Review Article Emerging Therapeutic Biomarkers in...

Hindawi Publishing CorporationBioMed Research InternationalVolume 2013 Article ID 130362 11 pageshttpdxdoiorg1011552013130362

Review ArticleEmerging Therapeutic Biomarkers in Endometrial Cancer

Peixin Dong1 Masanori Kaneuchi1 Yosuke Konno2 Hidemichi Watari2

Satoko Sudo2 and Noriaki Sakuragi2

1 Department of Womenrsquos Health Educational System Hokkaido University School of Medicine Hokkaido University N15 W7Sapporo 060-8638 Japan

2Department of Gynecology Hokkaido University School of Medicine Hokkaido University N15 W7 Sapporo 060-8638 Japan

Correspondence should be addressed to Peixin Dong dongpeixyahoocojp and Noriaki Sakuragi sakuragimedhokudaiacjp

Received 14 April 2013 Accepted 28 May 2013

Academic Editor Romonia Renee Reams

Copyright copy 2013 Peixin Dong 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

Although clinical trials of molecular therapies targeting critical biomarkers (mTOR epidermal growth factor receptorepidermalgrowth factor receptor 2 and vascular endothelial growth factor) in endometrial cancer show modest effects there are stillchallenges that might remain regarding primaryacquired drug resistance and unexpected side effects on normal tissues Newstudies that aim to target both genetic and epigenetic alterations (noncodingmicroRNA) underlyingmalignant properties of tumorcells and to specifically attack tumor cells using cell surface markers overexpressed in tumor tissue are emerging More importantlystrategies that disrupt the cancer stem cellepithelial-mesenchymal transition-dependent signals and reactivate antitumor immuneresponses would bring new hope for complete elimination of all cell compartments in endometrial cancer We briefly review thecurrent status ofmolecular therapies tested in clinical trials andmainly discuss the potential therapeutic candidates that are possiblyused to develop more effective and specific therapies against endometrial cancer progression and metastasis

1 Introduction

Endometrial cancer (EC) is the most common gynecologicalmalignancy amongwomenworldwidewith 287000 new casesand estimated 74000 deaths per year [1]

EC has been dichotomized into two types with distinctunderlying molecular profiling histopathology and clinicalbehavior less aggressive type I and highly aggressive type IIMost ECs are type I (approximately 75) and are estrogen-dependent adenocarcinomaswith endometrioidmorphology[2] They are usually diagnosed at an early stage and havea good prognosis (a 5-year survival rate of 80ndash85) aftersurgery [2 3] In contrast type II ECs with poorly differen-tiated endometrioid and serous histology are associated withmyometrial invasion extrauterine spread and a lower 5-yearsurvival rate (35) [3ndash6] Although patients with advancedor recurrent disease typically receive adjuvant chemotherapyand radiation they have an extremely poor prognosis Apotential strategy for the treatment of these cases is to targetEC cells by blocking key signaling pathways that are necessaryfor tumor development

2 Therapeutic Targets for EC

Type I EC frequently exhibits altered PI3KPTENAKTmTOR signal pathway [7ndash11] Type II cancer predominantlyshows mutations in p53 [12] and epidermal growth factorreceptor 2 (HER-2) overexpression [13] The upregulationof epidermal growth factor receptor (EGFR) [14 15] andvascular endothelial growth factor (VEGF) [16] dysregu-lated microRNA (miRNA) [17] and activation of cancerstem cell (CSC)epithelial-mesenchymal transition (EMT)programs are involved in oncogenesis and progression ofboth cancer types [18ndash20] Owing to the high-frequencyactivation of PI3KAKTmTOR EGFRHER2 and VEGF-related pathway and their important roles in promoting ECgrowth and metastasis new drug targeting these signalswould be valuable to a very large number of patients withEC Recently clinical trials assessing the efficacy of mTORinhibitor EGFRHER2 inhibitor and antiangiogenic agentfor EChave been conducted and demonstratedmodest effects[21 22] (Figure 1)

2 BioMed Research International

VEGFR-2EGFRHER2FGFR2

PPP

P

VEGF

PP P

P

EGFRHER2FGFR2 inhibitor

VEGFinhibitor

RASPI3KmTORinhibitor

VEGFRinhibitor

PI3K

Transcription

Cell proliferation cell survival EMT

AKT

PTEN

PI3K

Cell proliferation cell survivalangiogenesis EMT

PI3Kinhibitor

AKTinhibitor

mTORinhibitor

MEK

ERK

AKT

mTORC

mTORC1

mTORC2

Figure 1 Therapeutic molecular targets for endometrial cancer Type I endometrial cancer (EC) frequently exhibits alteredPI3KPTENAKTmTOR signal pathway whereas type II EC frequently showsmutations in p53 andHER-2 overexpressionThe upregulationof EGFR and VEGF dysregulated microRNAs and activation of cancer stem cell (CSC)epithelial-mesenchymal transition (EMT) programsare involved in oncogenesis and progression of both cancer types Currently clinical trials assessing the efficacy of mTOR inhibitorEGFRHER2 inhibitor and antiangiogenic agent for EC have been conducted and demonstrated modest effects

3 Challenges in the Molecular Therapeutics ofHuman Tumor

Although the therapeutic potential of targeted drugs forthe treatment of human tumors appears promising theclinical success of such drugs has been limited by keychallenges including primaryacquired drug resistance [23ndash25] and unexpected side effects on normal tissues due tononspecificity [26] (Figure 2)

A portion of patients unfortunately do not respondto targeted agents (primary resistance) and the remaindermight eventually acquire the resistance to targeted therapydespite an initial response Various mechanisms of resistancehave begun to be elucidated The most frequently reportedmechanism of primary resistance is genetic heterogeneityFor example mechanisms of resistance to EGFR inhibitorsare involved in point mutations deletions and amplificationsof genomic areas of EGFR [23] In addition to geneticalteration epigenetic changes such as DNA methylation atCpG islands have been linked to the development of resis-tance to multiple molecular drugs [27 28] The generationof a population of cancer cells with stem-cell propertiesmight provide another possible reason of resistance to EGFRinhibitor [29] Common mechanisms of acquired resistanceinclude secondary mutation in the target gene activation ofalternative pathway or feedback loop and induction of EMT[23 30] Therefore new therapy that concurrently attacks

multiple critical pathways inhibits the cross talk betweendiverse signals and suppresses the CSC and EMT propertiesmay be efficacious to overcome the resistance to molecularagents in EC

Moreover the administration of antiangiogenic agentsparticularly antibodies against VEGF leads to amore hypoxictumor microenvironment [31] which enhances tumor cellinvasion and metastasis by inducing the EMT- and CSC-like phenotype [32ndash34] These works clearly suggest the needto combine antiangiogenic treatment in human tumors withnew drugs targeting specific signaling pathways linked to theCSCEMT phenotype

Another challenge is toxicity or the side effects associatedwith targeted therapies such as harmful immune responsesThese include ldquoOff-targetrdquo adverse effects caused by a drugbinding to an unexpected target and ldquoOn-targetrdquo adverseeffects as a result of a drug binding to its intended target thatis not only present in tumor cells but also found in normaltissue [26]

4 Potential miRNA-Based Therapies in EC

Different from gene mutations epigenetic changes that areassociated with global gene regulation such as chromatinremodeling open a new field of cancer research [35] Epi-genetic silencing of tumor suppressor genes or epigenetic

BioMed Research International 3

Targeted therapies

Genetic and epigenetic heterogeneity

Normal cell

Toxicities Acquired drug

resistance

Cancer stem cellEMT

Tumor cell

Primary drug resistance

Limited efficaciesEnhancedmetastasis

side effects

Activation ofcomplementary pathway

or feedback loop Lack of specificity

Figure 2 Challenges in the molecular therapeutics of human tumor The clinical success of targeted drugs has been limited by keychallenges including primaryacquired drug resistance and unexpected side effects on normal tissues due to nonspecificityThemost frequentmechanisms of primary resistance are geneticepigenetic heterogeneity and the existence of cancer stemcell Acquired resistance can be causedby the secondary mutation in the target gene activation of alternative pathway or feedback loop and induction of EMT Treatment of tumorcells with antiangiogenic agents can lead to a more hypoxic tumor microenvironment and enhance tumor cell invasion and metastasis byinducing the EMT- and cancer-stem-cell-like phenotype

activation of oncogenes plays the important roles in the pro-motion of carcinogenesis and tumor progression [35] Twocommon epigenetic changes are methylation at the promoterregion andhistone acetylationwhich can bemodulated usinginhibitors of DNA methyltransferase (DNMT) and histonedeacetylase (HDAC) respectively Tumor suppressor genesincluding PTEN [36] DNA mismatch repair gene hMLH1[37] adenomatous polyposis coli (APC) [38] RAS-associateddomain family member protein 1 (RASSF1A) [39] and E-cadherin [40] are more frequently silenced in type I tumorthan in type II tumor DNMT and HDAC inhibitors arealready in clinical use for myelodysplasia and cutaneous T-cell lymphoma [41 42] Preclinical study has shown thatDNMT and HDAC inhibitors induce cell apoptosis andsuppress the growth of EC in vivo [43] The combination ofepigenetic modifiers with chemotherapy hormonal therapyand targeted therapy has been proposed [44] and this mayachieve better effect than single epigenetic agent for thetreatment of EC

Another important mechanism for epigenetic regulationof gene expression is involved in noncoding RNAs specifi-cally small regulatory microRNA (miRNA) MiRNAs post-transcriptionally control gene expression by base pairingwiththe 31015840 untranslated region of target mRNAs which triggerseither mRNA translation repression or RNA degradation[45]

As miRNAs are able to bind to their mRNA targetswith either perfect or imperfect complementary one miRNAmay possibly have multiple target genes and concurrentlyinfluence different cellular signaling pathways [45] SomemiRNAs can function as either promoter or suppressorparticipating in a wide variety of biological functions oftumor including cell proliferation differentiationmigrationapoptosis and recently EMTcancer-stem-cell-like features

[46] Therefore modulation of dysregulated miRNAs couldbe a powerful tool to correct abnormal signaling pathwaysrelated to EC

Altered expression profiles of microRNA have beenobserved in EC compared with normal endometrium[47] Several miRNAs are differentially expressed betweenendometrioid and serous papillary EC indicating that theycould infer mechanisms that are specific to individual tumorsubtypes [48] Among those miRNAs elevated in endometri-oid EC the expression of miR-7 can be downregulatedby using anti-miRNA oligonucleotides leading to repressedmigration and invasion of EC cells [49] On the other handthe level of miR-194 was significantly lower in EC patientswith more advanced stage and lower expression of thismiRNA was associated with worse survival [50] We foundthat overexpression of miR-194 by transfection with pre-miRNA molecule inhibited EMT phenotype and EC cellinvasion by targeting the oncogene BMI-1 [51] We alsoidentified miR-130b as one of the mutant p53-responsive23 miRNAs which is decreased in EC relative to adjacentnormal tissue and directly targets the key EMT promotergene ZEB1 to revert p53-mutations-induced EMT featuresof EC cells [52] MiRNAs are stable in various tissuesand bodily fluids [53] This property greatly facilitates thedelivery of miRNAs to recipient cells via the blood or othercompartments Collectively targeting those miRNAs that aredeeply involved in ECprogressionwould provide a promisingtherapeutic option for EC

Forced expression of tumor suppressor miRNA and sup-pression of oncogenic miRNA are two strategies to achievethe goal of miRNA-based cancer treatment (Figure 3)Although previous results demonstrated that restorationof tumor suppressor miR-152 effectively inhibited EC cellgrowth in vitro and in vivo [54] obvious challenges of


Cell surface markers overexpressed in endometrial

cancer

Nanoparticle

Antibody

Cell surface marker

EphA2

claudin-3

claudin-4

FOLR1

MSLN

Trop-2

HER2

EpCAM

L1CAM

Restoration of tumor suppressive miRNA

(194 130b etc)

Inhibitor of oncogenic miRNA

Suppression of tumor progression and metastasis

Tumor cell

Type I Type II

Figure 3 Potential miRNA-based therapies in ECThe use of antibodies against cell surfacemarkers overexpressed in EC tissuemight delivertargeted drugs to EC cells more specifically with fewer side effects on normal tissue The nanotechnology can be used to develop a moreeffective delivery system for targeted agents especially miRNA that might simultaneously modulate multiple signal pathways necessary formalignant phenotype of EC

obtaining efficient delivery systems and tumor cell specificitymust be resolved to allow clinical implementation

The biochemical similarity between miRNA and siRNAsuggests that the same delivery reagents developed for usewith siRNA could be applied to the delivery of miRNA[55 56] Many efforts have been made to develop moreeffective and stable delivery systems [57] Among themnanoparticles confer greater miRNA stability and the con-jugation of nanoparticles to antibodies or cancer-specificligands can notably improve their interactions with cancercells [57] By using the modification of GC4 single-chainfragment (a tumor-targeting human monoclonal antibody)nanoparticles injected intravenously showed greater accu-mulation in the tumor nodules rather than in liver andkidney Moreover the codelivery of three siRNAs togetherwith miR-34a resulted in a more significant inhibition (80)of metastatic melanoma than that obtained with siRNAsor miRNA alone [58] These data demonstrate that the useof antibody targeting cell surface marker allows a selectivedelivery of miRNA into the tumor and the combination ofsiRNA and miRNA could additively inhibit tumor growthand metastasis

As mentioned another major issue for molecular cancertherapy is toxicity To avoid potential side effects on normaltissue increasing attention has been directed to the identifi-cation of tumor-specific surface markers including receptorsand epitopes that are highly expressed in cancer cells butnot or minimally expressed in normal cells Some potentialtumor cell surface markers overexpressed in EC compared

with normal endometriummight be used for targeted therapy(Figure 3)

Eph receptor tyrosine kinases and their ephrin ligandsinfluence central nervous system development stem cellniches and cancer cells [59] Upon the binding of EphrinA1the EphA2 receptor becomes tyrosine phosphorylated andinteracts with several proteins to elicit downstream signalingwhich regulate cell adhesion proliferation migration andangiogenesis [60] Overexpression of EphA2 was found ina high proportion of endometrioid EC and correlated withadvanced disease and poor prognosis whereas its expressionis present at low levels in benign endometrial tissue [61]Themicrotubule inhibitor conjugated to EphA2 antibodywasshown to be specifically internalized by EphA2-positive ECcells resulting in significant growth inhibition of EC cellsboth in vitro and in vivo [62]

The tight junction proteins claudin-3 and claudin-4 arehighly expressed in endometrioid serous papillary andclear-cell EC [63] but less frequently found in normalendometrium [64] Importantly the intratumoral injectionof cytotoxic Clostridium perfringens enterotoxin (CPE) thatinteracts with claudin-3 and claudin-4 in subcutaneousserous EC xenografts led to tumor disappearance andextended survival of animals [65] indicating that targetingclaudin-3 and claudin-4 by CPE or other targeted treatmentmay efficiently suppress the progression of EC

Folate receptor alpha (FOLR1 a membrane-bound molecule) and mesothelin (MSLN a glycosyl-phosphatidylinositol-linked cell surface antigen) that are


RasRafMEK

PI3KAK

EpCAM

PICH1 SMO

Hedgehog

SMOinhibitor

Fz

Notch1

mTOR

EGFRHER2CD133

STAT3

SalinomycinNotch

inhibitor

Wnt

EpCAM inhibitor

TmTOR

EMTCSC program

Snail slug

TWIST1

BMI-1 ZEB1

Gli1

CD44 COX-2

inhibitor

Epigenetic regulation

CSLSmad

STAT3 inhibitor

120573-catenin

120573-catenin

TGF-120573

TGF-120573

120573-catenin

Figure 4 Targeting the CSCEMT signaling pathways in EC Tumor cells that undergo EMT not only increase their invasion ability but alsoconcurrently acquire cancer stem cell (CSC) properties On the other hand CSCs are associated with enhanced capacity to metastasize At amolecular level several signaling pathways involved in the self-renewal of CSCs including Wnt120573-catenin Hedgehog and Notch signalingcan also induce EMT programs Specific inhibitors targeting these CSC and EMT pathways efficiently suppress the malignant phenotype ofEC cells Other potential therapeutic candidates for EC treatment include Stattic (inhibitor of STAT3) Rapamycin (mTOR inhibitor) andCD133

upregulated in ovarian carcinoma [66] are also upregulatedin serous EC more frequently than in endometrioid EC [67]The expression of FOLR1 cannot be observed in normalendometrium tissue [67] suggesting that FOLR1 may serveas a good tumor cell surface marker for targeted therapyand antibodies against FOLR1 may facilitate tumor-specificcellular uptake of molecular drugs

Trophoblast cell surface marker (Trop-2 a cell surfaceglycoprotein) is often overexpressed in various late stageepithelial tumor types with low or no expression in normaltissues [68] Trop-2 is highly expressed in serous [69] andendometrioid EC [70] Serous EC cell lines overexpress-ing Trop-2 show increased sensitivity to immunotherapywith hRS7 a humanized anti-Trop-2 monoclonal antibody[69] Thus Trop-2 would be an attractive target for ECimmunotherapy

Epithelial cell adhesion molecule (EpCAM) is overex-pressed on malignant cells from a variety of different tumorsand is considered as a reliable marker for tumor-initiatingcells [71] The cell surface expression of EpCAM is signif-icantly higher among serous EC specimen compared to innormal endometrial tissue [72] Serous EC cell lines thatare positive for EpCAM exhibit high sensitivity to EpCAMantibody-mediated cytotoxicity suggesting that EpCAMmayrepresent a novel therapeutic target for serous EC

In normal epithelium the expression of L1 cell adhesionmolecule (L1CAM) is undetectable However overexpression

of L1CAM has been reported in many types of carcinomas[73] L1CAM has been defined as a key driver for tumor cellinvasion and EMT [73] Of interest L1CAM was absent innormal endometrium and the vast majority of endometrioidEC but it was strongly expressed in serous and clear-cell EC[74] The combined treatment with L1CAM antibodies andchemotherapeutic drugs in pancreatic and ovarian carcinomamodel systems in vivo reduced tumor growthmore efficientlythan treatment with the cytostatic drug alone [75] indicatingthe value of L1CAM as a target for chemosensitizer inanticancer therapy for aggressive EC

Taken together antibodies against various tumor cellsurface markers would provide a possibility of deliveringdrugs to EC cells with fewer side effects on normal tissueThe nanotechnology or other approaches might be used todevelop a more effective delivery system for targeted drugsespecially miRNAs that might simultaneously modulate abroad range of gene networks necessary for malignant phe-notype of EC

5 Targeting the CSCEMT SignalingPathways in EC

CSC is defined as a rare population having the ability toself-renew initiate tumor growth and give rise to the het-erogeneous tumor cell mass [76] Growing lines of evidence


suggest that CSCs do exist and support tumor maintenanceduring tumor formation [77] CSCs of EC might be locatedin the basal layer of endometrium and are responsible forproduction of EC cells [78] Sorted CD133 (+) subpopulationsfrom EC cell expressed higher levels of oncogene BMI-1[51] and showed more aggressive potential and increasedtumorigenicity in nudemice than CD133 (minus) cells [79] Stem-like cell subpopulations referred to as ldquoside populationrdquo (SP)cells have been isolated fromEC tissue and show self-renewalcapacity and enhanced tumorigenicity in vivo [80]Thereforethese results suggest that selective killing of such CSCs is anappealing therapeutic prospect for EC

Tumor cells that undergo EMT can increase their inva-sion ability and concurrently acquire CSC properties [81 82]Indeed CSC fractions within pancreatic cancer [83] andcolon cancer [84] are associated with enhanced capacity tometastasize a process that requires considerable invasivecapacity At a molecular level these findings are consistentwith the fact that several signaling pathways involved in theself-renewal of CSCs including Wnt120573-catenin Hedgehog(Hh) and Notch signaling [85] can also induce EMT pro-grams [86] (Figure 4) supporting a molecular link betweenEMT and CSC program in human tumor [87] Thereforedevelopment of specific therapies targeted at these CSC andEMT pathways raises a hope for eliminating recurrent andmetastatic disease and for improvement of patient survival

In malignant human mammary stem cells activation ofHh signal components (SMO PTCH1 and Gli1) increasesthe expression of downstream transcription factor BMI-1 andplays an important role in regulating stem cell self-renewal[88] The overexpression of Hh-signal-related molecules isdetected in EC tissue and involved in stimulated proliferationof EC cells [89] In the same study cyclopamine (a specificinhibitor of the SMO) has been shown to efficiently suppressthe growth of EC cells [89]

Activation of Wnt120573-catenin pathway represented bythe nuclear staining of 120573-catenin was shown to be morecommonly detected in type I than type II EC [12] Morerecent evidence suggests that gene sets indicating activationof Hh and Wnt120573-catenin signaling closely correlate withmore aggressive EC and worse survival [90] Wnt120573-cateninsignaling was shown to induce the expression of downstreamtargets EpCAM and CD44 in hepatocellular carcinoma andEC respectively [91 92] Salinomycin a selective inhibitorof breast CSCs [93] was shown to induce apoptosis inhibitWnt120573-catenin signaling and therefore repress the prolifera-tion migration invasiveness and tumorigenicity of SP cellsobtained from invasive EC cells [94] Thus it is importantto determine whether salinomycin alone or in combinationwith other agents such as EpCAM-specific monoclonal anti-body could effectively induce apoptosis in CSC-like EC cells

High expression of Notch1 has been detected in ECpatients with poor prognosis and treatment with a reportedNotch inhibitor DAPT [95] suppresses invasiveness of ECcells [96]

Other potential therapeutic candidates for EC treatmentmight include Stattic Rapamycin and CD133 Signal trans-ducer and activator of transcription 3 (STAT3) has been

shown to transcriptionally activate the expression of EMTinducer TWIST1 resulting in promoted oncogenic propertiesin breast cancer [97] Stattic (an inhibitor of STAT3) cansuppress EGF-enhanced invasive behavior of EC cells [98]Rapamycin (an mTOR inhibitor) has been used to counterthe effects of PTEN deletion and inhibit the developmentof leukemia-initiating cells while preserving normal stemcell populations [99] Targeting CD133 (+) cells by CD133antibody-cytotoxic drug conjugates effectively inhibits thegrowth of hepatocellular and gastric cancer cells in vivo andin vitro [100]

The most obvious concern is whether a therapy canselectively target CSC but not destroy normal stem cell thatcould share many characteristics as CSC such as the abilityto self-renew and differentiate However CSCs and normalstem cells display different biological behaviors mainlydue to aberrant activation of several pathways involved inproliferation self-renewal differentiation and metabolismin CSCs [101 102] Therefore exploiting these moleculardifferences could be helpful to specifically target CSCs whilepreserving normal stem cells Furthermore the combinedinhibition of Hh and EGFR signaling through the use ofspecific inhibitors can lead to the increased rate of apoptoticdeath and decreased invasiveness of prostate cancer cells[103] suggesting that this treatment might be affecting theCSCs

6 Targeting Immunosuppressive MolecularPathways in EC

ECs are immunogenic tumors [104] and they mount potentantitumor immune responses which might be ineffective atrejecting tumor but might be potentially harnessed thera-peutically [105] Immune escape has been considered as themajor malignant features of tumor cells Several mechanismsare responsible for tumor immune escape including thefailure to recognize tumor cells by the immune system dueto reduced major histocompatibility complex class I (MHC-I) expression immunosuppression caused by tumor-cell-released immunosuppressive factors such as TGF-120573 inter-leukin (IL)-10 VEGF and cyclooxygenase-2 (COX-2) andimmunoresistance resulting from the induction of EMTCSC[104 106 107] These data indicate that in addition todirect tumor cell killing new targeted therapy might be alsodesigned to reactivate the bodyrsquos immune response againsttumor cells (Figure 5)

Tumor stem cells (CD133+) have been shown to expresslow levels of MHC-I however the percentage of CD133-positive CSCs that expressed MHC-I can be significantlyincreased by the treatment with interferon-gamma [108]suggesting the possible use of MHC-I to generate anti-CSCimmunity for human tumor including EC [106]

Some signal pathways that are activated in tumor cellsare also dysregulated in immunosuppressive cells in cancermicroenvironment Immunosuppressive molecules releasedby tumor cells can activate STAT3 in immune cells leadingto tumour-induced immunosuppression [109] In gastriccancer cells oncogenicWnt120573-catenin pathways enhance the


Immunosuppressivecells

Anti-tumor immune response

Tumor cell Immune escape

T cell

Immunosuppressivemolecules Dendritic cell

Cancer stem cell

EMT tumor cell

(Activation of STAT3and Wnt120573-catenin)

(TGF-120573 IL-10VEGF COX-2)

Figure 5 Targeting immunosuppressive molecular pathways in EC Tumor cell induces immunosuppression by the production ofimmunosuppressive factors such as TGF-120573 IL-10 VEGF and COX-2 Tumor cells undergoing EMT can acquire both aggressive andimmunosuppressive properties Wnt120573-catenin pathway and STAT3-related pathway are activated in tumor cells and immunosuppressivecells and therefore they seem to be attractive targets for EC immunotherapy

transcription of COX-2 an immunosuppressive molecule[110] Importantly COX-2 is upregulated and associated withVEGF expression in EC tissue [111] and selective COX-2inhibitor etodolac exhibits antiproliferative effects on EC tis-sue [112] indicating that targeting COX-2may boost immuneresponses towards EC and repress EC progression [113]Although the adverse effects on normal immune cells shouldbe avoided targeting STAT3 or Wnt120573-catenin pathway byspecific inhibitor in tumor cells and immunosuppressivecells or along with other immunotherapy might restore theimmunocompetence of EC patients

7 Conclusion

Currently targeted therapies have not entered clinical prac-tice and clinical trials involving genetic biomarkers (mTORHER2 EGFR and VEGF) administered to ECs only resultedin modest effects Therapy targeting epigenetic regulatorymechanisms such as miRNA will need to be developedto achieve a broader impact on multiple signal pathwaysnecessary for EC development The use of targeted cancertherapy remains challenging because of the lack of specificityfor cancer cells Targeted agents that are specific to cellsurface markers overexpressed in tumor cells would avoidpotential side effects on normal tissue More importantly weexpect that new targeted therapies that specifically attack bothcancer cells and CSC-like cells can be used together withimmunotherapy that stimulates a hostrsquos immune responseand with other traditional treatments to achieve better clini-cal prognosis of EC patients in the near future

Conflict of Interests

The authors declare no competing financial interests

Authorsrsquo Contribution

Peixin Dong and Masanori Kaneuchi equally contributed tothis paper

Acknowledgments

This work was funded by a Grant from the Department ofWomenrsquos Health Educational System and a Grant-in-Aidfrom the Ministry of Health Labour and Welfare of Japanand Grant-in-Aid for Scientific Research (C) (23592428)Theauthors thank Dr Zhujie Xu for the continuous and excellentsupport

References

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[2] J V Bokhman ldquoTwo pathogenetic types of endometrial carci-nomardquo Gynecologic Oncology vol 15 no 1 pp 10ndash17 1983

[3] P Singh C L Smith G Cheetham T J Dodd and M L JDavy ldquoSerous carcinoma of the uterusmdashdetermination ofHER-2neu status using immunohistochemistry chromogenic in situhybridization and quantitative polymerase chain reaction tech-niques its significance and clinical correlationrdquo InternationalJournal of Gynecological Cancer vol 18 no 6 pp 1344ndash13512008

[4] T Alvarez E Miller L Duska and E Oliva ldquoMolecular profileof grade 3 endometrioid endometrial Carcinoma is it a type ior type ii endometrial carcinomardquoAmerican Journal of SurgicalPathology vol 36 no 5 pp 753ndash761 2012

[5] P Mhawech-Fauceglia D Wang J Kesterson et al ldquoGeneexpression profiles in stage I uterine serous carcinoma incomparison to grade 3 and grade 1 stage i endometrioid


adenocarcinomardquo PLoS ONE vol 6 no 3 Article ID e180662011

[6] K N Moore and A Nickles Fader ldquoUterine papillary serouscarcinomardquo Clinical Obstetrics and Gynecology vol 54 no 2pp 278ndash291 2011

[7] S Ma T K Lee B-J Zheng K W Chan and X-Y GuanldquoCD133+ HCC cancer stem cells confer chemoresistance bypreferential expression of theAktPKB survival pathwayrdquoOnco-gene vol 27 no 12 pp 1749ndash1758 2008

[8] B M Slomovitz and R L Coleman ldquoThe PI3KAKTmTORpathway as a therapeutic target in endometrial cancerrdquo ClinicalCancer Research vol 18 no 21 pp 5856ndash5864 2012

[9] S Sarmadi N Izadi-Mood K Sotoudeh and S M TavangarldquoAltered PTEN expression A diagnostic marker for differ-entiating normal hyperplastic and neoplastic endometriumrdquoDiagnostic Pathology vol 4 no 1 article 41 2009

[10] M L Rudd J C Price S Fogoros et al ldquoA unique spectrumof somatic PIK3CA (p110120572) mutations within primary endome-trial carcinomasrdquo Clinical Cancer Research vol 17 no 6 pp1331ndash1340 2011

[11] J V Lacey Jr G L Mutter B M Ronnett et al ldquoPTENexpression in endometrial biopsies as a marker of progressionto endometrial carcinomardquo Cancer Research vol 68 no 14 pp6014ndash6020 2008

[12] X Matias-Guiu and J Prat ldquoMolecular pathology of endome-trial carcinomardquoHistopathology vol 62 no 1 pp 111ndash123 2013

[13] S Acharya M L Hensley A C Montag and G F FlemingldquoRare uterine cancersrdquo Lancet Oncology vol 6 no 12 pp 961ndash971 2005

[14] G E Konecny L Santos B Winterhoff et al ldquoHER2 geneamplification and EGFR expression in a large cohort of surgi-cally staged patients with nonendometrioid (type II) endome-trial cancerrdquo British Journal of Cancer vol 100 no 1 pp 89ndash952009

[15] H Niikura H Sasano G Matsunaga et al ldquoPrognostic value ofepidermal growth factor receptor expression in endometrioidendometrial carcinomardquo Human Pathology vol 26 no 8 pp892ndash896 1995

[16] C M Holland K Day A Evans and S K Smith ldquoExpressionof the VEGF and angiopoietin genes in endometrial atypicalhyperplasia and endometrial cancerrdquo British Journal of Cancervol 89 no 5 pp 891ndash898 2003

[17] J Zhang and L Ma ldquoMicroRNA control of epithelial-mesenchymal transition andmetastasisrdquo Cancer andMetastasisReviews vol 31 no 3-4 pp 3653ndash3462 2012

[18] K Kato ldquoEndometrial cancer stem cells a new target for cancertherapyrdquoAnticancer Research vol 32 no 6 pp 2283ndash2293 2012

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[30] T Vu and F X Claret ldquoTrastuzumab updated mechanisms ofaction and resistance in breast cancerrdquo Frontiers in Oncologyvol 2 article 62 2012

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[32] S Cannito E Novo A Compagnone et al ldquoRedoxmechanismsswitch on hypoxia-dependent epithelial-mesenchymal transi-tion in cancer cellsrdquo Carcinogenesis vol 29 no 12 pp 2267ndash2278 2008

[33] B Keith and M C Simon ldquoHypoxia-inducible factors stemcells and cancerrdquo Cell vol 129 no 3 pp 465ndash472 2007

[34] M Paez-Ribes E Allen J Hudock et al ldquoAntiangiogenictherapy elicits malignant progression of tumors to increasedlocal invasion and distant metastasisrdquo Cancer Cell vol 15 no3 pp 220ndash231 2009

[35] S Sharma T K Kelly and P A Jones ldquoEpigenetics in cancerrdquoCarcinogenesis vol 31 no 1 pp 27ndash36 2009

[36] H B Salvesen N MacDonald A Ryan et al ldquoPTEN methy-lation is associated with advanced stage and microsatelliteinstability in endometrial carcinomardquo International Journal ofCancer vol 91 no 1 pp 22ndash26 2001

[37] J Bischoff A Ignatov A Semczuk et al ldquohMLH1 promoterhypermethylation and MSI status in human endometrial carci-nomas with and without metastasesrdquo Clinical and ExperimentalMetastasis vol 29 no 8 pp 889ndash900 2012

[38] G Moreno-Bueno D Hardisson C Sanchez et al ldquoAbnormal-ities of the APCbeta-catenin pathway in endometrial cancerrdquoOncogene vol 21 no 52 pp 7981ndash7990 2002

[39] X Liao M K-Y Siu K Y-K Chan et al ldquoHypermethylation ofRAS effector related genes andDNAmethyltransferase 1 expres-sion in endometrial carcinogenesisrdquo International Journal ofCancer vol 123 no 2 pp 296ndash302 2008

[40] T-Z Yi J Guo L Zhou et al ldquoPrognostic value of E-cadherinexpression and CDH1 promoter methylation in patients with


endometrial carcinomardquo Cancer Investigation vol 29 no 1 pp86ndash92 2011

[41] S D Gore and E R Hermes-DeSantis ldquoEnhancing survivaloutcomes in the management of patients with higher-riskmyelodysplastic syndromesrdquo Cancer Control vol 16 supple-ment pp 2ndash10 2009

[42] S A Kavanaugh L A White and J M Kolesar ldquoVorinostat anovel therapy for the treatment of cutaneous T-cell lymphomardquoAmerican Journal of Health-System Pharmacy vol 67 no 10 pp793ndash797 2010

[43] T-Z Yi J Li X Han et al ldquoDNMT inhibitors andHDAC inhibitors regulate E-Cadherin and Bcl-2 expression inendometrial carcinoma in vitro and in vivordquoChemotherapy vol58 no 1 pp 19ndash29 2012

[44] R Connolly and V Stearns ldquoEpigenetics as a therapeutic targetin breast cancerrdquo Journal of Mammary Gland Biology andNeoplasia vol 17 no 3-4 pp 3191ndash4204 2012

[45] D P Bartel ldquoMicroRNAs genomics biogenesis mechanismand functionrdquo Cell vol 116 no 2 pp 281ndash297 2004

[46] H Xia and K M Hui ldquoMicroRNAs involved in regulatingepithelial-mesenchymal transition and cancer stem cells asmolecular targets for cancer therapeuticsrdquo Cancer Gene Ther-apy vol 19 no 11 pp 723ndash730 2012

[47] T K H Chung T-H Cheung N-Y Huen et al ldquoDys-regulated microRNAs and their predicted targets associatedwith endometrioid endometrial adenocarcinoma inHongKongwomenrdquo International Journal of Cancer vol 124 no 6 pp1358ndash1365 2009

[48] E Chan D E Prado and J B Weidhaas ldquoCancer microRNAsfrom subtype profiling to predictors of response to therapyrdquoTrends in Molecular Medicine vol 17 no 5 pp 235ndash243 2011

[49] T K H Chung T S Lau T H Cheung et al ldquoDysregu-lation of microRNA-204 mediates migration and invasion ofendometrial cancer by regulating FOXC1rdquo International Journalof Cancer vol 130 no 5 pp 1036ndash1045 2012

[50] H Zhai M Karaayvaz P Dong N Sakuragi and J JuldquoPrognostic significance of miR-194 in endometrial cancerrdquoBiomarker Research vol 1 article 12 2013

[51] P DongM Kaneuchi HWatari et al ldquoMicroRNA-194 inhibitsepithelial tomesenchymal transition of endometrial cancer cellsby targeting oncogene BMI-1rdquoMolecular Cancer vol 10 article99 2011

[52] P Dong M Karaayvaz et al ldquoMutant p53 gain-of-functioninduces epithelial-mesenchymal transition through modula-tion of the miR-130b-ZEB1 axisrdquo Oncogene 2012

[53] P S Mitchell R K Parkin E M Kroh et al ldquoCirculatingmicroRNAs as stable blood-based markers for cancer detec-tionrdquo Proceedings of the National Academy of Sciences of theUnited States of America vol 105 no 30 pp 10513ndash10518 2008

[54] T Tsuruta K-I Kozaki A Uesugi et al ldquomiR-152 is a tumorsuppressor microRNA that is silenced by DNA hypermethyla-tion in endometrial cancerrdquo Cancer Research vol 71 no 20 pp6450ndash6462 2011

[55] C S Gondi and J S Rao ldquoConcepts in in vivo siRNA deliveryfor cancer therapyrdquo Journal of Cellular Physiology vol 220 no2 pp 285ndash291 2009

[56] J A Broderick and P D Zamore ldquoMicroRNA therapeuticsrdquoGene Therapy vol 18 no 12 pp 1104ndash1110 2011

[57] Y W Kong D Ferland-McCollough T J Jackson and MBushell ldquomicroRNAs in cancer managementrdquo The LancetOncology vol 13 no 6 pp e249ndashe258 2012

[58] Y Chen X Zhu X Zhang B Liu and LHuang ldquoNanoparticlesmodified with tumor-targeting scFv deliver siRNA andmiRNAfor cancer therapyrdquo Molecular Therapy vol 18 no 9 pp 1650ndash1656 2010

[59] E B Pasquale ldquoEph receptors and ephrins in cancer bidirec-tional signalling and beyondrdquo Nature Reviews Cancer vol 10no 3 pp 165ndash180 2010

[60] M Tandon S V Vemula and S K Mittal ldquoEmerging strategiesfor EphA2 receptor targeting for cancer therapeuticsrdquo ExpertOpinion onTherapeutic Targets vol 15 no 1 pp 31ndash51 2011

[61] A A Kamat D Coffey W M Merritt et al ldquoEphA2 overex-pression is associated with lack of hormone receptor expressionand poor outcome in endometrial cancerrdquo Cancer vol 115 no12 pp 2684ndash2692 2009

[62] J-W Lee R L Stone S J Lee et al ldquoEphA2 targetedchemotherapy using an antibody drug conjugate in endometrialcarcinomardquo Clinical Cancer Research vol 16 no 9 pp 2562ndash2570 2010

[63] G E Konecny R Agarwal G A Keeney et al ldquoClaudin-3and claudin-4 expression in serous papillary clear-cell andendometrioid endometrial cancerrdquo Gynecologic Oncology vol109 no 2 pp 263ndash269 2008

[64] X Y Pan B Wang Y C Che Z P Weng H Y Dai andW Peng ldquoExpression of claudin-3 and claudin-4 in normalhyperplastic and malignant endometrial tissuerdquo InternationalJournal of Gynecological Cancer vol 17 no 1 pp 233ndash241 2007

[65] A D Santin S Bellone M Marizzoni et al ldquoOverexpressionof claudin-3 and claudin-4 receptors in uterine serous papillarycarcinoma novel targets for a type-specific therapy usingClostridium perfringens enterotoxin (CPE)rdquo Cancer vol 109no 7 pp 1312ndash1322 2007

[66] CDHoughCA Sherman-Baust E S Pizer et al ldquoLarge-scaleserial analysis of gene expression reveals genes differentiallyexpressed in ovarian cancerrdquo Cancer Research vol 60 no 22pp 6281ndash6287 2000

[67] L A Dainty J I Risinger C Morrison et al ldquoOverexpressionof folate binding protein and mesothelin are associated withuterine serous carcinomardquo Gynecologic Oncology vol 105 no3 pp 563ndash570 2007

[68] R Cubas M Li C Chen and Q Yao ldquoTrop2 a possible thera-peutic target for late stage epithelial carcinomasrdquo Biochimica etBiophysica Acta vol 1796 no 2 pp 309ndash314 2009

[69] J Varughese E Cocco S Bellone et al ldquoUterine serous pap-illary carcinomas overexpress human trophoblast-cell- surfacemarker (trop-2) and are highly sensitive to immunotherapywith hRS7 a humanized anti-trop-2 monoclonal antibodyrdquoCancer vol 117 no 14 pp 3163ndash3172 2011

[70] E Bignotti L Zanotti S Calza et al ldquoTrop-2 protein over-expression is an independent marker for predicting diseaserecurrence in endometrioid endometrial carcinomardquo BMCClinical Pathology vol 12 no 1 article 22 2012

[71] S Imrich M Hachmeister and O Gires ldquoEpCAM and itspotential role in tumor-initiating cellsrdquo Cell Adhesion andMigration vol 6 no 1 pp 30ndash38 2012

[72] K El-Sahwi S Bellone E Cocco et al ldquoOverexpression ofEpCAM in uterine serous papillary carcinoma implicationsfor EpCAM-specific immunotherapy with human monoclonalantibody adecatumumab (MT201)rdquo Molecular Cancer Thera-peutics vol 9 no 1 pp 57ndash66 2010

[73] H Kiefel S Bondong J Hazin et al ldquoL1CAM a major driverfor tumor cell invasion andmotilityrdquoCell AdhesionampMigrationvol 6 no 4 pp 374ndash384 2012


[74] M Huszar M Pfeifer U Schirmer et al ldquoUp-regulation ofLICAM is linked to loss of hormone receptors and E-cadherinin aggressive subtypes of endometrial carcinomasrdquo Journal ofPathology vol 220 no 5 pp 551ndash561 2010

[75] H Schafer C Dieckmann O Korniienko et al ldquoCombinedtreatment of L1CAM antibodies and cytostatic drugs improvethe therapeutic response of pancreatic and ovarian carcinomardquoCancer Letters vol 319 no 1 pp 66ndash82 2012

[76] L V Nguyen R Vanner P Dirks and C J Eaves ldquoCancer stemcells an evolving conceptrdquo Nature Reviews Cancer vol 12 no2 pp 133ndash143 2012

[77] R J Gilbertson and T A Graham ldquoCancer resolving the stem-cell debaterdquo Nature vol 488 no 7412 pp 462ndash463 2012



[80] K Kato ldquoStem cells in human normal endometrium andendometrial cancer cells characterization of side populationcellsrdquo Kaohsiung Journal of Medical Sciences vol 28 no 2 pp63ndash71 2012

[81] S A Mani W Guo M-J Liao et al ldquoThe epithelial-mesenchymal transition generates cells with properties of stemcellsrdquo Cell vol 133 no 4 pp 704ndash715 2008

[82] A Singh and J Settleman ldquoEMT cancer stem cells and drugresistance an emerging axis of evil in the war on cancerrdquoOncogene vol 29 no 34 pp 4741ndash4751 2010

[83] P C Hermann S L Huber T Herrler et al ldquoDistinct pop-ulations of cancer stem cells determine tumor growth andmetastatic activity in human pancreatic cancerrdquo Cell Stem Cellvol 1 no 3 pp 313ndash323 2007

[84] R Pang W L Law A C Y Chu et al ldquoA subpopulation ofCD26+ cancer stem cells with metastatic capacity in humancolorectal cancerrdquoCell Stem Cell vol 6 no 6 pp 603ndash615 2010

[85] B-B S ZhouH ZhangMDamelin KGGeles J CGrindleyand P B Dirks ldquoTumour-initiating cells challenges and oppor-tunities for anticancer drug discoveryrdquo Nature Reviews DrugDiscovery vol 8 no 10 pp 806ndash823 2009

[86] J M Bailey P K Singh and M A Hollingsworth ldquoCancermetastasis facilitated by developmental pathways sonic hedge-hog notch and bonemorphogenic proteinsrdquo Journal of CellularBiochemistry vol 102 no 4 pp 829ndash839 2007

[87] A Biddle and I C Mackenzie ldquoCancer stem cells and EMT incarcinomardquo Cancer and Metastasis Reviews vol 31 no 1-2 pp285ndash293 2012

[88] S Liu G Dontu I D Mantle et al ldquoHedgehog signaling andBmi-1 regulate self-renewal of normal and malignant humanmammary stem cellsrdquoCancer Research vol 66 no 12 pp 6063ndash6071 2006

[89] Y-Z Feng T Shiozawa T Miyamoto et al ldquoOverexpressionof hedgehog signaling molecules and its involvement in theproliferation of endometrial carcinoma cellsrdquo Clinical CancerResearch vol 13 no 5 pp 1389ndash1398 2007

[90] E Wik M B Raeligder C Krakstad et al ldquoLack of estrogenreceptor-120572 is associated with epithelial-mesenchymal transitionandPI3K alterations in endometrial carcinomardquoClinical CancerResearch vol 19 no 5 pp 1094ndash1105 2013

[91] M Munz P A Baeuerle and O Gires ldquoThe emerging role ofEpCAM in cancer and stem cell signalingrdquoCancer Research vol69 no 14 pp 5627ndash5629 2009

[92] Y Wang P Hanifi-Moghaddam E E Hanekamp et alldquoProgesterone inhibition of Wnt120573-catenin signaling in nor-mal endometrium and endometrial cancerrdquo Clinical CancerResearch vol 15 no 18 pp 5784ndash5793 2009

[93] P BGupta T TOnderG Jiang et al ldquoIdentification of selectiveinhibitors of cancer stem cells by high-throughput screeningrdquoCell vol 138 no 4 pp 645ndash659 2009

[94] S Kusunoki K Kato K Tabu et al ldquoThe inhibitory effectof salinomycin on the proliferation migration and invasionof human endometrial cancer stem-like cellsrdquo GynecologicOncology vol 129 no 3 pp 598ndash605 2013

[95] C Groth and M E Fortini ldquoTherapeutic approaches to modu-latingNotch signaling current challenges and future prospectsrdquoSeminars in Cell and Developmental Biology vol 23 no 4 pp465ndash472 2012

[96] Y Mitsuhashi A Horiuchi T Miyamoto H Kashima ASuzuki and T Shiozawa ldquoPrognostic significance of Notchsignalling molecules and their involvement in the invasivenessof endometrial carcinoma cellsrdquo Histopathology vol 60 no 5pp 826ndash837 2012

[97] G Z ChengW Zhang M Sun et al ldquoTwist is transcriptionallyinduced by activation of STAT3 andmediates STAT3 oncogenicfunctionrdquo Journal of Biological Chemistry vol 283 no 21 pp14665ndash14673 2008

[98] C H Chen S W Wang C W Chen et al ldquoMUC20overexpression predicts poor prognosis and enhances EGF-induced malignant phenotypes via activation of the EGFR-STAT3 pathway in endometrial cancerrdquo Gynecologic Oncologyvol 128 no 3 pp 560ndash567 2013

[99] O H Yilmaz R Valdez B K Theisen et al ldquoPten depen-dence distinguishes haematopoietic stem cells from leukaemia-initiating cellsrdquo Nature vol 441 no 7092 pp 475ndash482 2006

[100] L M Smith A Nesterova M C Ryan et al ldquoCD133prominin-1 is a potential therapeutic target for antibody-drug conjugatesin hepatocellular and gastric cancersrdquo British Journal of Cancervol 99 no 1 pp 100ndash109 2008

[101] M V Verga Falzacappa C Ronchini L B Reavie and P GPelicci ldquoRegulation of self-renewal in normal and cancer stemcellsrdquo FEBS Journal vol 279 no 19 pp 3559ndash3572 2012

[102] C Pecqueur L Oliver K Oizel L Lalier and F M ValletteldquoTargeting metabolism to induce cell death in cancer cells andcancer stem cellsrdquo International Journal of Cell Biology vol 2013Article ID 805975 13 pages 2013

[103] M Mimeault E Moore N Moniaux et al ldquoCytotoxic effectsinduced by a combination of cydopamine and gefitinib theselective hedgehog and epidermal growth factor receptor sig-naling inhibitors in prostate cancer cellsrdquo International Journalof Cancer vol 118 no 4 pp 1022ndash1031 2006

[104] N Brooks and D S Pouniotis ldquoImmunomodulation in endo-metrial cancerrdquo International Journal of Gynecological Cancervol 19 no 4 pp 734ndash740 2009

[105] L E Kandalaft N Singh J B Liao et al ldquoThe emergenceof immunomodulation combinatorial immunochemotherapyopportunities for the next decaderdquo Gynecologic Oncology vol116 no 2 pp 222ndash233 2010

[106] M Vanneman and G Dranoff ldquoCombining immunotherapyand targeted therapies in cancer treatmentrdquo Nature ReviewsCancer vol 12 no 4 pp 237ndash251 2012


[107] C Kudo-Saito H Shirako T Takeuchi and Y KawakamildquoCancer metastasis is accelerated through immunosuppressionduring snail-induced EMT of cancer cellsrdquo Cancer Cell vol 15no 3 pp 195ndash206 2009

[108] A Wu S Wiesner J Xiao et al ldquoExpression of MHC I andNK ligands on human CD133+ glioma cells possible targets ofimmunotherapyrdquo Journal of Neuro-Oncology vol 83 no 2 pp121ndash131 2007

[109] H Yu M Kortylewski and D Pardoll ldquoCrosstalk betweencancer and immune cells role of STAT3 in the tumourmicroen-vironmentrdquoNature Reviews Immunology vol 7 no 1 pp 41ndash512007

[110] F Nunez S Bravo F Cruzat M Montecino and G V deFerrari ldquoWnt120573-catenin signaling enhances cyclooxygenase-2(COX2) transcriptional activity in gastric cancer cellsrdquo PLoSONE vol 6 no 4 Article ID e18562 2011

[111] R Fujiwaki K Iida H Kanasaki T Ozaki K Hata andK Miyazaki ldquoCyclooxygenase-2 expression in endometrialcancer correlation with microvessel count and expression ofvascular endothelial growth factor and thymidine phosphory-laserdquo Human Pathology vol 33 no 2 pp 213ndash219 2002

[112] K Hasegawa Y Torii R Ishii S Oe R Kato and Y UdagawaldquoEffects of a selective COX-2 inhibitor in patients with uterineendometrial cancersrdquoArchives of Gynecology andObstetrics vol284 no 6 pp 1515ndash1521 2011

[113] S Ohno Y Ohno N Suzuki et al ldquoMultiple roles ofcyclooxygenase-2 in endometrial cancerrdquo Anticancer Researchvol 25 no 6 pp 3679ndash3687 2005

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


VEGFR-2EGFRHER2FGFR2

PPP

P

VEGF

PP P

P

EGFRHER2FGFR2 inhibitor

VEGFinhibitor

RASPI3KmTORinhibitor

VEGFRinhibitor

PI3K

Transcription

Cell proliferation cell survival EMT

AKT

PTEN

PI3K

Cell proliferation cell survivalangiogenesis EMT

PI3Kinhibitor

AKTinhibitor

mTORinhibitor

MEK

ERK

AKT

mTORC

mTORC1

mTORC2

Figure 1 Therapeutic molecular targets for endometrial cancer Type I endometrial cancer (EC) frequently exhibits alteredPI3KPTENAKTmTOR signal pathway whereas type II EC frequently showsmutations in p53 andHER-2 overexpressionThe upregulationof EGFR and VEGF dysregulated microRNAs and activation of cancer stem cell (CSC)epithelial-mesenchymal transition (EMT) programsare involved in oncogenesis and progression of both cancer types Currently clinical trials assessing the efficacy of mTOR inhibitorEGFRHER2 inhibitor and antiangiogenic agent for EC have been conducted and demonstrated modest effects

3 Challenges in the Molecular Therapeutics ofHuman Tumor

Although the therapeutic potential of targeted drugs forthe treatment of human tumors appears promising theclinical success of such drugs has been limited by keychallenges including primaryacquired drug resistance [23ndash25] and unexpected side effects on normal tissues due tononspecificity [26] (Figure 2)

A portion of patients unfortunately do not respondto targeted agents (primary resistance) and the remaindermight eventually acquire the resistance to targeted therapydespite an initial response Various mechanisms of resistancehave begun to be elucidated The most frequently reportedmechanism of primary resistance is genetic heterogeneityFor example mechanisms of resistance to EGFR inhibitorsare involved in point mutations deletions and amplificationsof genomic areas of EGFR [23] In addition to geneticalteration epigenetic changes such as DNA methylation atCpG islands have been linked to the development of resis-tance to multiple molecular drugs [27 28] The generationof a population of cancer cells with stem-cell propertiesmight provide another possible reason of resistance to EGFRinhibitor [29] Common mechanisms of acquired resistanceinclude secondary mutation in the target gene activation ofalternative pathway or feedback loop and induction of EMT[23 30] Therefore new therapy that concurrently attacks

multiple critical pathways inhibits the cross talk betweendiverse signals and suppresses the CSC and EMT propertiesmay be efficacious to overcome the resistance to molecularagents in EC

Moreover the administration of antiangiogenic agentsparticularly antibodies against VEGF leads to amore hypoxictumor microenvironment [31] which enhances tumor cellinvasion and metastasis by inducing the EMT- and CSC-like phenotype [32ndash34] These works clearly suggest the needto combine antiangiogenic treatment in human tumors withnew drugs targeting specific signaling pathways linked to theCSCEMT phenotype

Another challenge is toxicity or the side effects associatedwith targeted therapies such as harmful immune responsesThese include ldquoOff-targetrdquo adverse effects caused by a drugbinding to an unexpected target and ldquoOn-targetrdquo adverseeffects as a result of a drug binding to its intended target thatis not only present in tumor cells but also found in normaltissue [26]

4 Potential miRNA-Based Therapies in EC

Different from gene mutations epigenetic changes that areassociated with global gene regulation such as chromatinremodeling open a new field of cancer research [35] Epi-genetic silencing of tumor suppressor genes or epigenetic


Targeted therapies


Normal cell


resistance

Cancer stem cellEMT

Tumor cell



side effects












cancer

Nanoparticle

Antibody

Cell surface marker

EphA2

claudin-3

claudin-4

FOLR1

MSLN

Trop-2

HER2

EpCAM

L1CAM


(194 130b etc)



Tumor cell

Type I Type II










RasRafMEK

PI3KAK

EpCAM

PICH1 SMO

Hedgehog

SMOinhibitor

Fz

Notch1

mTOR

EGFRHER2CD133

STAT3

SalinomycinNotch

inhibitor

Wnt

EpCAM inhibitor

TmTOR

EMTCSC program

Snail slug

TWIST1

BMI-1 ZEB1

Gli1

CD44 COX-2

inhibitor


CSLSmad

STAT3 inhibitor

120573-catenin

120573-catenin

TGF-120573

TGF-120573

120573-catenin



























T cell


Cancer stem cell

EMT tumor cell





7 Conclusion






Acknowledgments


References































































































































Volume 2014

Zoology






















Advances in

Virolog y



Volume 2014




Enzyme Research



Microbiology


Targeted therapies


Normal cell


resistance

Cancer stem cellEMT

Tumor cell



side effects












cancer

Nanoparticle

Antibody

Cell surface marker

EphA2

claudin-3

claudin-4

FOLR1

MSLN

Trop-2

HER2

EpCAM

L1CAM


(194 130b etc)



Tumor cell

Type I Type II










RasRafMEK

PI3KAK

EpCAM

PICH1 SMO

Hedgehog

SMOinhibitor

Fz

Notch1

mTOR

EGFRHER2CD133

STAT3

SalinomycinNotch

inhibitor

Wnt

EpCAM inhibitor

TmTOR

EMTCSC program

Snail slug

TWIST1

BMI-1 ZEB1

Gli1

CD44 COX-2

inhibitor


CSLSmad

STAT3 inhibitor

120573-catenin

120573-catenin

TGF-120573

TGF-120573

120573-catenin



























T cell


Cancer stem cell

EMT tumor cell





7 Conclusion






Acknowledgments


References































































































































Volume 2014

Zoology






















Advances in

Virolog y



Volume 2014




Enzyme Research



Microbiology



cancer

Nanoparticle

Antibody

Cell surface marker

EphA2

claudin-3

claudin-4

FOLR1

MSLN

Trop-2

HER2

EpCAM

L1CAM


(194 130b etc)



Tumor cell

Type I Type II










RasRafMEK

PI3KAK

EpCAM

PICH1 SMO

Hedgehog

SMOinhibitor

Fz

Notch1

mTOR

EGFRHER2CD133

STAT3

SalinomycinNotch

inhibitor

Wnt

EpCAM inhibitor

TmTOR

EMTCSC program

Snail slug

TWIST1

BMI-1 ZEB1

Gli1

CD44 COX-2

inhibitor


CSLSmad

STAT3 inhibitor

120573-catenin

120573-catenin

TGF-120573

TGF-120573

120573-catenin



























T cell


Cancer stem cell

EMT tumor cell





7 Conclusion






Acknowledgments


References































































































































Volume 2014

Zoology






















Advances in

Virolog y



Volume 2014




Enzyme Research



Microbiology


RasRafMEK

PI3KAK

EpCAM

PICH1 SMO

Hedgehog

SMOinhibitor

Fz

Notch1

mTOR

EGFRHER2CD133

STAT3

SalinomycinNotch

inhibitor

Wnt

EpCAM inhibitor

TmTOR

EMTCSC program

Snail slug

TWIST1

BMI-1 ZEB1

Gli1

CD44 COX-2

inhibitor


CSLSmad

STAT3 inhibitor

120573-catenin

120573-catenin

TGF-120573

TGF-120573

120573-catenin



























T cell


Cancer stem cell

EMT tumor cell





7 Conclusion






Acknowledgments


References































































































































Volume 2014

Zoology






















Advances in

Virolog y



Volume 2014




Enzyme Research



Microbiology


















T cell


Cancer stem cell

EMT tumor cell





7 Conclusion






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 Emerging Therapeutic Biomarkers in...

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Transcript of Review Article Emerging Therapeutic Biomarkers in...