofactor zinc binding[9] It shows a highly conserved sequence homology withother species with only minor changes in amino acidsequences CD10 activity is inhibited by phosphoramidonwhich binds to its active enzymatic site Phosphoramidon isa metabolite isolated from Streptomyces initially identifiedas a thermolysin inhibitor [8] CD10 present on pre-B cellis transiently expressed during different stages in B cellmaturation stages and it disappears in mature B cells Thissuggests that CD10 might play a role in pre-B cell maturationand differentiation [10] Apart from pre-B cells it is expressedby endometrial stromal cells [11] liver [12] and stomach andcolon [13] cells

3 CD10 Expression in NormalB Cell Development

Timeof appearance anddisappearance of cell surfacemarkerscan be very helpful in tracing the events involved in thecourse of a cell development The mature and immature Bcells can be easily identified at the developmental stage bythe presence or absence of immunoglobulin which is not(or is poorly) present on the cell surface of the immature Bcells but is expressed later on the differentiated later stages















[36]










Bombesin

ET-1





Alteration in CD10



(a)

(c)

(b)

Cancerous cell

Normal cell

CD10 receptor

Substrates

signalling




















Competing Interests


Acknowledgments


References















































































Volume 2014

Zoology






















Advances in

Virolog y



Volume 2014




Enzyme Research



Microbiology















[36]










Bombesin

ET-1





Alteration in CD10



(a)

(c)

(b)

Cancerous cell

Normal cell

CD10 receptor

Substrates

signalling




















Competing Interests


Acknowledgments


References















































































Volume 2014

Zoology






















Advances in

Virolog y



Volume 2014




Enzyme Research



Microbiology



Bombesin

ET-1





Alteration in CD10



(a)

(c)

(b)

Cancerous cell

Normal cell

CD10 receptor

Substrates

signalling




















Competing Interests


Acknowledgments


References















































































Volume 2014

Zoology






















Advances in

Virolog y



Volume 2014




Enzyme Research



Microbiology















Competing Interests


Acknowledgments


References















































































Volume 2014

Zoology






















Advances in

Virolog y



Volume 2014




Enzyme Research



Microbiology





















































Volume 2014

Zoology






















Advances in

Virolog y



Volume 2014




Enzyme Research



Microbiology

review article role of b cell development marker cd10 in...

Documents