review article the roles of cd73 in cancerdownloads.hindawi.com/journals/bmri/2014/460654.pdfreview...

Review ArticleThe Roles of CD73 in Cancer

Zhao-wei Gao Ke Dong and Hui-zhong Zhang

Department of Clinical Diagnosis Tangdu Hospital Fourth Military Medical University Xinsi Road Xirsquoan Shanxi 710038 China

Correspondence should be addressed to Hui-zhong Zhang huizz328163com

Received 29 April 2014 Revised 7 July 2014 Accepted 8 July 2014 Published 14 July 2014

Academic Editor Beric Henderson

Copyright copy 2014 Zhao-wei Gao et al This is an open access article distributed under the Creative Commons Attribution Licensewhich permits unrestricted use distribution and reproduction in any medium provided the original work is properly cited

Purinergic signaling has emerged as an important player in cancer progression and is regulated by a series of nucleotidases Amongthe enzyme cascade CD73 which catelyzes AMP breakdown to adenosine has been found to be overexpressed in many types ofcancer Various factors andmechanisms are employed to regulate expression of CD73 Accumulating studies have shown that CD73is a key regulatory molecule of cancer cells proliferation migration and invasion in vitro tumor angiogenesis and tumor immuneescape in vivoWith such important roles in cancer CD73 has become an appealing therapy target Recent evidences inmicemodelsdemonstrated that targeted blockade of CD73 could be a favorable therapeutic approach for cancer patients in the future In thisreview we will summarize themultiple roles of CD73 in cancer development including its clinical significance its promotive effectson tumor growth metastasis and angiogenesis and its suppressive effects on immune response regulatory mechanisms of CD73expression and current situation of anti-CD73 cancer therapy

1 Introduction

Tumorigenesis progression andmetastasis are complexmal-ignance process in vivo that involves a series of eventsincluding rapid proliferation of mutant cells in an uncontrol-lable manner inhibition of programmed cell death abundantangiogenesis escaped from immune surveillance invasionand colonization into distant organs Many signaling path-ways have been identified to be involved in cancer progres-sion Recent years the purinergic signaling pathway wherethe extracellularATP (adenosine triphosphate) ADP (adeno-sine diphosphate) and adenosine act as the main signalingmolecules has emerged as an important player in cancer pro-gression [1] Purinergic signaling is a multistep coordinatedcascade including stimulated release of ATPADP triggeringof signaling events via P2 receptors and then nucleotideinactivated to adenosine Further adenosine binds to its ownactivated P1 receptors and influences biological pathwayssuch as cell survival proliferation and cell motility [2] Moreimportantly it is now evident that the adenosine is one of themost important immunosuppressive regulatory molecules inthe tumor microenvironment [3]

Nucleotides are released by a variety of cell types inresponse to multiple stress signals such as injury hypoxiaand inflammatory condition etc Further the nucleotides

are hydrolyzed by the enzyme cascade as follows ATPADPinto AMP by NTPDases AMP into adenosine by ecto-51015840-nucleotidase (known asCD73) and adenosine into inosine byadenosine deaminase [4] Therefore purinergic signaling isregulated by a series of cell surface-located ectonucleotidasesThe balance between ATPADP AMP and adenosine iscrucial in the control of tumor progression

CD73 is a 70-kD glycosylphosphatidylinositol (GPI)anchored cell surface protein that is encoded by NT5E genealso known as ecto-51015840-nucleotidase (ecto-51015840-NT EC 3135)plays a crucial role in switch on adenosinergic signalingCD73 has both enzymatic and nonenzymatic functions incells [5] As a nucleotidase CD73 catalyzes the hydrolysis ofAMP into adenosine and phosphate Notably CD73-gener-ated adenosine plays an important role in tumor immu-noescape [6] In addition to its enzymatic function CD73 isalso a signal and adhesive molecule that can regulate cellinteraction with extracellular matrix (ECM) componentssuch as laminin and fibronectin to mediate cancer invasiveandmetastatic properties [7] Indeed the enzymatic andnon-enzymatic functions of CD73 are both involved in cancerassociated process and not completely independent of eachother

CD73 has been found to be overexpressed in many typesof cancer cell lines and patientrsquos biopsies including breast

Hindawi Publishing CorporationBioMed Research InternationalVolume 2014 Article ID 460654 9 pageshttpdxdoiorg1011552014460654

2 BioMed Research International

Table 1 CD73 expression in different cancer cell lines

Cancer type Cell line Expression Reference

Glioblastoma Multiforme T98G Higher level of mRNA and protein than normal glialcell line SVGp12 [8]

Melanoma

C8161 PMW SBCL2SKMel28 SKMel30KMel147 SKMel173Mel224 WM266-4

M902-6

Higher mRNA expression thanWM35 et al because theabsent of methylation [9]

MelanomaWM35 Mel501Mel505 SKMel2SKMel23 C81-61

Lower mRNA expression caused by the NT5E CpGisland methylation [9]

Melanoma A375 High expression levels and activity [10]Mouse breastcancer 4T12 E0771 Higher expression levels than nonmetastatic variant of

4T12 [11]

Ovarian cancer SKOV3 SKOV3 human ovarian cancer cells highly expressedCD73 [12]

Breast cancer MB-MDA-231 T-47D T-47D with lower expression of CD73 andMB-MDA-231 with higher expression of CD73 [13]

Primary MedulloblastomaMetastatic Medulloblastoma

Daoy ONS76D283

Daoy and ONS76 express higher levels of CD73 whileD283 revealed poor expression of CD73 [14]

Bladder cancer RT4 T24 Both cell lines expressed CD73 [15]

cancer colorectal cancer ovarian cancer gastric cancer andgallbladder cancer and associated with clinical character-istics or prognosis of cancer patients (Tables 1 and 2)Increasing evidence has verified that CD73 is a key regulatorymolecule in cancer development [27] In particular dueto the favorable effect on tumor-bearing mice modelsalthough have not been investigated in clinical patients anti-CD73 therapy has become a promising approach for thetreatment of cancer patients in the future [28 29] In thispresent paper we will summarize the roles of CD73 in cancerdevelopment including its clinical significance in cancerpatients its promotive effects on tumor growth metastasisand angiogenesis and its suppressive effects on immune sys-temunder tumormicroenvironment regulationmechanismsof CD73 expression and opportunities for anti-CD73 cancertherapy in the future

2 Clinical Significance of CD73 inCancer Patients

Overexpression of CD73 has been observed in broad types ofcancers and its clinical significance has also been found bycorrelative analysis (Table 2) In breast cancer Loi et aldemonstrated that CD73 expression was significantly associ-ated with a worse prognosis in triple negative breast cancer(TNBC) patients (119899 = 661 119875 = 0029) but not in patientswith luminal (119899 = 2083 119875 = 07) or HER2+ (119899 = 487119875 = 086) breast cancer [26] In contrast another retrospec-tive study (119899 = 136) reported that positive CD73 expressionwas strongly correlated with longer disease-free survival (119875 =00044) and overall survival (119875 = 0027) of breast cancerpatients [25] which suggested that elevated CD73 expres-sion could predict a good prognosis in stages IndashIII breastcancer patients Notably the prognostic implication of CD73

expression in breast cancer remains controversial and is notindependent of other clinical indexes Now a retrospectiveanalysis by our team in more clinical specimens is in processwhich will take more factors into consideration such aspatientrsquos age subtype and population treatment

In digestive system cancers recently Lu et al evaluatedthe clinical significance and prognostic value of CD73 inhuman gastric cancer (119899 = 68 patients) analysis of CD73expression by immune histochemistry (IHC) revealed thatoverexpression of CD73 was positively correlated with differ-entiation of tumor depth of invasion (119875 lt 0001) nodal sta-tus (119875 = 0003) metastasis (119875 = 0013) and the cancer stage(119875 lt 0001) and the overall survival rate was low in thepatients with high expression of CD73 (119875 lt 0001) [19] Inaddition to gastric cancer other studies showed that highlevels of CD73 in colorectal cancer (CRC) patients were cor-related with a poor prognosis [16 17] Moreover Xiong et alrecently reported that CD73 expression was associated withtumor progression and survival of patients with gallbladdercancer [20]

In hematologic neoplasm Zhao et al investigated theexpression of CD73 in various leukemia subtypes (119899 = 86)and revealed that the expression of CD73 was associated withleukemia subtype differentiation and development [21]Serra et al assessed the clinical implication of CD73 inchronic lymphoblastic leukemia (CLL 119899 = 299) and foundthat high expression of CD73 was associated with a moreaggressive clinical behavior [22] whereas another studyshowed that CD73 expression had no prognostic value inchildren (1ndash18 years old) with acute lymphoblastic leukemia(ALL 119899 = 338) [23]

In other cancers Yang et al reported that overexpressionof CD73 in prostate cancer was associated with lymph nodemetastasis [24] And Oh et al showed that overexpression

BioMed Research International 3

Table 2 The clinical significance of CD73 in cancer patients

Cancer type Number ofpatients Clinical implication of CD73 Reference

Colorectal cancer 358 Overexpression of CD73 is an independent poor prognosticbiomarker for human CRC [16 17]

Epithelial ovarian carcinoma 167Overexpression of CD73 in epithelial ovarian carcinoma isassociated with better prognosis lower stage and betterdifferentiation

[18]

Gastric cancer 68

CD73 overexpression was positively correlated withdifferentiation of tumor histopathology depth of invasionnodal status metastasis cancer stage and low overall survivalrate of patients

[19]

Gallbladder cancer 108 Survival time of patients with NT5E expression was significantlyshorter than those without NT5E expression [20]

Leukemia 86 Expression of CD73 was associated with leukemia subtypedifferentiation and development [21]

Chronic lymphoblasticleukemia 229 High expression of CD73 was associated with a more aggressive

and proliferation disease [22]

Acute lymphoblastic leukemia(children) 338 CD73 expression had no prognostic value in children with acute

lymphoblastic leukemia [23]

Prostate cancer 116 Overexpression of CD73 in prostate cancer is associated withlymph node metastasis [24]

Malignant melanoma 52 CD73 expression is epigenetically regulated in malignantmelanoma and associated with metastatic site specificity [9]

Breast cancer (stages IndashIII) 136 Elevated CD73 expression in stages IndashIII breast cancer canpredict a good prognosis [25]

Triple negative breast cancerLuminal breast cancerHER2+ breast cancer

6612083487

CD73 gene expression was significantly associated with a worseprognosis in TNBC patients but not in patients with luminal orHER2+ breast cancer

[26]

of CD73 in epithelial ovarian carcinoma was associatedwith better prognosis lower stage and better differentiation[18] Wang et al found that CD73 expression in malignantmelanoma was associated with metastatic site specificity [9]Taken together these results supported that CD73 was animportant clinical or prognostic biomarker in several types ofcancer which presented the potential value of CD73 forclinical diagnosis and prognosis

3 CD73 and Drug Resistance

In addition to being as a clinical and prognostic marker incancer patients overexpression of CD73 has also been foundto be associated with resistance to antitumor agents Actuallyas far as in 1996 Ujhazy et al firstly reported that thechemoresistant phenotype of cell lines (MDR positive) wascorrelated with a coexpression of elevated CD73 levels [30]Recently Quezada and his colleagues reported that inhibi-tion of CD73 activity or knocking down CD73 expressionby siRNA reversed the vincristine resistance phenotype ofglioblastoma multiforme (GBM) cells [8] Notably in GBMtissues and cells CD73 was cooverexpressed with multipledrug protein-1 (Mrp1) which was the most important trans-porter conferring multiple drug resistance in tumor cells [831] Consistently knockdown of CD73 expression by siRNAinGBMcells reducedMrp1 expression [8]These results indi-cated that overexpression of CD73 might mediate vincristine

resistance in GBM cells through regulating the expression ofMrp1

Recently Loi et al evaluated the connection betweenCD73 expression level and pathologic complete responses(pCR) rate in triple negative breast cancer patients (119899 = 59)treated with anthracycline-only preoperative chemotherapyTheir result showed that low CD73 expression was signifi-cantly associated with an increased pCR rate (119875 = 000002)[26] Furthermore by using mouse models of breast cancerthey demonstrated that CD73 overexpression in tumor cellsconferred chemoresistance to doxorubicin dependent on theactivation of A2A adenosine receptor Not surprisingly tar-geted blockade of A2A adenosine receptors could rescue dox-orubicin sensitivity of CD73-overexpressing tumors in micemodels

Moreover despite the growing interest of cancer immu-notherapy clinical benefits are still modest because themech-anisms of immune escape As a key regulatory molecule ofimmune escape in vivo CD73 is certainly involved inimmunotherapy resistance [12] Thus as the link betweenCD73 and resistance to some antitumor therapy combininganti-CD73 treatment with chemotherapy or immunotherapymay be an effective approach for these patients with highCD73 levels In the future while in the coming age of individ-ual cancer therapy CD73 expression in cancer patients maybe served as a detectable gene marker to choose anduse applicable drugs for cancer treatment


4 CD73 and Tumor Growth

Overexpression of CD73 has been found to promote cancercells proliferation in vitro Zhi et al observed that expressionsuppression of CD73 by shRNA could inhibit proliferationof breast cancer cells (MB-MDA-231) via inducing cell-cyclearrest and cell apoptosis [32] In addition treatment withAPCP (120572 120573-methylene adenosine-51015840-disphosphate) whichis a specific inhibitor of CD73 enzymatic activity can alsoinhibit cancer cells proliferation in a dose-dependentmanner[32ndash34] Correspondingly in pcDNA-NT5E transfectedbreast cancer cells (MCF-7) CD73 overexpression increasedcell viability and promoted cell-cycle progression Bavarescoet al found that APCP treatment caused a significant reduc-tion of 30 in glioma cell proliferation while treatment withadenosine increased cell proliferation by 35 Together theseresults supported that CD73 promote cancer cells growthdependent on its enzymatic activity that is production ofadenosine [35]

However there were conflicting studies which showedthat adenosine can also inhibit cell growth and induceapoptosis Wang and Ren found that extracellular adeno-sine induce apoptosis of gastric carcinoma cells in a dose-dependent manner and this effect can be decreased by theinhibition of adenosine uptake using the nucleoside transportblockermdashdipyridamole [36] Recently Shirali et al found thatadenosine could induce apoptosis of ovarian cancer cells viaBax up-regulation and caspase-3 activation which are bothcrucial apoptotic regulatory molecules [37] These resultssuggested that adenosine induce apoptosis dependent on theuptake of adenosine into cells and activation of intracellularapoptotic pathways Thus the promotive effect of CD73 oncancer cells proliferation in vitro may via other moleculewhich independent with adenosine such as EGFR which is akey molecule involved in cell growth Recently Zhi et al havefound the regulative effect of CD73 on EGFR expression andphosphorylation in human breast cancer [38]

In vivo overexpression of CD73 in tumor cells can pro-mote subcutaneous tumor growth in mice model Zhi et alshowed that subcutaneous tumor in nude mice (produced byinjecting with pcDNA-NT5E transfected MCF-7 cells) grewin amore rapid fashionwhen comparedwith parentalMCF-7cells produced subcutaneous tumor And consistently CD73downregulation by siRNA could retard tumorigenicity inmurine xenograft models [7 32] Notably besides the CD73in tumor cells host CD73 also play important role incancer development in vivo Stagg et al reported thatCD73 deficiency in mice inhibited the development of 3-methylcholanthrene- (MCA-) induced fibrosarcomas com-pared with wild-type mice Similarly CD73 deficiency alsosuppressed tumorigenesis in transgenic adenocarcinoma ofmouse prostate (TRAMP) mice models [39] Yegutkin et alinvestigated the contribution of host CD73 to tumor growthin melanoma models and found that primary tumors weresignificantly attenuated in CD73 lacking mice [40] Takentogether since both host and tumor CD73 contribute toprimary tumor growth in vivo the optimal antitumor effect ofCD73 blockage drug may require targeting both host andtumor CD73

5 CD73 and Tumor Metastasis

Metastasis is a vicious characteristic of malignance cancersand is the dominating cause of mortality in cancer patientsTherefore identification of metastasis-promotingmolecule isprimary importance for anticancer research anddevelopmentof target drugs To date accumulating data have shown thatCD73 is associated with tumor metastasis in experimentalmodels and clinical patients

Acquirement of ldquoinvasive phenotyperdquo which means thelost of cell-cell junction and enhanced cell migration abilityin tumor cells is the prerequisite for cancer metastasis InpcDNA-NT5E transfected breast cancer T-47D cells upreg-ulation of CD73 promoted cell migration and invasion andin the meantime increased cell mobility by CD73 overex-pression could be inhibited by APCP [7 13 41] NotablymRNA and protein expression levels of EGFR were increasedsignificantly in pcDNA-NT5E transfected T-47D cells [41]More interestingly downregulation of EGFR by siRNAresulted in inhibition of migration and invasion activities inpcDNA-NT5E transfected T-47D cells In another studyresearchers found that CD73 expression correlated positivelyto EGFR expression inMB-MDA-231 cells and EGFR expres-sion could be decreased by suppressing CD73 expressionwith siRNA [38] These observations suggested that CD73promoted tumor cell migration and invasion via regulatingEGFR expression

Recently Xiong et al identified CD73 as a key regulator ofepithelial-mesenchymal transition (EMT) in gallbladder can-cer which indicated that CD73might promote cell migrationand invasion via inducing EMT of tumor cells [20] Interest-ingly the dual functions of CD73 seemed to fulfill distinctroles in the cell interaction and mobility on ECM Sadejand Skladanowski observed that the enzymatic function wasprimarily involved in invasion of cancer cell whereas thenonenzymatic action of CD73 was proved to promote cellmigration on ECM through activation of focal adhesionkinase (FAK) in melanoma cells [10]

In vivo Stagg et al showed that CD73-deficientmice wereresistant to development of lung metastasis after intravenousinjection of B16F10 melanoma cells moreover host CD73deficiency increased tumor antigen-specific T-cell homing totumors [42] Similarly Yegutkin et al also reported that for-mation of melanoma metastasis was significantly retarded inCD73-deficient mice [40] In clinical cancer patients severalretrospective studies revealed that CD73 overexpression intumor was associated with metastasis of gastric cancerprostate cancer and malignant melanoma respectively [919 24] Taken together above results demonstrated thatboth host and tumor CD73 significantly contribute to tumormetastasis importantly the resistant effect of host CD73deficiency on tumors metastasis is associated with increasedendogenous antitumor immunity

6 CD73 and Tumor Angiogenesis

The uncontrolled proliferation of cancer cells needs abun-dance of nutrition and oxygen High density of angiogenesis


can support the sustenance for tumor cells growth In addi-tion to sustenance supply angiogenesis is also the importantpathway for distant invasion of tumor cells Via infiltratinginto immature vessels tumor cells can be carried into distantorgans by blood Thus abundant tumor angiogenesis isnecessary for cancer growth and metastasis

Formation of capillary-like tubes by endothelial cells isthe basic process during angiogenesis Wang et al found thatcapillary-like structures were formed more in CD73 (++)pulmonary microvascular endothelial cells (PMECs) than inCD73 (minusminus) PMECs in vitro In particular the difference wasmore pronounced when PMECs were cultured in cancer-conditioned medium Consistent with these results in vitrothey also observed that the extent and density of tumorangiogenesis were greater in CD73 (++) mice than inCD73 (minusminus) mice in vivo [43] These results supported thatCD73 contributed to endothelial cells forming new vesselsespecially in cancer condition

Recently Koszalka et al reported that inhibition of CD73resulted in impaired angiogenesis and reduced melanomagrowth in mice models [44] Allard et al investigated theimportance of CD73 expression during tumor angiogenesisand the effect of anti-CD73 mAb therapy on angiogenesisBy detecting the formation of capillary-like tubes by humanumbilical vein endothelial cells (HUVEC) in vitro they foundthat CD73 gene silencing by shRNA in HUVEC cells wasassociated with a significant decrease in tube formation Byusingmicemodels of breast cancer they found that treatmentof tumor bearing mice with either anti-CD73 mAb or APCPdecreased tumor angiogenesis [45] Furthermore Allardrsquosstudy found that both tumor and host-derived CD73 wereinvolved in tumor angiogenesis Tumor-derived CD73increase VEGF production by tumor cells while host-derived CD73 is required for optimal angiogenic responsesto VEGF Tumor grown in CD73-deficient mice appeared tohave less angiogenesis These results support that tumor andhost CD73 synergistically contribute to angiogenesis undertumor condition in vivo In contrast to above results anotherrecent study in a model of hind limb ischemia showed thatCD73 deficiency had no effect on angiogenesis [46]Thus theeffect of CD73 on angiogenesis might be different in tumorand nontumor microenvironment

As the promotive effect of angiogenesis in tumor growthand metastasis several inhibitors antiangiogenic agent havereceived FDA approval and been used in clinical includingthe bevacizumab (ie anti-VEGF mAb) However patientsthat initially respond to antiangiogenic treatment ultimatelybecome resistant [47] The mechanisms may rely on theabnormal activation of VEGF pathway As mentioned aboveCD73 can promote angiogenesis via up-regulation of VEGFexpression which indicated that CD73 contribute toacquired-resistance of anti-VEGF therapy Indeed we havedetected the elevated CD73 level in a bevacizumab resistantpatientThusCD73may represent new target for treatment toovercome bevacizumab resistance in the future

7 CD73 and Immune Suppression

Immunoescape has been considered as one of the ldquohallmarksrdquoof cancer During tumor growth progression andmetastasis

tumor cells employ multiple pathways to evade immunesurveillance [48] One such mechanism relies on the adeno-sine signaling [49 50] Among purinergic signaling cascadeCD73 catalyzed the hydrolysis of AMP into adenosine thus itis a keymolecule in tumor immunoescape [51] Tomediate itsimmunosuppressive functionCD73 generated adenosine canbind to four distinct G-protein-coupled receptors A1 A2AA2B and A3 Adenosine can exert effect on immune systemthrough multiple pathways [52 53]

High concentrations of adenosine could blunt the capac-ity of nature killer (NK) cells to produce tumor necrosisfactor-120572 (TNF-120572) and interferon-120574 (IFN-120574) and also inhibitthe lytic activity of NK cells in an A2A receptor dependentmanner thus limiting the ability of NK cells to mediate thelysis of tumor cells [54] In addition macrophages were alsoaffected by adenosine By binding to A2A receptor expressedon macrophage adenosine led to release of IL-4 and IL-10which contributed to suppression of antitumor immuneresponse and promoted tumor growth [52]

Dendritic cells (DCs) are critical component of immunesystem and bridge innate immunity and adaptive immunityHigh concentrations of adenosine are in contract with DCsand skews DCs differentiation towards a distinct cell pop-ulation (ie adenosine-differentiated DCs) via binding toA2B receptor on DCs Novitskiy et al reported thatadenosine-differentiated DCs expressed high levels of angio-genic immune suppressor and tolerogenic factors (VEGFIL-8 IL-10 COX-2 TGF120573 and IDO) [55] Moreover viabinding to A2A receptor on DCs adenosine strongly inhib-ited production of IL-12 which was an important antitumorcytokine

T cells comprise the major constituent of adaptive immu-nity and help to fight against infections and tumors Adeno-sine can impact T cells activity by increasing of intracellularcAMP levels [56] In addition adenosinemediated inhibitionof IL-2 production in tumor microenvironment preventsclonal expansion of immunologically active antitumorT cellsJin et al reported that overexpression of CD73 on tumor cellspromoted T-cell apoptosis in vitro and inhibited antitumoreffect of T-cell in vivo while these impairments could bereversed via knockdown of CD73 expression [12] MoreoverRyzhov et al found that CD73 in tumor was involved ininfiltration and accumulation of myeloid-derived suppressorcells (MDSCs) that had been identified as a population ofimmature myeloid cells with the ability to suppress T-cellactivation [57]

Taken together these results demonstrated that CD73-generated adenosine played a key role in the regulationof inflammatory reactions and immune responses throughvarious pathways Inhibition CD73 or adenosinergic pathwaycan be a potential target for cancer immunotherapy in thefuture

8 Regulation of CD73 Expression in Cancer

As mentioned above CD73 plays important roles in malig-nant tumor progression and has been found overexpressed inmany types of cancers How is the expression level of CD73


regulated in tumors There are several mechanisms canexplain this question Firstly CD73 expression has beenfound to be negatively regulated by estrogen receptor (ER) inbreast cancer whereby loss of ER significantly enhancesCD73expression Thus CD73 is highly expressed in ER negativethan ER positive breast cancer patients and might constitutea promising target for clinical treatment of ER negative breastcancer patients [26] In contrast to ER thyroid hormoneshave been identified as a molecule that can increase CD73expression in several types of cells (glioma cells vascularsmooth muscle cells and ventricular myocytes) that belongto nervous and cardiovascular system [58ndash60]

Secondly hypoxic microenvironment can drive CD73expression since there is a HIF-1120572 (hypoxia-inducible factor-1120572) binding site (namely hypoxia response element HRE)in the CD73 gene promoter expression level of CD73 isincreased under hypoxia condition Correspondingly sup-pression of HIF-1120572 by antisense oligonucleotides or pointmutations in theHRE of CD73 gene has been found to inhibithypoxia-induced CD73 expression [61 62]

The third inflammatory factors can also regulate CD73expression Brisevac et al have estimated the effect of sev-eral inflammatory factors (LPS lipopolysaccharide TNF-120572tumor necrosis factor-alpha IFN-120574 interferon-gamma andGlu glutamate) on CD73 expression Interestingly the resultsdemonstrated that IFN-120574 LPS and Glu could significantlydecrease the expression levels of CD73 while TNF-120572 did notlead to significant alterations of CD73 levels [63] In additionIFN-120572 and IFN-120573 have also been reported that they have anup-regulating effect on CD73 expression [64ndash66]

CD73 expression is also regulated by epigenetic mod-ification Lo Nigro et al reported that CD73 expressionwas inhibited by its CpG island methylation in breast car-cinoma cell lines and clinical tumor tissues [67] SimilarlyWang et al showed that CD73 expression was downregu-lated by methylation-dependent transcriptional silencing inmelanoma cell lines And in clinical cases of melanomamethylation in the CD73 CpG islands was correlated withdownregulated CD73 expression and was associated withmetastatic site specificity [9]

Finally some other studies have also reported that Wntpathway [68] polyunsaturated fatty acid (PUFA) [69] andintracellular cAMP are also involved in regulation of CD73expression [70] Taken together these results demonstratethat expression levels of CD73 are regulated by various factorsvia different mechanisms

9 CD73 Targeting Therapy in Cancer

The emerging roles of CD73 in tumor growth and metastasisespecially as a key immunosuppressive factor in tumormicroenvironment have presented potential opportunities todevelop anti-CD73 therapy for various human cancers Inthis regard accumulating results with small molecularinhibitors or monoclonal antibodies targeting CD73 in micetumor models suggest that targeted CD73 therapy is animportant approach to effective control of tumor growth andmetastasis Recently Hausler et al reported that anti-CD73

mAb enhanced the lytic activity of polyclonalNK cells againsthuman ovarian cancer cell lines (SKOV-3 and OAW-42)Likewise blocking of CD73 by mAb significantly increasedproliferation of CD4+ T cells in coculture with ovarian cancercells [71] Thus anti-CD73 treatment improves the immunecytotoxicity response against ovarian cancer cells Stagg etal found that anti-CD73 mAb therapy significantly delayed4T12 and E0771 (two cell lines expressed high levels of CD73)primary tumor growth in immune-competent mice modelswhile it was ineffective in severe immunodeficient micewhich suggests that anti-CD73 mAb therapy requires adap-tive immunity [11] Obviously above results demonstratedthat anti-CD73 therapy was essentially dependent on itspromotive effect on antitumor immune responses in vivo

Cancer immunotherapy has becoming interesting inrecent years Drugs like anti-PD1 mAb and anti-CTLA-4mAb which block programmed death-1 (PD-1) and cytotoxicT lymphocyte antigen (CTLA-4) receptors have shown veryimpressive objective response in patients [72] InterestinglyAllard found that anti-CD73 mAb significantly enhanced theactivity of both anti-CTLA-4 and anti-PD-1 mAbs againstMC38-OVA (colon) tumor RM-1 (prostate) subcutaneoustumors and metastatic 4T12 breast cancer in mice models[73] Recently Lannone et al reported that combinationtreatment with both APCP and anti-CTLA-4 mAb displayedsignificant retard of tumor growth compared with APCPor anti-CTLA-4 mAb treatment alone in mouse melanomamodels [74]

Taken together despite the anti-CD73 therapy has notbeen translated into clinical cancer patients these resultsin tumor-bearing mice models have revealed that targetedblockade of CD73 may be an alternative and realistic ther-apeutic approach for cancer patients in the future Humanimmune response is a complex process in vivo besides CD73mediated immunosuppression tumormay also employ othermechanisms to facilitate immune escape In consideration ofthis combined use of drugs which target different immuno-suppressivemoleculesmay be useful therapeutic strategies forcancer patients in the future

10 Conclusion

In summary CD73 plays multiple roles in cancer relatedprocessesThe connection betweenCD73 overexpression andcancer subtype prognosis drug response of patients has pre-sented the potential value of CD73 that served as a detectablebiomarker in the coming age of individual cancer therapy Inaddition the promotive effect of CD73 on tumor growth andmetastasis suggests that CD73 is a potential therapeutic targetfor cancer treatment Targeting CD73 therapy with inhibitoror mAb has displayed favorable antitumor effects in micetumor models Combination treatment with both CD73blockade and other developed immune-therapeutic agents(anti-CTLA-4 mAb anti-PD1 mAb) seems especially attrac-tive These observations present a good opportunity todevelop anti-CD73 therapy for the treatment of certain cancerpatients Based on these knowledge although there are still along way to go future studies aiming at translating anti-CD73


therapy into clinical cancer patients can be expected Notablybecause of the multiple functions of CD73 in vivo althoughadverse events has not yet been observed in anti-CD73 treatedmice models the potential toxic risk of anti-CD73 therapymust be argued carefully before translating this therapeuticapproach into cancer patients

Conflict of Interests

The authors declare that there is no conflict of interestsregarding the publication of this paper

Acknowledgment

This work is supported by the National Natural Science Fundof China (no 81172148)

References

[1] G Burnstock and F Di Virgilio ldquoPurinergic signalling andcancerrdquo Purinergic Signalling vol 9 no 4 pp 491ndash324 2013

[2] MHelenius S Jalkanen andG G Yegutkin ldquoEnzyme-coupledassays for simultaneous detection of nanomolar ATP ADPAMP adenosine inosine and pyrophosphate concentrations inextracellular fluidsrdquo Biochimica et Biophysica Acta MolecularCell Research vol 1823 no 10 pp 1967ndash1975 2012

[3] M J L Bours E L R Swennen F di Virgilio B N Cronsteinand P C Dagnelie ldquoAdenosine 51015840-triphosphate and adenosineas endogenous signalingmolecules in immunity and inflamma-tionrdquo Pharmacology and Therapeutics vol 112 no 2 pp 358ndash404 2006

[4] G G Yegutkin ldquoNucleotide- and nucleoside-converting ecto-enzymes important modulators of purinergic signalling cas-caderdquo Biochimica et Biophysica Acta vol 1783 no 5 pp 673ndash694 2008

[5] J Stagg and M J Smyth ldquoExtracellular adenosine triphosphateand adenosine in cancerrdquo Oncogene vol 29 no 39 pp 5346ndash5358 2010

[6] F GhiringhelliM Bruchard F Chalmin andC Rebe ldquoProduc-tion of adenosine by ectonucleotidases a key factor in tumorimmunoescaperdquo Journal of Biomedicine and Biotechnology vol2012 Article ID 473712 9 pages 2012

[7] X Zhi S Chen P Zhou et al ldquoRNA interference of ecto-51015840-nucleotidase (CD73) inhibits human breast cancer cell growthand invasionrdquo Clinical and Experimental Metastasis vol 24 no6 pp 439ndash448 2007

[8] C QuezadaWGarrido C Oyarzun et al ldquo51015840-ectonucleotidasemediates multiple-drug resistance in glioblastoma multiformecellsrdquo Journal of Cellular Physiology vol 228 no 3 pp 602ndash6082013

[9] H Wang S Lee C Lo Nigro et al ldquoNT5E (CD73) is epige-netically regulated in malignant melanoma and associated withmetastatic site specificityrdquo British Journal of Cancer vol 106 no8 pp 1446ndash1452 2012

[10] R Sadej and A C Skladanowski ldquoDual enzymatic and non-enzymatic function of ecto-51015840-nucleotidase (eN CD73) inmigration and invasion of A375 melanoma cellsrdquoActa Biochim-ica Polonica vol 59 no 4 pp 647ndash652 2012

[11] J Stagg U Divisekera N McLaughlin et al ldquoAnti-CD73 anti-body therapy inhibits breast tumor growth and metastasisrdquo

Proceedings of the National Academy of Sciences of the UnitedStates of America vol 107 no 4 pp 1547ndash1552 2010

[12] D Jin J Fan L Wang et al ldquoCD73 on tumor cells impairsantitumor T-cell responses a novel mechanism of tumor-induced immune suppressionrdquo Cancer Research vol 70 no 6pp 2245ndash2255 2010

[13] L Wang X Zhou T Zhou et al ldquoEcto-51015840-nucleotidase pro-motes invasionmigration and adhesion of human breast cancercellsrdquo Journal of Cancer Research and Clinical Oncology vol 134no 3 pp 365ndash372 2008

[14] A R Cappellari L Rockenbach F Dietrich et al ldquoCharac-terization of ectonucleotidases in human medulloblastoma celllines ecto-5 1015840NTCD73 in metastasis as potential prognosticfactorrdquo PLoS ONE vol 7 no 10 Article ID e47468 2012

[15] J Stella L Bavaresco E Braganhol et al ldquoDifferential ectonu-cleotidase expression in human bladder cancer cell linesrdquoUrologic Oncology Seminars and Original Investigations vol 28no 3 pp 260ndash267 2010

[16] N Liu X D Fang and Q Vadis ldquoCD73 as a novel prognosticbiomarker for human colorectal cancerrdquo Journal of SurgicalOncology vol 106 no 7 pp 918ndash919 2012

[17] XWu X He Y Chen et al ldquoHigh expression of CD73 as a poorprognostic biomarker in human colorectal cancerrdquo Journal ofSurgical Oncology vol 106 no 2 pp 130ndash137 2012

[18] H K Oh J I Sin J Choi S H Park T S Lee and Y SChoi ldquoOverexpression of CD73 in epithelial ovarian carcinomais associated with better prognosis lower stage better differ-entiation and lower regulatory t cell infiltrationrdquo Journal ofGynecologic Oncology vol 23 no 4 pp 274ndash281 2012

[19] X X Lu Y T Chen B Feng X Y Mao B Yu and X ChuldquoExpression and clinical significance of CD73 and hypoxia-inducible factor-1120572 in gastric carcinomardquo World Journal ofGastroenterology vol 19 no 12 pp 1912ndash1918 2013

[20] L Xiong Y Wen X Miao and Z Yang ldquoNT5E and FcGBPas key regulators of TGF-1-induced epithelial-mesenchymaltransition (EMT) are associated with tumor progression andsurvival of patients with gallbladder cancerrdquo Cell and TissueResearch vol 355 no 2 pp 365ndash374 2014

[21] S X Zhao H M Zhang S X Dong et al ldquoCharacteristics andclinical significance of CD73 expression in subtypes of leuk-emiardquo Journal of experimental hematologyChinese Associationof Pathophysiology vol 19 no 5 pp 1141ndash1144 2011

[22] S Serra A L Horenstein T Vaisitti et al ldquoCD73-generatedextracellular adenosine in chronic lymphocytic leukemia cre-ates local conditions counteracting drug-induced cell deathrdquoBlood vol 118 no 23 pp 6141ndash6152 2011

[23] E Wieten B E M van der Linden-Schrever E Sonneveld AJ Veerman and R Pieters ldquoCD73 (51015840-nucleotidase) expressionhas no prognostic value in children with acute lymphoblasticleukemiardquo Leukemia vol 25 no 8 pp 1374ndash1376 2011

[24] Q Yang J Du and L Zu ldquoOverexpression of CD73 in prostatecancer is associated with lymph node metastasisrdquo PathologyOncology Research vol 19 no 4 pp 811ndash814 2013

[25] A Supernat M Wełnicka-Jaskiewicz A Markiewicz et alldquoCD73 expression as a potential marker of good prognosis inbreast carcinomardquo Applied Immunohistochemistry and Molecu-lar Morphology vol 20 no 2 pp 103ndash107 2012

[26] S Loi S Pommey B Haibe-Kains et al ldquoCD73 promotesanthracycline resistance and poor prognosis in triple negativebreast cancerrdquo Proceedings of the National Academy of Sciencesof the United States of America vol 110 no 27 pp 11091ndash110962013


[27] B Zhang ldquoCD73 promotes tumor growth and metastasisrdquoOncoimmunology vol 1 no 1 pp 67ndash70 2012

[28] B Zhang ldquoOpportunities and challenges for anti-CD73 cancertherapyrdquo Immunotherapy vol 4 no 9 pp 861ndash865 2012

[29] J Stagg ldquoThe double-edge sword effect of anti-CD73 cancertherapyrdquo Oncoimmunology vol 1 no 2 pp 217ndash218 2012

[30] P Ujhazy E S Berleth J M Pietkiewicz et al ldquoEvidence for theinvolvement of ecto-51015840-nucleotidase (CD73) in drug resistancerdquoInternational Journal of Cancer vol 68 no 4 pp 493ndash500 1996

[31] W GarridoMMunoz R SanMartın and C Quezada ldquoFK506confers chemosensitivity to anticancer drugs in glioblastomamultiforme cells by decreasing the expression of the multipleresistance-associated protein-1rdquo Biochemical and BiophysicalResearch Communications vol 411 no 1 pp 62ndash68 2011

[32] X Zhi Y Wang X Zhou et al ldquoRNAi-mediated CD73 sup-pression induces apoptosis and cell-cycle arrest in human breastcancer cellsrdquoCancer Science vol 101 no 12 pp 2561ndash2569 2010

[33] X Zhou X Zhi P Zhou et al ldquoEffects of ecto-51015840-nucleotidaseon human breast cancer cell growth in vitro and in vivordquoOncology Reports vol 17 no 6 pp 1341ndash1346 2007

[34] L Rockenbach L Bavaresco P Fernandes Farias et al ldquoAlter-ations in the extracellular catabolismof nucleotides are involvedin the antiproliferative effect of quercetin in human bladdercancer T24 cellsrdquoUrologic Oncology vol 31 no 7 pp 1204ndash12112013

[35] L Bavaresco A Bernardi E Braganhol et al ldquoThe role ofecto-51015840nucleotidaseCD73 in glioma cell line proliferationrdquoMolecular and Cellular Biochemistry vol 319 no 1-2 pp 61ndash682008

[36] M Wang and L Ren ldquoGrowth inhibitory effect and apoptosisinduced by extracellular ATP and adenosine on human gastriccarcinoma cells involvement of intracellular uptake of adeno-sinerdquo Acta Pharmacologica Sinica vol 27 no 8 pp 1085ndash10922006

[37] S Shirali M Aghaei M Shabani M Fathi M Sohrabi and MMoeinifard ldquoAdenosine induces cell cycle arrest and apoptosisvia cyclinD1Cdk4 and Bcl-2Bax pathways in human ovariancancer cell line OVCAR-3rdquo Tumor Biology vol 34 no 2 pp1085ndash1095 2013

[38] X Zhi Y Wang J Yu et al ldquoPotential prognostic biomarkerCD73 regulates epidermal growth factor receptor expression inhuman breast cancerrdquo IUBMB Life vol 64 no 11 pp 911ndash9202012

[39] J Stagg P A Beavis U Divisekera et al ldquoCD73-Deficient miceare resistant to carcinogenesisrdquo Cancer Research vol 72 no 9pp 2190ndash2196 2012

[40] GG Yegutkin FMarttila-IchiharaMKarikoski et al ldquoAlteredpurinergic signaling in CD73-deficient mice inhibits tumorprogressionrdquo European Journal of Immunology vol 41 no 5 pp1231ndash1241 2011

[41] P Zhou X Zhi T Zhou et al ldquoOverexpression of ecto-51015840-nucleotidase (CD73) promotes T-47D human breast cancercells invasion and adhesion to extracellular matrixrdquo CancerBiology andTherapy vol 6 no 3 pp 426ndash431 2007

[42] J Stagg U Divisekera H Duret et al ldquoCD73-deficient micehave increased antitumor immunity and are resistant to exper-imental metastasisrdquo Cancer Research vol 71 no 8 pp 2892ndash2900 2011

[43] L Wang S Tang Y Wang et al ldquoEcto-51015840-nucleotidase(CD73) promotes tumor angiogenesisrdquoClinical and Experimen-tal Metastasis vol 30 no 5 pp 671ndash680 2013

[44] P Koszalka A PryszlakMGolunska et al ldquoInhibition of CD73stimulates the migration and invasion of B16F10 melanomacells in vitro but results in impaired angiogenesis and reducedmelanoma growth in vivordquo Oncology Reports vol 31 no 2 pp819ndash827 2014

[45] B Allard M Turcotte K Spring S Pommey I Royal andJ Stagg ldquoAnti-CD73 therapy impairs tumor angiogenesisrdquoInternational Journal of Cancer vol 134 no 6 pp 1466ndash14732014

[46] Y C Boring U Flogel C Jacoby M Heil W Schaper and JSchrader ldquoLack of ecto-51015840-nucleotidase (CD73) promotes arte-riogenesisrdquo Cardiovascular Research vol 97 no 1 pp 88ndash962013

[47] S Giuliano and G Pages ldquoMechanisms of resistance to anti-angiogenesis therapiesrdquo Biochimie vol 95 no 6 pp 1110ndash11192013

[48] D Hanahan and R AWeinberg ldquoHallmarks of cancer the nextgenerationrdquo Cell vol 144 no 5 pp 646ndash674 2011

[49] L Antonioli P Pacher E S Vizi and G Hasko ldquoCD39 andCD73 in immunity and inflammationrdquo Trends in MolecularMedicine vol 19 no 6 pp 355ndash367 2013

[50] M S Longhi S C Robson S H Bernstein S Serra and SDeaglio ldquoBiological functions of ecto-enzymes in regulatingextracellular adenosine levels in neoplastic and inflammatorydisease statesrdquo Journal of Molecular Medicine vol 91 no 2 pp165ndash172 2013

[51] P A Beavis J Stagg P K Darcy and M J Smyth ldquoCD73 apotent suppressor of antitumor immune responsesrdquo Trends inImmunology vol 33 no 5 pp 231ndash237 2012

[52] V Kumar ldquoAdenosine as an endogenous immunoregulator incancer pathogenesis where to gordquo Purinergic Signalling vol 9no 2 pp 145ndash165 2013

[53] R Sorrentino A Pinto and S Morello ldquoThe adenosinergicsystem in cancer key therapeutic targetrdquoOncoimmunology vol2 no 1 Article ID e22448 2013

[54] T Raskovalova X Huang M Sitkovsky L C Zacharia E KJackson and E Gorelik ldquoGS protein-coupled adenosine recep-tor signaling and lytic function of activated NK cellsrdquo Journal ofImmunology vol 175 no 7 pp 4383ndash4391 2005

[55] S V Novitskiy S Ryzhov R Zaynagetdinov et al ldquoAdenosinereceptors in regulation of dendritic cell differentiation andfunctionrdquo Blood vol 112 no 5 pp 1822ndash1831 2008

[56] T L Whiteside M Mandapathil and P Schuler ldquoThe role ofthe adenosinergic pathway in immunosuppressionmediated byhuman regulatory T cells (Treg)rdquo Current Medicinal Chemistryvol 18 no 34 pp 5217ndash5223 2011

[57] S Ryzhov S V Novitskiy A E Goldstein et al ldquoAdenosinergicregulation of the expansion and immunosuppressive activity ofCD11b+Gr1+ cellsrdquo Journal of Immunology vol 187 no 11 pp6120ndash6129 2011

[58] M R Wink A S K Tamajusuku E Braganhol et al ldquoThyroidhormone upregulates ecto-51015840-nucleotidaseCD73 in C6 ratglioma cellsrdquoMolecular andCellular Endocrinology vol 205 no1-2 pp 107ndash114 2003

[59] A S K Tamajusuku M A Carrillo-Sepulveda E Braganholet al ldquoActivity and expression of ecto-51015840-nucleotidaseCD73are increased by thyroid hormones in vascular smooth musclecellsrdquoMolecular and Cellular Biochemistry vol 289 no 1-2 pp65ndash72 2006

[60] M S Carneiro-Ramos V B da Silva M B Coutinho Jr A MOliveira Battastini J J Freitas Sarkis and M L M Barreto-Chaves ldquoThyroid hormone stimulates 51015840-ecto-nucleotidase of


neonatal rat ventricular myocytesrdquo Molecular and CellularBiochemistry vol 265 no 1-2 pp 195ndash201 2004

[61] G L Semenza ldquoHypoxia-inducible factor 1 regulator of mito-chondrial metabolism and mediator of ischemic precondition-ingrdquo Biochimica et Biophysica ActamdashMolecular Cell Researchvol 1813 no 7 pp 1263ndash1268 2011

[62] X Li T Zhou X Zhi F Zhao L Yin and P Zhou ldquoEffect ofhypoxiareoxygenation on CD73 (ecto-51015840-nucleotidase) in mo-use microvessel endothelial cell linesrdquo Microvascular Researchvol 72 no 1-2 pp 48ndash53 2006

[63] D Brisevac I Bjelobaba A Bajic et al ldquoRegulation of ecto-51015840-nucleotidase (CD73) in cultured cortical astrocytes by differentinflammatory factorsrdquoNeurochemistry International vol 61 no5 pp 681ndash688 2012

[64] J Niemela T Henttinen G G Yegutkin et al ldquoIFN-120572 inducedadenosine production on the endothelium a mechanismmedi-ated by CD73 (Ecto-51015840-Nucleotidase) up-regulationrdquo Journal ofImmunology vol 172 no 3 pp 1646ndash1653 2004

[65] L Airas J Niemela G Yegutkin and S Jalkanen ldquoMechanismof action of IFN-120573 in the treatment of multiple sclerosis aspecial reference to CD73 and adenosinerdquo Annals of the NewYork Academy of Sciences vol 1110 pp 641ndash648 2007

[66] J Kiss G G Yegutkin K Koskinen T Savunen S Jalkanenand M Salmi ldquoIFN-120573 protects from vascular leakage via up-regulation of CD73rdquo European Journal of Immunology vol 37no 12 pp 3334ndash3338 2007

[67] C Lo Nigro M Monteverde S Lee et al ldquoNT5E CpG islandmethylation is a favourable breast cancer biomarkerrdquo BritishJournal of Cancer vol 107 no 1 pp 75ndash83 2012

[68] J Spychala and J Kitajewski ldquoWnt and 120573-catenin signalingtarget the expression of ecto-51015840-nucleotidase and increase extra-cellular adenosine generationrdquo Experimental Cell Research vol296 no 2 pp 99ndash108 2004

[69] V T Thom M Wendel and A Deussen ldquoRegulation of ecto-51015840-nucleotidase by docosahexaenoic acid in human endothelialcellsrdquo Cellular Physiology and Biochemistry vol 32 no 2 pp355ndash366 2013

[70] S Narravula P F Lennon B U Mueller and S P ColganldquoRegulation of endothelial CD73 by adenosine paracrine path-way for enhanced endothelial barrier functionrdquo Journal ofImmunology vol 165 no 9 pp 5262ndash5268 2000

[71] S F Hausler I M del Barrio J Diessner et al ldquoAnti-CD39and anti-CD73 antibodies A1 and 7G2 improve targeted therapyin ovarian cancer by blocking adenosine-dependent immuneevasionrdquo American Journal of Translational Research vol 6 no2 pp 129ndash139 2014

[72] D M Pardoll ldquoThe blockade of immune checkpoints in cancerimmunotherapyrdquoNature Reviews Cancer vol 12 no 4 pp 252ndash264 2012

[73] BAllard S PommeyM J Smyth and J Stagg ldquoTargetingCD73enhances the antitumor activity of anti-PD-1 and anti-CTLA-4mAbsrdquo Clinical Cancer Research vol 19 no 20 pp 5626ndash56352013

[74] R Iannone L Miele P Maiolino A Pinto and S MorelloldquoAdenosine limits the therapeutic effectiveness of anti-CTLA4mAb in amousemelanomamodelrdquoAmerican Journal of CancerResearch vol 4 no 2 pp 172ndash181 2014

Submit your manuscripts athttpwwwhindawicom

Stem CellsInternational

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014


MEDIATORSINFLAMMATION

of


Behavioural Neurology

EndocrinologyInternational Journal of



Disease Markers


BioMed Research International

OncologyJournal of



Oxidative Medicine and Cellular Longevity


PPAR Research

The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014

Immunology ResearchHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Journal of

ObesityJournal of



Computational and Mathematical Methods in Medicine

OphthalmologyJournal of


Diabetes ResearchJournal of



Research and TreatmentAIDS


Gastroenterology Research and Practice


Parkinsonrsquos Disease

Evidence-Based Complementary and Alternative Medicine

Volume 2014Hindawi Publishing Corporationhttpwwwhindawicom


Table 1 CD73 expression in different cancer cell lines

Cancer type Cell line Expression Reference

Glioblastoma Multiforme T98G Higher level of mRNA and protein than normal glialcell line SVGp12 [8]

Melanoma

C8161 PMW SBCL2SKMel28 SKMel30KMel147 SKMel173Mel224 WM266-4

M902-6

Higher mRNA expression thanWM35 et al because theabsent of methylation [9]

MelanomaWM35 Mel501Mel505 SKMel2SKMel23 C81-61

Lower mRNA expression caused by the NT5E CpGisland methylation [9]

Melanoma A375 High expression levels and activity [10]Mouse breastcancer 4T12 E0771 Higher expression levels than nonmetastatic variant of

4T12 [11]

Ovarian cancer SKOV3 SKOV3 human ovarian cancer cells highly expressedCD73 [12]

Breast cancer MB-MDA-231 T-47D T-47D with lower expression of CD73 andMB-MDA-231 with higher expression of CD73 [13]

Primary MedulloblastomaMetastatic Medulloblastoma

Daoy ONS76D283

Daoy and ONS76 express higher levels of CD73 whileD283 revealed poor expression of CD73 [14]

Bladder cancer RT4 T24 Both cell lines expressed CD73 [15]

cancer colorectal cancer ovarian cancer gastric cancer andgallbladder cancer and associated with clinical character-istics or prognosis of cancer patients (Tables 1 and 2)Increasing evidence has verified that CD73 is a key regulatorymolecule in cancer development [27] In particular dueto the favorable effect on tumor-bearing mice modelsalthough have not been investigated in clinical patients anti-CD73 therapy has become a promising approach for thetreatment of cancer patients in the future [28 29] In thispresent paper we will summarize the roles of CD73 in cancerdevelopment including its clinical significance in cancerpatients its promotive effects on tumor growth metastasisand angiogenesis and its suppressive effects on immune sys-temunder tumormicroenvironment regulationmechanismsof CD73 expression and opportunities for anti-CD73 cancertherapy in the future

2 Clinical Significance of CD73 inCancer Patients

Overexpression of CD73 has been observed in broad types ofcancers and its clinical significance has also been found bycorrelative analysis (Table 2) In breast cancer Loi et aldemonstrated that CD73 expression was significantly associ-ated with a worse prognosis in triple negative breast cancer(TNBC) patients (119899 = 661 119875 = 0029) but not in patientswith luminal (119899 = 2083 119875 = 07) or HER2+ (119899 = 487119875 = 086) breast cancer [26] In contrast another retrospec-tive study (119899 = 136) reported that positive CD73 expressionwas strongly correlated with longer disease-free survival (119875 =00044) and overall survival (119875 = 0027) of breast cancerpatients [25] which suggested that elevated CD73 expres-sion could predict a good prognosis in stages IndashIII breastcancer patients Notably the prognostic implication of CD73

expression in breast cancer remains controversial and is notindependent of other clinical indexes Now a retrospectiveanalysis by our team in more clinical specimens is in processwhich will take more factors into consideration such aspatientrsquos age subtype and population treatment

In digestive system cancers recently Lu et al evaluatedthe clinical significance and prognostic value of CD73 inhuman gastric cancer (119899 = 68 patients) analysis of CD73expression by immune histochemistry (IHC) revealed thatoverexpression of CD73 was positively correlated with differ-entiation of tumor depth of invasion (119875 lt 0001) nodal sta-tus (119875 = 0003) metastasis (119875 = 0013) and the cancer stage(119875 lt 0001) and the overall survival rate was low in thepatients with high expression of CD73 (119875 lt 0001) [19] Inaddition to gastric cancer other studies showed that highlevels of CD73 in colorectal cancer (CRC) patients were cor-related with a poor prognosis [16 17] Moreover Xiong et alrecently reported that CD73 expression was associated withtumor progression and survival of patients with gallbladdercancer [20]

In hematologic neoplasm Zhao et al investigated theexpression of CD73 in various leukemia subtypes (119899 = 86)and revealed that the expression of CD73 was associated withleukemia subtype differentiation and development [21]Serra et al assessed the clinical implication of CD73 inchronic lymphoblastic leukemia (CLL 119899 = 299) and foundthat high expression of CD73 was associated with a moreaggressive clinical behavior [22] whereas another studyshowed that CD73 expression had no prognostic value inchildren (1ndash18 years old) with acute lymphoblastic leukemia(ALL 119899 = 338) [23]

In other cancers Yang et al reported that overexpressionof CD73 in prostate cancer was associated with lymph nodemetastasis [24] And Oh et al showed that overexpression






[18]

Gastric cancer 68


[19]











6612083487


[26]












































10 Conclusion






Acknowledgment


References




















































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of





















[18]

Gastric cancer 68


[19]











6612083487


[26]












































10 Conclusion






Acknowledgment


References




















































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of





















































10 Conclusion






Acknowledgment


References




















































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of




















Acknowledgment


References




















































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of








































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of
















review article the roles of cd73 in cancerdownloads.hindawi.com/journals/bmri/2014/460654.pdfreview...

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