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Cancer and Pregnancy: Parallels in Growth, Invasion, and Immune Modulation and Implications for Cancer Therapeutic Agents

      Many proliferative, invasive, and immune tolerance mechanisms that support normal human pregnancy are also exploited by malignancies to establish a nutrient supply and evade or edit the host immune response. In addition to the shared capacity for invading through normal tissues, both cancer cells and cells of the developing placenta create a microenvironment supportive of both immunologic privilege and angiogenesis. Systemic alterations in immunity are also detectable, particularly with respect to a helper T cell type 2 polarization evident in advanced cancers and midtrimester pregnancy. This review summarizes the similarities between growth and immune privilege in cancer and pregnancy and identifies areas for further investigation. Our PubMed search strategy included combinations of terms such as immune tolerance, pregnancy, cancer, cytokines, angiogenesis, and invasion. We did not place any restrictions on publication dates. The knowledge gained from analyzing similarities and differences between the physiologic state of pregnancy and the pathologic state of cancer could lead to identification of new potential targets for cancer therapeutic agents.
      CTL (CD8+ T cytotoxic lymphocyte), DC (dendritic cell), EVT (extravillous trophoblast), HLA (human leukocyte antigen), IL (interleukin), NK (natural killer), TH1 (helper T cell type 1), TH2 (helper T cell type 2), Treg (regulatory T cell), uNK (uterine NK)
      A substantial body of literature exists describing the mechanisms cancer cells use to escape apoptosis and migrate through normal structures while evading a host immune response. What is not well known, however, is how these complex and interrelated mechanisms are orchestrated, starting with modulation of the immune response within the tumor microenvironment and ending with migration and proliferation of cancer cells at distant sites. One potential model to further study how a single malignant cell could proliferate and then metastasize undetected within a host is that of normal human pregnancy, in which the developing placenta invades the uterus and a semiallogeneic fetus escapes rejection from the maternal immune system.
      • Medawar PB
      Some immunological and endocrinological problems raised by the evolution of viviparty in vertebrates.
      A multitude of immunomodulatory properties of the fetomaternal interface (placenta) have evolved to allow the survival of the immunologically distinct fetus to parturition without an attack from the maternal immune system. The similarities between the mechanisms involved in fetomaternal and tumor-associated immunologic tolerance are intriguing and suggest a common pattern; however, neither system of immune evasion is perfect. A clear example of placental failure to protect the fetus against maternal immunity is that of Rh incompatibility. In multiparous women sensitized against fetal Rh antigens, re-exposure to fetal Rh antigens with subsequent pregnancy may lead to hemolytic disease of the newborn and fetal death.
      • Clarke CA
      Immunology of pregnancy: significance of blood group incompatibility between mother and foetus.
      Such imperfections of shared mechanisms of immune tolerance between pregnancy and cancer suggest that cancer rejection via immunologic means may be possible, even considering the myriad mechanisms extending immunologic privilege to the fetus as well as cancer cells.
      This review summarizes the parallels in proliferation, invasion, and immune privilege between cancer and pregnancy by first detailing shared characteristics of fetal-derived trophoblast cells of the placenta and tumor cells. It then describes the similarities between tolerogenic systems within the tumor microenvironment and the fetomaternal interface. Finally, it provides an overview of the evidence for systemic immune modulation in cancer and pregnancy and suggests the implications of these similarities in designing an integrated approach to cancer therapy. Our PubMed search strategy included combinations of terms such as immune tolerance, pregnancy, cancer, cytokines, angiogenesis, and invasion. We also searched for articles on cellular subsets, including natural killer (NK) cells, dendritic cells (DCs), regulatory T cells (Treg), and other lymphocyte populations with respect to their presence and function in pregnancy and cancer. We did not place any restrictions on publication dates. A better understanding of how the maternal immune system is altered during the normal processes of implantation, gestation, and labor may translate into individualized, novel therapies aimed at restoring immune competency in patients with advanced malignancies.

      SHARED CHARACTERISTICS OF TROPHOBLAST CELLS AND TUMOR CELLS

      Five days after fertilization, the human zygote forms into a structure consisting of 2 primary cell lines: the inner cellmass (or embryoblast) and the trophoblast.
      • Staun-Ram E
      • Shalev E
      Human trophoblast function during the implantation process.
      Trophoblast cells constitute the outer layer of the blastocyst, rapidly proliferating and invading the maternal endometrial decidua around day 7. A monolayer of cytotrophoblast cells surrounds the embryonic disc as the embryo completely embeds beneath the uterine decidua. By day 9, cytotrophoblast cells have differentiated into 2 distinct cell types: the syncytiotrophoblast and the extravillous trophoblast (EVT). The multinucleated syncytiotrophoblast cells form the external layer and are terminally differentiated. These cells are involved in fetomaternal nutrient exchanges and endocrine functions (such as β-human chorionic gonadotropic production). In contrast, EVT cells have a proliferative and invasive phenotype, migrating through the syncytiotrophoblast into the uterine wall to anchor the placenta beginning around day 14 after implantation.
      • Lunghi L
      • Ferretti ME
      • Medici S
      • Biondi C
      • Vesce F
      Control of human trophoblast function.
      These EVT cells display a phenotype strikingly similar to cancer cells with their capacity for proliferation, migration, and establishment of a blood supply, making them a compelling model for oncologic comparison (Figure). This review highlights several shared characteristics of trophoblast and tumor cells and discusses them in the context of existing or developmental targeted cancer therapeutics (Table 1).
      Figure thumbnail gr1
      FIGURESimilarities between the fetomaternal interface and tumor microenvironment. For expansion of all gene symbols, see Glossary of Genetics Terminology at the end of the article. HLA = human leukocyte antigen; IL = interleukin; VM = vasculogenic mimicry.
      TABLE 1Tumorlike Attributes of the Human Trophoblast Cells and a Selection of Representative Targeted Cancer Therapeutic Strategies in Use or Development
      HLA = human leukocyte antigen. For expansion of all gene symbols, see Glossary of Genetics Terminology at the end of the article.
      Shared trophoblast-tumor attributeMechanismTargeted therapeutic strategyDrug/compound name
      Data regarding drug compounds are from Mayo Clin Proc,53 unless a citation is given to indicate otherwise.
      Self-sufficiency in growth signalsActivation of MAPK pathwayInhibition of RAS-RAF-MEK-ERK signalingSorafenib; ARRY-142886; PLX-4032; XL281; RAF265; PD0325901
      • Fecher LA
      • Amaravadi RK
      • Flaherty KT
      The MAPK pathway in melanoma.
      Activation of PI3K-AKT pathwayInhibition of RAS-PI3K-AKT-MTOR signalingQuercitin, XL147, and XL765; GDC-0941; BEZ235; PX-866
      • Ihle NT
      • Powis G
      Take your PIK: phosphatidylinositol 3-kinase inhibitors race through the clinic and toward cancer therapy.
      ; sirolimus; everolimus; temsirolimus
      FAK activationFAK inhibitionTAE226
      • Liu TJ
      • LaFortune T
      • Honda T
      • et al.
      Inhibition of both focal adhesion kinase and insulin-like growth factor-I receptor kinase suppresses glioma proliferation in vitro and in vivo.
      ; dasatinib
      HGF autocrine loopHGF or C-MET inhibitionOA-5D5
      • Martens T
      • Schmidt NO
      • Eckerich C
      • et al.
      A novel one-armed anti-c-Met antibody inhibits glioblastoma growth in vivo.
      ; AMG-102
      • Jun HT
      • Sun J
      • Rex K
      • et al.
      AMG 102, a fully human anti-hepatocyte growth factor/scatter factor neutralizing antibody, enhances the efficacy of temozolomide or docetaxel in U-87 MG cells and xenografts.
      ; SGX-523; PF-0234106; XL880
      EGF autocrine loopEGF or EGFR inhibitionErlotinib; cetuximab; panitumumab; XL647
      IGF autocrine loopIGF or IGFR inhibitionAEW541
      • García-Echeverría C
      • Pearson MA
      • Marti A
      • et al.
      In vivo antitumor activity of NVP-AEW541-A novel, potent, and selective inhibitor of the IGF-IR kinase.
      CSF autocrine loopCSF1 or CSF1R inhibitionGW2580
      • Conway JG
      • McDonald B
      • Parham J
      • et al.
      Inhibition of colony-stimulating-factor-1 signaling in vivo with the orally bioavailable cFMS kinase inhibitor GW2580.
      ; CYC10268
      • Irvine KM
      • Burns CJ
      • Wilks AF
      • Su S
      • Hume DA
      • Sweet MJ
      A CSF-1 receptor kinase inhibitor targets effector functions and inhibits pro-inflammatory cytokine production from murine macrophage populations.
      PDGF autocrine loopPDGF or PDGFR inhibitionAZD2171; pazopanib; sorafenib; sunitinib: E7080; ZD6474; AG-013736
      VEGF autocrine loopVEGF or VEGFR inhibitionBevacizumab; RAF265; BMS-690514
      Insensitivity to antigrowth signalsTGF-β pathway activationTGF-β2 blockadeAP 12009
      • Schlingensiepen KH
      • Fischer-Blass B
      • Schmaus S
      • Ludwig S
      Antisense therapeutics for tumor treatment: the TGF-beta2 inhibitor AP 12009 in clinical development against malignant tumors.
      ; LY-2157299
      • Yingling JM
      • Blanchard KL
      • Sawyer JS
      Development of TGF-β signalling inhibitors for cancer therapy.
      CDKCDK inhibitionSNS-032
      • Chen R
      • Wierda WG
      • Chubb S
      • et al.
      Mechanism of action of SNS-032, a novel cyclin-dependent kinase inhibitor, in chronic lymphocytic leukemia.
      ; AT7519
      • Squires MS
      • Feltell RE
      • Wallis NG
      • et al.
      Biological characterization of AT7519, a small-molecule inhibitor of cyclin-dependent kinases, in human tumor cell lines.
      ;flavopiridol
      SMADALK inhibition leading to decreased SMAD phosphorylationA 83-01
      • Tojo M
      • Hamashima Y
      • Hanyu A
      • et al.
      The ALK-5 inhibitor A-83-01 inhibits Smad signaling and epithelial-to-mesenchymal transition by transforming growth factor-β.
      Evasion of apoptosisIGF1R signalingIGF1R blockadeConcept reviewed by Werhova and Haluska
      • Weroha SJ
      • Haluska P
      IGF-1 receptor inhibitors in clinical trials–early lessons.
      ; R1507: CP-751,871
      • Haluska P
      • Shaw HM
      • Batzel GN
      • et al.
      Phase I dose escalation study of the anti insulin-like growth factor-I receptor monoclonal antibody CP-751,871 in patients with refractory solid tumors.
      • Lacy MQ
      • Alsina M
      • Fonseca R
      • et al.
      Phase I, pharmacokinetic and pharmacodynamic study of the anti-insulinlike growth factor type 1 Receptor monoclonal antibody CP-751,871 in patients with multiple myeloma.
      PDGFR signalingPDGFR blockadeImatinib; sorafenib; sunitinib; E7080; ZD6474; AG-013736; pazopanib
      BCL2BCL2 inhibitionOblimersen
      SurvivinSurvivin inhibitionYM-155; terameprocol
      XIAPXIAP antisenseAEG35156
      EndoreduplicationMaintain p53 integrity; Aurora kinase inhibition; induction of p21 (waf1/cip1)Nutlin-3a (promotes endoreduplication)
      • Shen H
      • Moran DM
      • Maki CG
      Transient nutlin-3a treatment promotes endoreduplication and the generation of therapy-resistant tetraploid cells.
      ; VX-680
      • Gizatullin F
      • Yao Y
      • Kung V
      • Harding MW
      • Loda M
      • Shapiro GI
      The Aurora kinase inhibitor VX-680 induces endoreduplication and apoptosis preferentially in cells with compromised p53-dependent postmitotic checkpoint function.
      ; theaflavins
      • Prasad S
      • Kaur J
      • Roy P
      • Kalra N
      • Shukla Y
      Theaflavins induce G2/M arrest by modulating expression of p21waf1/cip1, cdc25C and cyclin B in human prostate carcinoma PC-3 cells.
      Limitless replicative potentialTelomeraseTelomerase inhibitionGRN163L; RHPS4
      HGF–C-MET signalingMET inhibitionPF-0234106
      Sustained angiogenesisVEGFR signalingVEGF inhibitionBevacizumab; sorafenib; sunitinib; E7080; ZD6474; AG-013736; pazopanib; IMC-1121B; AZD2171; CHIR-265; ABT-510; BMS-690514; XL880; aflibercept
      HIF-1αHIF-1α inhibitionPX-478
      PGFPGF inhibitionTB-403

      Phase I study on monoclonal antibody TB-403 directed against PlGF in patients with solid tumours. ClinicalTrials.gov Web site. http://clinicaltrials.gov/ct2/show/NCT00702494. First received June 19, 2008. Last updated September 5, 2008. Accessed June 17, 2009.

      FGFFGF inhibitionPI-88
      Tissue invasionIntegrinsα2 integrin inhibition; αν integrin inhibition; ανβ3 + ανβ5 integrin inhibition; ανβ3 integrin inhibitionE 7820; CNTO 95; cilengitide; abergrin (MEDI 522)
      MMPsDown-regulation of MMPsCurcumin
      • Yodkeeree S
      • Chaiwangyen W
      • Garbisa S
      • Limtrakul P
      Curcumin, demethoxycurcumin and bisdemethoxycurcumin differentially inhibit cancer cell invasion through the down-regulation of MMPs and uPA.
      ; Saponins
      • Lee KJ
      • Hwang SJ
      • Choi JH
      • Jeong HG
      Saponins derived from the roots of Platycodon grandiflorum inhibit HT-1080 cell invasion and MMPs activities: regulation of NF-κB activation via ROS signal pathway.
      Wnt signalingCyclooxygenase-2 inhibitionCelecoxib
      • Tuynman JB
      • Vermeulen L
      • Boon EM
      • et al.
      Cyclooxygenase-2 inhibition inhibits c-Met kinase activity and Wnt activity in colon cancer.
      HSP273-hydroxy-3-methylglutaryl coenzyme-A reductase inhibitionLipophilic statin medications: atorvastatin, simvastatin, lovastatin, or fluvastatin
      • Karp I
      • Behlouli H
      • Lelorier J
      • Pilote L
      Statins and cancer risk.
      Immune evasionDecreased HLA class I expressionIncreased HLA class I expressionGamma irradiation
      • Chiriva-Internati M
      • Grizzi F
      • Pinkston J
      • et al.
      Gamma-radiation upregulates MHC class I/II and ICAM-I molecules in multiple myeloma cell lines and primary tumors.
      ; samarium-153-ethylenedi-aminetetramethylenephosphonate
      • Chakraborty M
      • Wansley EK
      • Carrasquillo JA
      • et al.
      The use of chelated radionuclide (samarium-153-ethylenediaminetetramethylenephosphonate) to modulate phenotype of tumor cells and enhance T cell-mediated killing.
      ; DNA-demethylating agent 5-aza-2'-deoxycytidine
      • Adair SJ
      • Hogan KT
      Treatment of ovarian cancer cell lines with 5-aza-2′-deoxycytidine upregulates the expression of cancer-testis antigens and class I major histocompatibility complex-encoded molecules.
      Nonclassical HLAG expressionNeutralization of soluble HLAG or reduced gene transcription of HLAGNone yet developed, but 5-aza-2'-deoxycytidine increases HLAG in leukemia cell lines with unknown clinical immunomodulatory impact
      • Poláková K
      • Bandzuchová E
      • Kuba D
      • Russ G
      Demethylating agent 5-aza-2′-deoxycytidine activates HLA-G expression in human leukemia cell lines.
      PGE2Decreased PGE2 synthesisCelecoxib
      • Zweifel BS
      • Davis TW
      • Ornberg RL
      • Masferrer JL
      Direct evidence for a role of cyclooxygenase 2-derived prostaglandin E2 in human head and neck xenograft tumors.
      Complement regulatory proteinsNeutralization of miniantibodies to CD55 and CD59MB55 and MB59 tested in mouse models only at time of writing of this manuscript
      • Macor P
      • Tripodo C
      • Zorzet S
      • et al.
      In vivo targeting of human neutralizing antibodies against CD55 and CD59 to lymphoma cells increases the antitumor activity of rituximab.
      IDODecreased IDO expression, IDO blockadeCelecoxib,
      • Basu GD
      • Tinder TL
      • Bradley JM
      • et al.
      Cyclooxygenase-2 inhibitor enhances the efficacy of a breast cancer vaccine: role of IDO.
      1-methyl D-tryptophan
      • Jia L
      • Schweikart K
      • Tomaszewski J
      • et al.
      Toxicology and pharmacokinetics of 1-methyl-d-tryptophan: absence of toxicity due to saturating absorption.
      CD44 expression (also soluble)CD44 ligationAnti-CD44 monoclonal antibodies
      • Charrad RS
      • Li Y
      • Delpech B
      • et al.
      Ligation of the CD44 adhesion molecule reverses blockage of differentiation in human acute myeloid leukemia.
      MUC1MUC1 radioimmunotherapyRadioimmunotherapy with MUC1 monoclonal antibody
      • Song EY
      • Qu CF
      • Rizvi SM
      • et al.
      Bismuth-213 radioimmunotherapy with C595 anti-MUC1 monoclonal antibody in an ovarian cancer ascites model.
      • Richman CM
      • Denardo SJ
      • O'Donnell RT
      • et al.
      High-dose radioimmunotherapy combined with fixed, low-dose paclitaxel in metastatic prostate and breast cancer by using a MUC-1 monoclonal antibody, m170, linked to indium-111/yttrium-90 via a cathepsin cleavable linker with cyclosporine to prevent human anti-mouse antibody.
      Neuropilin 1 and 2Neuropilin receptor blockadeNone yet available, but concept reviewed by Mac Gabhann and Popel
      • Mac Gabhann F
      • Popel AS
      Targeting neuropilin-1 to inhibit VEGF signaling in cancer: comparison of therapeutic approaches.
      B7H1B7H1 blockadeNone yet available, but concept reviewed by Thompson et al
      • Thompson RH
      • Dong H
      • Kwon ED
      Implications of B7-H1 expression in clear cell carcinoma of the kidney for prognostication and therapy.
      FASLRecombinant FASLAPO010
      • Verbrugge I
      • Wissink EH
      • Rooswinkel RW
      • et al.
      Combining radiotherapy with APO010 in cancer treatment.
      CCL5CCL5 vaccine adjuvantEngineered CCL5 superagonist
      • Dorgham K
      • Abadie V
      • Iga M
      • Hartley O
      • Gorochov G
      • Combadière B
      Engineered CCR5 superagonist chemokine as adjuvant in anti-tumor DNA vaccination.
      TRAILRTRAILR2 agonistLexatumumab
      TIM3TIM3 blockadeNone yet available, but concept reviewed by Anderson
      • Anderson DE
      TIM-3 as a therapeutic target in human inflammatory diseases.
      TLRSynthetic TLR agonistsAmpligen (TLR3 agonist)
      • Navabi H
      • Jasani B
      • Reece A
      • et al.
      A clinical grade poly I:C-analogue (Ampligen) promotes optimal DC maturation and Th1-type T cell responses of healthy donors and cancer patients in vitro.
      ; imiquimod (TLR7 agonist)
      • Prins RM
      • Craft N
      • Bruhn KW
      • et al.
      The TLR-7 agonist, imiquimod, enhances dendritic cell survival and promotes tumor antigen-specific T cell priming: relation to central nervous system antitumor immunity.
      GalectinsGalectin inhibitionGCS-100 (Galectin 3 antagonist)
      • Chauhan D
      • Li G
      • Podar K
      • et al.
      A novel carbohydrate-based therapeutic GCS-100 overcomes bortezomib resistance and enhances dexamethasone-induced apoptosis in multiple myeloma cells.
      ; thiodigalactoside ester derivatives
      • Delaine T
      • Cumpstey I
      • Ingrassia L
      • et al.
      Galectin-inhibitory thiodigalactoside ester derivatives have antimigratory effects in cultured lung and prostate cancer cells.
      CD200CD200 antibodyALXN6000
      • Kretz-Rommel A
      • Qin F
      • Dakappagari N
      • Cofiell R
      • Faas SJ
      • Bowdish KS
      Blockade of CD200 in the presence or absence of antibody effector function: implications for anti-CD200 therapy.
      SDF1 (also known as CXCL12)CXCR4 (CXCL12 receptor) antagonismPlerixafor
      • De Clercq E
      Potential clinical applications of the CXCR4 antagonist bicyclam AMD3100.
      ; CTCE-9908
      • Richert MM
      • Vaidya KS
      • Mills CN
      • et al.
      Inhibition of CXCR4 by CTCE-9908 inhibits breast cancer metastasis to lung and bone.
      OsteopontinDown-regulation of osteopontin expressionSmall interfering RNA therapy
      • Gong M
      • Lu Z
      • Fang G
      • Bi J
      • Xue X
      A small interfering RNA targeting osteopontin as gastric cancer therapeutics.
      a HLA = human leukocyte antigen. For expansion of all gene symbols, see Glossary of Genetics Terminology at the end of the article.
      b Data regarding drug compounds are from Mayo Clin Proc,
      • Sekulic A
      • Haluska Jr, P
      • Miller AJ
      • Melanoma Study Group of Mayo Clinic Cancer Center
      • et al.
      Malignant melanoma in the 21st century: the emerging molecular landscape.
      unless a citation is given to indicate otherwise.

      PROLIFERATION

      Like tumor cells, trophoblast cells have a very high proliferative capacity and exhibit molecular characteristics found in rapidly dividing cancer cells.
      • Bulmer JN
      • Morrison L
      • Johnson PM
      Expression of the proliferation markers Ki67 and transferrin receptor by human trophoblast populations.
      For example, increased telomerase activity, typically not observed to a substantial degree in normal somatic cells, is detectable in 85% of human cancers.
      • Kim NW
      • Piatyszek MA
      • Prowse KR
      • et al.
      Specific association of human telomerase activity with immortal cells and cancer.
      In fact, the intracellular concentration of telomerase is exponentially related to the proliferative capacity of a cell.
      • Blagoev KB
      Cell proliferation in the presence of telomerase.
      In human pregnancy, telomerase activity is highest during the first trimester and decreases with maturation of the placenta.
      • Kyo S
      • Takakura M
      • Tanaka M
      • et al.
      Expression of telomerase activity in human chorion.
      Survivin, a protein that promotes proliferation and inhibits apoptosis, is overexpressed in many cancers
      • Li F
      • Ambrosini G
      • Chu EY
      • et al.
      Control of apoptosis and mitotic spindle checkpoint by survivin.
      and is also up-regulated by trophoblast cells.
      • Lehner R
      • Bobak J
      • Kim NW
      • Shroyer AL
      • Shroyer KR
      Localization of telomerase hTERT protein and survivin in placenta: relation to placental development and hydatidiform mole.
      Inhibition of survivin by knockdown with small interfering RNA leads to a marked decrease in proliferation introphoblast cell lines.
      • Fest S
      • Brachwitz N
      • Schumacher A
      • et al.
      Supporting the hypothesis of pregnancy as a tumor: survivin is upregulated in normal pregnant mice and participates in human trophoblast proliferation.
      A similar decrease in proliferation is seen with survivin in small interfering RNA treatment of prostate,
      • Shen J
      • Liu J
      • Long Y
      • et al.
      Knockdown of survivin expression by siRNAs enhances chemosensitivity of prostate cancer cells and attenuates its tumorigenicity.
      glioma,
      • Zhen HN
      • Li LW
      • Zhang W
      • et al.
      Short hairpin RNA targeting survivin inhibits growth and angiogenesis of glioma U251 cells.
      non-Hodgkin lymphoma,
      • Congmin G
      • Mu Z
      • Yihui M
      • Hanliang L
      Survivin–an attractive target for RNAi in non-Hodgkin's lymphoma, Daudi cell line as a model.
      cervical cancer cells, and breast cancer cells.
      • Li QX
      • Zhao J
      • Liu JY
      • et al.
      Survivin stable knockdown by siRNA inhibits tumor cell growth and angiogenesis in breast and cervical cancers.
      Both survivin and telomerase levels are dramatically higher in hydatidiform moles than in normal placentas, providing insight into the potential involvement of these 2 different mechanisms in neoplastic transformation.
      • Lehner R
      • Bobak J
      • Kim NW
      • Shroyer AL
      • Shroyer KR
      Localization of telomerase hTERT protein and survivin in placenta: relation to placental development and hydatidiform mole.
      Another pathway supportive of both trophoblast and cancer cell proliferation is the IGF pathway (for expansion of all gene symbols, see Glossary of Genetics Terminology at the end of the article). By binding to the IGF1R on cytotrophoblast cells, IGF stimulates proliferation through the MAPK pathway and survival via activation of the PI3K pathway.
      • Forbes K
      • Westwood M
      • Baker PN
      • Aplin JD
      Insulin-like growth factor I and II regulate the life cycle of trophoblast in the developing human placenta.
      Normally, levels of IGF are tightly regulated by IGF-binding proteins and protease pregnancy-associated plasma protein A, a binding protein.
      • Boldt HB
      • Conover CA
      Pregnancy-associated plasma protein-A (PAPP-A): a local regulator of IGF bioavailability through cleavage of IGFBPs.
      Loss of binding protein regulation may contribute to the malignant phenotype.
      • Pollak M
      Insulin and insulin-like growth factor signalling in neoplasia.
      In cancer cells, the IGF1R pathway is not only mitogenic and antiapoptotic but is involved in protecting cancer cells from damaging effects of chemotherapy and radiation, potentially as a result of its effects on downstream signaling pathways.
      • Tao Y
      • Pinzi V
      • Bourhis J
      • Deutsch E
      Mechanisms of disease: signaling of the insulin-like growth factor 1 receptor pathway–therapeutic perspectives in cancer.
      Additionally, the fetal form of the insulin receptor IR-A, which is highly expressed in fetal tissues and responsive to IGF2, is also a member of the IGF-signaling system.
      • Hill DJ
      • Petrik J
      • Arany E
      Growth factors and the regulation of fetal growth.
      In many cancers, including those of the breast and ovary, dysregulation of this fetal form of the insulin receptor becomes the predominant isoform leading to IGF2-stimulated proliferation and survival.
      • Papa V
      • Pezzino V
      • Costantino A
      • et al.
      Elevated insulin receptor content in human breast cancer.
      • Kalli KR
      • Conover CA
      The insulin-like growth factor/insulin system in epithelial ovarian cancer.

      INVASION

      The sine qua non of both a successful pregnancy and the growth of cancer is the establishment of a blood and nutrient supply, and invasion through normal tissues is required for this process. However, whereas cancer cells spread throughout the host and then engage in local proliferation, trophoblasts follow an organized pattern of differentiation from proliferation to invasion without distant metastasis.
      • Marco DE
      • Cannas SA
      • Montemurro MA
      • Hu B
      • Cheng SY
      Comparable ecological dynamics underlie early cancer invasion and species dispersal, involving self-organizing processes.
      Some of the molecular switches involved in this differentiation pattern and their relevance for cancer therapeutic agents are discussed in the sections that follow.
      As EVT cells migrate down the cytotrophoblast cell columns into the maternal decidua (Figure), they encircle and erode into the maternal spiral arteries and differentiate from a proliferative phenotype into an invasive phenotype.
      • Pollheimer J
      • Knöfler M
      Signalling pathways regulating the invasive differentiation of human trophoblasts: a review.
      This differentiation occurs at about 10 to 12 weeks of gestation and is associated with opening of the intervillous space and exposure to maternal blood. Many parallels can be observed between invasive EVT cells and cancer cells. Some of these similarities are highlighted in the sections to follow; for a more in-depth discussion, readers should refer to excellent reviews by Soundararajan and Rao
      • Soundararajan R
      • Rao AJ
      Trophoblast ‘pseudo-tumorigenesis’: significance and contributory factors.
      and Ferretti et al.
      • Ferretti C
      • Bruni L
      • Dangles-Marie V
      • Pecking AP
      • Bellet D
      Molecular circuits shared by placental and cancer cells, and their implications in the proliferative, invasive and migratory capacities of trophoblasts.
      Requirements for cellular invasion include changes in cell adhesion molecules, secretion of proteases, and availability of growth factors. An example of a cellular program used by both cancer cells
      • Yang J
      • Weinberg RA
      Epithelial-mesenchymal transition: at the crossroads of development and tumor metastasis.
      and trophoblast cells
      • Vicovac L
      • Aplin JD
      Epithelial-mesenchymal transition during trophoblast differentiation.
      to promote invasion is epithelial-mesenchymal transition, which results in loss of cell-to-cell contact inhibition. Associated with this program are changes in integrin expression and loss of E cadherin, allowing loss of polarity and enhanced motility.
      • Floridon C
      • Nielsen O
      • Holund B
      • et al.
      Localization of E-cadherin in villous, extravillous and vascular trophoblasts during intrauterine, ectopic and molar pregnancy.
      • Blechschmidt K
      • Mylonas I
      • Mayr D
      • et al.
      Expression of E-cadherin and its repressor snail in placental tissue of normal, preeclamptic and HELLP pregnancies.
      Both trophoblast and cancer cells secrete proteases to degrade extracellular matrix proteins required for dispersal through tissues. The cytoplasm of migratory EVT cells express HSP27, which is correlated with MMP2 activity.
      • Matalon ST
      • Drucker L
      • Fishman A
      • Ornoy A
      • Lishner M
      The role of heat shock protein 27 in extravillous trophoblast differentiation.
      Basal HSP27 levels are unusually high in cancer cells, protecting them from apoptotic stimuli,
      • Jäättelä M
      Escaping cell death: survival proteins in cancer.
      and are associated with metastatic potential.
      • Ciocca DR
      • Calderwood SK
      Heat shock proteins in cancer: diagnostic, prognostic, predictive, and treatment implications.
      Finally, growth factors such as epidermal growth factor stimulate motility of EVT cells through phosphorylation of p42 and p44 MAPKs and the PI3K-dependent proteins, AKT and p38.
      • LaMarca HL
      • Dash PR
      • Vishnuthevan K
      • et al.
      Epidermal growth factor-stimulated extravillous cytotrophoblast motility is mediated by the activation of PI3-K, Akt and both p38 and p42/44 mitogen-activated protein kinases.
      Epidermal growth factor is associated with tumor cell invasiveness through expression of MMPs.
      • Binker MG
      • Binker-Cosen AA
      • Richards D
      • Oliver B
      • Cosen-Binker LI
      EGF promotes invasion by PANC-1 cells through Rac1/ROS-dependent secretion and activation of MMP-2.
      Switches involved in triggering trophoblast and cancer cell molecular programs for invasion are not completely understood. The Wnt pathway, a system highly conserved across species involved in cellular proliferation and motility, has recently been implicated in switching trophoblast cells from a proliferative to an invasive phenotype.
      • Pollheimer J
      • Loregger T
      • Sonderegger S
      • et al.
      Activation of the canonical wingless/T-cell factor signaling pathway promotes invasive differentiation of human trophoblast.
      Activation of the Wnt pathway is aberrant in many cancers, resulting in escape of β-catenin from proteosomal degradation, with subsequent β-catenin translocation into the cell nucleus and activation of multiple target genes.
      • Polakis P
      The many ways of Wnt in cancer.
      Although direct activation of β-catenin alone has shown no effect on motility of EVT cells, inhibition of the Wnt—β-catenin pathway can block blastocyst implantation.
      • Xie H
      • Tranguch S
      • Jia X
      • et al.
      Inactivation of nuclear Wnt-β-catenin signaling limits blastocyst competency for implantation.
      In EVT cells, activation of PAR1 (also known as the thrombin receptor) also stabilizes β-catenin and is associated with a proliferative and invasive capacity, whereas application of PAR1-silencing RNA inhibits EVT invasion.
      • Grisaru-Granovsky S
      • Maoz M
      • Barzilay O
      • Yin YJ
      • Prus D
      • Bar-Shavit R
      Protease activated receptor-1, PAR1, promotes placenta trophoblast invasion and β-catenin stabilization.
      Consistent with the need for tight regulation of invasive trophoblast cells, PAR1 is expressed in EVT cells between the 7th and 10th gestational week but is abruptly shut off by the 12th week.
      • Even-Ram SC
      • Grisaru-Granovsky S
      • Pruss D
      • et al.
      The pattern of expression of protease-activated receptors (PARs) during early trophoblast development.
      Constitutive increased expression of PAR1 can be seen in cancer cells, especially in cells lacking normal p53 activity.
      • Salah Z
      • Haupt S
      • Maoz M
      • et al.
      p53 controls hPar1 function and expression.
      In vitro assays have shown PAR1 antagonism to inhibit MMP1-induced endothelial cell activation in tumor—endothelial cell communication.
      • Goerge T
      • Barg A
      • Schnaeker EM
      • et al.
      Tumor-derived matrix metalloproteinase-1 targets endothelial proteinase-activated receptor 1 promoting endothelial cell activation.
      Whether this system could successfully be targeted for cancer therapy is under investigation. Other signal transduction pathways common in both trophoblast and cancer cell invasion include the JAK-STAT pathway,
      • Fitzgerald JS
      • Poehlmann TG
      • Schleussner E
      • Markert UR
      Trophoblast invasion: the role of intracellular cytokine signalling via signal transducer and activator of transcription 3 (STAT3).
      FAKs, G proteins, Rho-associated kinase, MAPKs, PI3K, and SMAD family proteins.
      • Pollheimer J
      • Knöfler M
      Signalling pathways regulating the invasive differentiation of human trophoblasts: a review.
      All of these pathways represent areas of current anticancer therapeutic development.
      As EVTs acquire an invasive phenotype during placental development, they become polyploid (4N-8N) by switching from mitotic division to endoreduplication,
      • Zybina TG
      • Frank HG
      • Biesterfeld S
      • Kaufmann P
      Genome multiplication of extravillous trophoblast cells in human placenta in the course of differentiation and invasion into endometrium and myometrium: II, Mechanisms of polyploidization.
      a process in which G2 or M phase (4N) cells replicate DNA without undergoing mitosis. In trophoblast cell lines, polyploid trophoblast giant cells are relatively resistant to the DNA-damaging effects of radiation,
      • MacAuley A
      • Cross JC
      • Werb Z
      Reprogramming the cell cycle for endoreduplication in rodent trophoblast cells.
      illustrating a mechanism by which survival is promoted in invasive trophoblast cells. This process can also be observed in cancer cells treated with DNA-damaging agents. Endoreduplication can be induced in tumor cells on exposure to genotoxic agents such as paclitaxel
      • Lanzi C
      • Cassinelli G
      • Cuccuru G
      • et al.
      Cell cycle checkpoint efficiency and cellular response to paclitaxel in prostate cancer cells.
      and cisplatin; a nonproliferative, senescent state in a small population of cells is induced in the latter case. The polyploid tumor cells can undergo depolyploidization to form diploid, cisplatin-resistant escape cells.
      • Puig PE
      • Guilly MN
      • Bouchot A
      • et al.
      Tumor cells can escape DNA-damaging cisplatin through DNA endoreduplication and reversible polyploidy.
      In cells with an impaired p53 system, treatment with the Aurora kinase inhibitor VX-680 leads to endoreduplication followed by apoptosis.
      • Gizatullin F
      • Yao Y
      • Kung V
      • Harding MW
      • Loda M
      • Shapiro GI
      The Aurora kinase inhibitor VX-680 induces endoreduplication and apoptosis preferentially in cells with compromised p53-dependent postmitotic checkpoint function.
      However, in 2 wild-type p53 cancer cell lines, stabilization of p53 by Nutlin-3a, an inhibitor of the p53-binding protein MDM2, leads to initial endoreduplication followed by the emergence of stable radiation- and cisplatin-resistant tetraploid clones.
      • Shen H
      • Moran DM
      • Maki CG
      Transient nutlin-3a treatment promotes endoreduplication and the generation of therapy-resistant tetraploid cells.
      A better understanding of the EVT endoreduplication process may lead to the development of targeted drugs to maintain tumor cell chemotherapeutic sensitivity.

      VASCULOGENIC MIMICRY

      As trophoblasts invade maternal spiral arteries, they further differentiate to display a vascular phenotype in a process termed vasculogenic mimicry, in which cells other than endothelial cells form vascular structures.
      • Zhou Y
      • Fisher SJ
      • Janatpour M
      • et al.
      Human cytotrophoblasts adopt a vascular phenotype as they differentiate: a strategy for successful endovascular invasion?.
      Vasculogenic mimicry can also be observed in aggressive cancers, and the genes and signaling pathways involved with the process of vasculogenic mimicry may be shared between EVT and cancer cells.
      • Robertson GP
      Mig-7 linked to vasculogenic mimicry.
      For example, the matrix glycoprotein—binding galectin 3 is highly expressed in EVT cells.
      • Maquoi E
      • van den Brûle FA
      • Castronovo V
      • Foidart JM
      Changes in the distribution pattern of galectin-1 and galectin-3 in human placenta correlates with the differentiation pathways of trophoblasts.
      Galectin-3 also appears to be a key factor in the development of an endothelial phenotype and the tube formation well described in aggressive melanomas.
      • Mourad-Zeidan AA
      • Melnikova VO
      • Wang H
      • Raz A
      • Bar-Eli M
      Expression profiling of Galectin-3-depleted melanoma cells reveals its major role in melanoma cell plasticity and vasculogenic mimicry.
      Galectin inhibitors are in preclinical testing as cancer therapeutic agents.
      • Iurisci I
      • Cumashi A
      • Sherman AA
      • Consorzio Interuniversitario Nazionale Per la Bio-Oncologia (Cinbo), Italy
      • et al.
      Synthetic inhibitors of galectin-1 and -3 selectively modulate homotypic cell aggregation and tumor cell apoptosis.
      Mig-7 was found in circulating tumor cells and tumor tissue (regardless of tissue of origin) from more than 200 patients with cancer; notably, it was absent from healthy controls.
      • Phillips TM
      • Lindsey JS
      Carcinoma cell-specific Mig-7: a new potential marker for circulating and migrating cancer cells.
      Mig-7 expression is associated with invasion and vasculogenic mimicry in cancer cells and also has recently been demonstrated in invasive embryonic cytotrophoblasts, peaking when EVT cells invade maternal decidua and remodel the vasculature during early placental development.
      • Petty AP
      • Garman KL
      • Winn VD
      • Spidel CM
      • Lindsey JS
      Overexpression of carcinoma and embryonic cytotrophoblast cell-specific Mig-7 induces invasion and vessel-like structure formation.
      This finding represents the only known expression of Mig-7 in noncancerous cells. Cancers with an endothelial phenotype have not been shown to be responsive to antiangiogenic therapies.
      • van der Schaft DW
      • Seftor RE
      • Seftor EA
      • et al.
      Effects of angiogenesis inhibitors on vascular network formation by human endothelial and melanoma cells.
      Because cancer therapy aimed at proliferating cells is less likely to be effective in invading cells,
      • Condeelis J
      • Singer RH
      • Segall JE
      The great escape: when cancer cells hijack the genes for chemotaxis and motility [published online ahead of print July 5, 2005].
      galactin-3, Mig-7, and other pathways involved in vasculogenic mimicry may also be important targets for cancer therapy.

      ANGIOGENESIS

      Molecular circuits involved in neoangiogenesis separate from vasculogenic mimicry are also likely shared between EVT and tumor cells. Angiopoietins and VEGF family members are extremely important in both spiral artery remodeling in placentation
      • Schiessl B
      • Innes BA
      • Bulmer JN
      • et al.
      Localization of angiogenic growth factors and their receptors in the human placental bed throughout normal human pregnancy.
      and the growth of many tumor types.
      • Cao Y
      • Liu Q
      Therapeutic targets of multiple angiogenic factors for the treatment of cancer and metastasis.
      Inhibition of VEGF has become an important therapeutic strategy in many cancers, although resistance can develop,
      • Jain RK
      • Duda DG
      • Clark JW
      • Loeffler JS
      Lessons from phase III clinical trials on anti-VEGF therapy for cancer.
      resulting from the induction of an angiogenic rescue program characterized by the up-regulation of multiple angiogenic genes in hypoxic tumor cells and supporting stroma.
      • Shojaei F
      • Ferrara N
      Role of the microenvironment in tumor growth and in refractoriness/resistance to anti-angiogenic therapies.
      • Fischer C
      • Jonckx B
      • Mazzone M
      • et al.
      Anti-PlGF inhibits growth of VEGF(R)-inhibitor-resistant tumors without affecting healthy vessels.
      Another member of the VEGF family, PGF, is a part of the VEGF blockade—associated rescue program that is involved in the response to pathologic conditions, such as wounds, ischemia, inflammation, or cancer.
      • Loges S
      • Roncal C
      • Carmeliet P
      Development of targeted angiogenic medicine.
      Both VEGF and PGF are highly expressed in trophoblast cells.
      • Shore VH
      • Wang TH
      • Wang CL
      • Torry RJ
      • Caudle MR
      • Torry DS
      Vascular endothelial growth factor, placenta growth factor and their receptors in isolated human trophoblast.
      It is interesting that serum levels of PGF increase after treatment of patients with cancer with the anti-VEGF monoclonal antibody bevacizumab.
      • Willett CG
      • Boucher Y
      • Duda DG
      • et al.
      Surrogate markers for antiangiogenic therapy and dose-limiting toxicities for bevacizumab with radiation and chemotherapy: continued experience of a phase I trial in rectal cancer patients [letter].
      Preclinical studies indicate that PGF blockade reduces neoangiogenesis and lymphangiogenesis, hampers recruitment of intratumoral macrophages, and is not associated with the typical anti-VEGF adverse effects (thrombosis, hypertension, proteinuria, and microvascular pruning) in healthy mice.
      • Fischer C
      • Jonckx B
      • Mazzone M
      • et al.
      Anti-PlGF inhibits growth of VEGF(R)-inhibitor-resistant tumors without affecting healthy vessels.
      Also important for angiogenesis is the oxygen-sensitive MTOR pathway.
      • Guertin DA
      • Sabatini DM
      Defining the role of mTOR in cancer.
      Central to controlling trophoblast cell proliferation in response to nutrients and growth factors,
      • Wen HY
      • Abbasi S
      • Kellems RE
      • Xia Y
      mTOR: a placental growth signaling sensor.
      MTOR is expressed on the transporting epithelium of intact human placenta.
      • Roos S
      • Jansson N
      • Palmberg I
      • Säljö K
      • Powell TL
      • Jansson T
      Mammalian target of rapamycin in the human placenta regulates leucine transport and is down-regulated in restricted fetal growth.
      It is downstream of the PI3K/AKT pathway; controls cell cycle progression and cell size and mass; is involved in angiogenesis via the VEGF, IGF, and HIF-1α—signaling pathways; and is constitutively activated in many malignancies.
      • Guertin DA
      • Sabatini DM
      Defining the role of mTOR in cancer.
      • Abraham RT
      • Eng CH
      Mammalian target of rapamycin as a therapeutic target in oncology.
      The MTOR inhibitor everolimus has antiangiogenic properties.
      • Lane HA
      • Wood JM
      • McSheehy PM
      • et al.
      mTOR inhibitor RAD001 (everolimus) has antiangiogenic/vascular properties distinct from a VEGFR tyrosine kinase inhibitor.
      A better understanding of the PI3K/AKT/MTOR pathway and other molecular circuits used by trophoblast cells in proliferation, invasion, and endothelial interactions may lead to the development of targeted therapies for cancer.
      • Ferretti C
      • Bruni L
      • Dangles-Marie V
      • Pecking AP
      • Bellet D
      Molecular circuits shared by placental and cancer cells, and their implications in the proliferative, invasive and migratory capacities of trophoblasts.
      Overall, we are in our infancy of understanding the complexity, redundancy, and interrelatedness of these molecular pathways in both placentation and neoplasia.

      IMMUNOLOGIC PROPERTIES OF THE FETOMATERNAL INTERFACE AND TUMOR MICROENVIRONMENT

      In addition to sharing many proliferative and invasive features, the cells of the trophoblast, like cancer cells, actively modulate the host immune response to develop and sustain a nutrient supply. Historically, the placenta was considered an inert, mechanical barrier protecting the semiallogeneic fetus from maternal immunologic attack.
      • Mor G
      Pregnancy reconceived: what keeps a mother's immune system from treating her baby as foreign tissue? A new theory resolves the paradox.
      Current evidence, however, supports just the opposite—many maternal and placental immunomodulatory factors are required for adequate placental invasion. Around 40% of decidual cells are cells of the innate immune system (eg, NK cells, macrophages, and DCs), a substantial proportion considering that the uterus is a nonlymphoid organ.
      • Moffett-King A
      Natural killer cells and pregnancy.
      Likewise, although cancer previously has been considered immunologically invisible to the host, many recent studies support the notion that cancer cells actively engage immune cells; for example, the presence of tumor-infiltrating lymphocytes has been well described in the literature.
      • Chiou SH
      • Sheu BC
      • Chang WC
      • Huang SC
      • Hong-Nerng H
      Current concepts of tumor-infiltrating lymphocytes in human malignancies.
      The main components of the maternal immune response at the fetomaternal interface and the similarities to the tumor microenvironment are discussed in the sections that follow.
      The most abundant immune cell present at the fetomaternal interface is the uterine NK (uNK) cell, which constitutes approximately 70% of all immune cells found in this tissue.
      • Carlino C
      • Stabile H
      • Morrone S
      • et al.
      Recruitment of circulating NK cells through decidual tissues: a possible mechanism controlling NK cell accumulation in the uterus during early pregnancy.
      Uterine NK cells are thought to be recruited from peripheral blood when interleukin (IL)-15 is secreted by endometrial stromal cells.
      • Verma S
      • Hiby SE
      • Loke YW
      • King A
      Human decidual natural killer cells express the receptor for and respond to the cytokine interleukin 15.
      They are distinct from peripheral blood NK cells in that they do not express CD16, the FcRγIIIA receptor required for antibody-dependent cell-mediated cytotoxicity.
      • Moffett-King A
      Natural killer cells and pregnancy.
      The mechanisms associated with this loss of CD16 are unclear but may be related to high levels of TGF-β within the microenvironment.
      • Keskin DB
      • Allan DS
      • Rybalov B
      • et al.
      TGFβ promotes conversion of CD16+ peripheral blood NK cells into CD16- NK cells with similarities to decidual NK cells.
      Also, in contrast to peripheral blood NK cells, uNK cells are more immunomodulatory than cytotoxic, secreting galectin 1 to induce tolerogenic DCs
      • Koopman LA
      • Kopcow HD
      • Rybalov B
      • et al.
      Human decidual natural killer cells are a unique NK cell subset with immunomodulatory potential.
      as well as angiogenic factors VEGF and PGF that are important for decidual remodeling.
      • Hanna J
      • Goldman-Wohl D
      • Hamani Y
      • et al.
      Decidual NK cells regulate key developmental processes at the human fetal-maternal interface.
      An improper balance of cytotoxic to regulatory NK cells could contribute to recurrent miscarriage and pre-eclampsia.
      • Saito S
      • Nakashima A
      • Myojo-Higuma S
      • Shiozaki A
      The balance between cytotoxic NK cells and regulatory NK cells in human pregnancy.
      Expression of IL-15 and NK cell infiltration have been reported in many different malignancies,
      • Wald O
      • Weiss ID
      • Wald H
      • et al.
      IFN-γ acts on T cells to induce NK cell mobilization and accumulation in target organs.
      including renal cell carcinoma,
      • Wittnebel S
      • Da Rocha S
      • Giron-Michel J
      • et al.
      Membrane-bound interleukin (IL)-15 on renal tumor cells rescues natural killer cells from IL-2 starvation-induced apoptosis.
      with variable prognostic implications. Recently, tumor-infiltrating CD16-NK cells have also been characterized and appear to behave similarly to uNK cells with respect to cytokine production and reduced cytotoxic activity.
      • Carrega P
      • Morandi B
      • Costa R
      • et al.
      Natural killer cells infiltrating human nonsmall-cell lung cancer are enriched in CD56 bright CD16 (-) cells and display an impaired capability to kill tumor cells.
      A closer look at factors that determine the balance of killer and regulatory NK cells during pregnancy may help identify mechanisms that shift immunity toward NK cytotoxic activity in patients with cancer.
      Also infiltrating the decidua, albeit in smaller numbers than uNK cells, are macrophages, Treg, and DCs. Macrophages phagocytose apoptotic EVT cells and secrete IL-10 and IDO, contributing to the tolerogenic TH2 milieu.
      • Abumaree MH
      • Stone PR
      • Chamley LW
      The effects of apoptotic, deported human placental trophoblast on macrophages: possible consequences for pregnancy.
      Gene expression profiling of decidual macrophages supports an immunosuppressive/anti-inflammatory phenotype with higher expression of CCL18, IGF1, IDO, neuropilin 1, and other genes associated with M2-polarized macrophages.
      • Gustafsson C
      • Mjösberg J
      • Matussek A
      • et al.
      Gene expression profiling of human decidual macrophages: evidence for immunosuppressive phenotype.
      Tumor-associated macrophages can be both inflammatory and immunosuppressive, and TH1/TH2 polarization is effected through the activation of NF-κB (also known as NFKB1).
      • Hagemann T
      • Biswas SK
      • Lawrence T
      • Sica A
      • Lewis CE
      Regulation of macrophage function in tumors: the multifaceted role of NF-κB.
      In fact, in vitro studies suggest that tumor-associated macrophages may be re-educated to display a classically activated rather than an M2 phenotype by inhibition of inhibitory kappa B kinase β, the major activator of NF-κB.
      • Hagemann T
      • Lawrence T
      • McNeish I
      • et al.
      “Re-educating” tumor-associated macrophages by targeting NF-κB.
      Regulatory T cells are additional important mediators of tolerance in both pregnancy and cancer. Immunophenotypically, these cells express surface CD4, CD25, and FOXP3, and they expand in both decidua
      • Heikkinen J
      • Möttönen M
      • Alanen A
      • Lassila O
      Phenotypic characterization of regulatory T cells in the human decidua.
      and peripheral blood
      • Somerset DA
      • Zheng Y
      • Kilby MD
      • Sansom DM
      • Drayson MT
      Normal human pregnancy is associated with an elevation in the immune suppressive CD25+ CD4+ regulatory T-cell subset.
      during normal pregnancies. This expansion is antigen-specific and is induced by paternal/fetal alloantigens
      • Zhao JX
      • Zeng YY
      • Liu Y
      Fetal alloantigen is responsible for the expansion of the CD4 (+)CD25 (+) regulatory T cell pool during pregnancy.
      and not simply by hormonal changes in pregnancy.
      • Schumacher A
      • Wafula PO
      • Bertoja AZ
      • et al.
      Mechanisms of action of regulatory T cells specific for paternal antigens during pregnancy.
      A decrease in this lymphocyte subset is associated with spontaneous abortion
      • Sasaki Y
      • Sakai M
      • Miyazaki S
      • Higuma S
      • Shiozaki A
      • Saito S
      Decidual and peripheral blood CD4+CD25+ regulatory T cells in early pregnancy subjects and spontaneous abortion cases.
      and pre-eclampsia.
      • Steinborn A
      • Haensch GM
      • Mahnke K
      • et al.
      Distinct subsets of regulatory T cells during pregnancy: is the imbalance of these subsets involved in the pathogenesis of preeclampsia?.
      Regulatory T cells are also expanded in cancer and are implicated in impaired antitumor immunity,
      • Beyer M
      • Schultze JL
      Regulatory T cells in cancer.
      suppression of effector T lymphocyte proliferation,
      • Shen LS
      • Wang J
      • Shen DF
      • et al.
      CD4+CD25+CD127 (low/-) regulatory T cells express Foxp3 and suppress effector T cell proliferation and contribute to gastric cancers progression.
      and increased tumor blood vessel density,
      • Giatromanolaki A
      • Bates GJ
      • Koukourakis MI
      • et al.
      The presence of tumor-infiltrating FOXP3+ lymphocytes correlates with intratumoral angiogenesis in endometrial cancer.
      suggesting an important link between immunity and angiogenesis. Regulatory T cells in patients with cancer also recognize tumor-specific antigens and proliferate in response to antigenic stimulation.
      • Piersma SJ
      • Welters MJ
      • van der Burg SH
      Tumor-specific regulatory T cells in cancer patients.
      Targeting the Treg population to boost antitumor immunity is under investigation with agents such as denileukin diftitox (IL2/diphtheria fusion protein) or LMB-2 (Fv fragment of CD25 antibody/Pseudomonas endotoxin A fusion protein) and CTLA-4 inhibitors.
      • Beyer M
      • Schultze JL
      Immunoregulatory T cells: role and potential as a target in malignancy.
      • Colombo MP
      • Piconese S
      Regulatory-T-cell inhibition versus depletion: the right choice in cancer immunotherapy.
      Some of the benefit of cytotoxic chemotherapy may be derived from concomitant impairment of the immunosuppressive Treg proliferation driven by the cancer.
      • Zhang L
      • Dermawan KT
      • Jin ML
      • Xiong SD
      • Chu YW
      Does chemotherapy augment anti-tumor immunotherapy by preferential impairment of regulatory T cells?.
      Antigen-presenting CD83+ DCs are involved in the maintenance of the TH2-predominant state in decidual tissues,
      • Miyazaki S
      • Tsuda H
      • Sakai M
      • et al.
      Predominance of Th2-promoting dendritic cells in early human pregnancy decidua.
      as well as at other mucosal surfaces.
      • Kämmerer U
      • Schoppet M
      • McLellan AD
      • et al.
      Human decidua contains potent immunostimulatory CD83+ dendritic cells.
      However, the role of the DC is likely more complex than antigen presentation and secretion of immunosuppressive cytokines. Ablation of uterine DCs leads to decidualization failure and embryo resorption in mice; this occurs even with syngeneic pregnancy in mice in which alloantigens are absent.
      • Plaks V
      • Birnberg T
      • Berkutzki T
      • et al.
      Uterine DCs are crucial for decidua formation during embryo implantation in mice.
      Dendritic cells also represent another link between immunity and angiogenesis, secreting soluble FLT1 (also known as VEGFR1) and TGF-β1 required for endothelial cell survival and vascular maturation. In the absence of DCs, angiogenesis is severely impaired. In cancer, DCs also play a role that is more than immunoregulatory through their production of potent angiogenic growth factors. Moreover, cancer cells can secrete substances that suppress maturation of DCs, including VEGF, TGF-β, hepatocyte growth factor, and osteopontin, thereby maintaining a proangiogenic, immature DC phenotype.
      • Murdoch C
      • Muthana M
      • Coffelt SB
      • Lewis CE
      The role of myeloid cells in the promotion of tumour angiogenesis.
      Expression of certain cell surface molecules on both trophoblast and cancer cells can also confer immunologic protection. Among the most important of these molecules is the nonpolymorphic, highly conserved class I human leukocyte antigen (HLA) molecules such as HLAG
      • Hunt JS
      • Orr HT
      HLA and maternal-fetal recognition.
      ; in contrast, the highly diverse classical HLA class I proteins A, B, and C are essential in cell-mediated immune responses. In fact, in trophoblast cells, interferon-γ fails to stimulate classical HLA class I expression.
      • Hunt JS
      • Andrews GK
      • Wood GW
      Normal trophoblasts resist induction of class I HLA.
      A similar property of down-regulated or absent classical HLA class I expression can cloak cancer cells from the host's immune system.
      • Campoli M
      • Ferrone S
      HLA antigen changes in malignant cells: epigenetic mechanisms and biologic significance.
      Cancer treatment modalities including gamma irradiation,
      • Chiriva-Internati M
      • Grizzi F
      • Pinkston J
      • et al.
      Gamma-radiation upregulates MHC class I/II and ICAM-I molecules in multiple myeloma cell lines and primary tumors.
      radiopharmaceutical samarium-153-ethylenediaminetetramethylenephosphonate,
      • Chakraborty M
      • Wansley EK
      • Carrasquillo JA
      • et al.
      The use of chelated radionuclide (samarium-153-ethylenediaminetetramethylenephosphonate) to modulate phenotype of tumor cells and enhance T cell-mediated killing.
      and chemotherapeutic agents such as 5-fluorouracil
      • Marchal JA
      • Boulaiz H
      • Rodriguez-Serrano F
      • et al.
      5-fluorouracil derivatives induce differentiation mediated by tubulin and HLA class I modulation.
      and hypomethylating agents
      • Fonsatti E
      • Nicolay HJ
      • Sigalotti L
      • et al.
      Functional up-regulation of human leukocyte antigen class I antigens expression by 5-aza-2′-deoxycytidine in cutaneous melanoma: immunotherapeutic implications.
      increase HLA class I expression.
      Expression of HLAG on trophoblast cells and cancer cells has important immunomodulatory effects. In the placenta, HLAG expression is most evident on EVTs at the fetomaternal interface, with lower expression at the proliferative area of the villous column and increased expression with invasive, interstitial, and endovascular EVT cells.
      • McMaster MT
      • Librach CL
      • Zhou Y
      • et al.
      Human placental HLA-G expression is restricted to differentiated cytotrophoblasts.
      On the basis of sequence homologies, HLAG has been proposed as the ancestral MHC class I gene and has only a few known sequence variations in humans, in sharp contrast to the profound allelic diversity (measured in the hundreds of allelic variants) of classical MHC class I genes.
      • Arnaiz-Villena A
      • Morales P
      • Gomez-Casado E
      • et al.
      Evolution of MHC-G in primates: a different kind of molecule for each group of species.
      Human leukocyte antigen-G interacts with NK cells via inhibitory receptors, such as CD94/NKG2A, ILT2, and killer cell immunoglobulin-like receptor KIR2DL4.
      • Moffett-King A
      Natural killer cells and pregnancy.
      The role of HLAG is to suppress cytolytic killing by both NK and cytotoxic T cells, induce apoptosis of immune cells, regulate cytokine production in blood mononuclear cells, and reduce stimulatory capacity and impair maturation of DCs (reviewed in Hunt et al
      • Hunt JS
      • Langat DK
      • McIntire RH
      • Morales PJ
      The role of HLA-G in human pregnancy.
      ). Within the tumor microenvironment, the generation of HLAG+—suppressive NK cells occurs by trogocytosis (ie, the rapid cell-to-cell contact-dependent transfer of membranes and associated molecules from one cell to another), leading to the inhibition of other HLAG+ (cross-inhibition) or HLAG NK cells through HLAG and ILT2 cross-linking.
      • Caumartin J
      • Favier B
      • Daouya M
      • et al.
      Trogocytosis-based generation of suppressive NK cells.
      Expression of HLAG is associated with a poor prognosis in patients with lymphoproliferative disorders,
      • Amiot L
      • Le Friec G
      • Sebti Y
      • et al.
      HLA-G and lymphoproliferative disorders.
      melanoma,
      • Bezuhly M
      • Howlett A
      • Colp P
      • et al.
      Quantitative HLA-G expression in metastasising and non-metastasising primary thin cutaneous melanomas [letter].
      mesothelioma,
      • Kleinberg L
      • Flørenes VA
      • Skrede M
      • et al.
      Expression of HLA-G in malignant mesothelioma and clinically aggressive breast carcinoma.
      breast carcinoma,
      • Kleinberg L
      • Flørenes VA
      • Skrede M
      • et al.
      Expression of HLA-G in malignant mesothelioma and clinically aggressive breast carcinoma.
      ovarian carcinoma,
      • Davidson B
      • Elstrand MB
      • McMaster MT
      • et al.
      HLA-G expression in effusions is a possible marker of tumor susceptibility to chemotherapy in ovarian carcinoma.
      renal cell carcinoma,
      • Seliger B
      • Schlaf G
      Structure, expression and function of HLA-G in renal cell carcinoma.
      squamous esophageal cancer,
      • Yie SM
      • Yang H
      • Ye SR
      • Li K
      • Dong DD
      • Lin XM
      Expression of HLA-G is associated with prognosis in esophageal squamous cell carcinoma.
      gastric carcinoma,
      • Yie SM
      • Yang H
      • Ye SR
      • Li K
      • Dong DD
      • Lin XM
      Expression of human leukocyte antigen G (HLA-G) correlates with poor prognosis in gastric carcinoma.
      cervical cancer,
      • Yoon BS
      • Kim YT
      • Kim JW
      • Kim SH
      • Kim JH
      • Kim SW
      Expression of human leukocyte antigen-G and its correlation with interleukin-10 expression in cervical carcinoma.
      non—small cell lung cancer,
      • Boucher LD
      • Yoneda K
      The expression of trophoblastic cell markers by lung carcinomas.
      bladder cancer,
      • El-Chennawi FA
      • Auf FA
      • El-Diasty AM
      • et al.
      Expression of HLA-G in cancer bladder.
      prostate cancer,
      • Langat DK
      • Sue Platt J
      • Tawfik O
      • Fazleabas AT
      • Hunt JS
      Differential expression of human leukocyte antigen-G (HLA-G) messenger RNAs and proteins in normal human prostate and prostatic adenocarcinoma.
      endometrial cancer,
      • Barrier BF
      • Kendall BS
      • Sharpe-Timms KL
      • Kost ER
      Characterization of human leukocyte antigen-G (HLA-G) expression in endometrial adenocarcinoma.
      colorectal cancer,
      • Ye SR
      • Yang H
      • Li K
      • Dong DD
      • Lin XM
      • Yie SM
      Human leukocyte antigen G expression: as a significant prognostic indicator for patients with colorectal cancer.
      and myeloid malignancies, including acute myeloid leukemia.
      • Rebmann V
      • Regel J
      • Stolke D
      • Grosse-Wilde H
      Secretion of sHLA-G molecules in malignancies.
      • Yan WH
      • Lin A
      • Chen BG
      • et al.
      Unfavourable clinical implications for HLA-G expression in acute myeloid leukaemia.
      However, relatively little is known about the regulation of the expression of this important immunomodulatory molecule.
      • Rebmann V
      • Regel J
      • Stolke D
      • Grosse-Wilde H
      Secretion of sHLA-G molecules in malignancies.
      Regulation of HLAG expression may be at the epigenetic level, with transcription of HLAG being detectable in acute myeloid leukemia cell lines after treatment with 5-aza-2′-deoxycytidine.
      • Poláková K
      • Bandzuchová E
      • Kuba D
      • Russ G
      Demethylating agent 5-aza-2′-deoxycytidine activates HLA-G expression in human leukemia cell lines.
      Some preliminary evidence also supports a micro-RNA regulatory mechanism.
      • Veit TD
      • Chies JA
      Tolerance versus immune response: MicroRNAs as important elements in the regulation of the HLA-G gene expression.
      Clearly, HLAG represents an attractive target for immune-based cancer therapies given its preferential expression in many malignancies as well as limited expression in normal tissues.
      • Onno M
      • Guillaudeux T
      • Amiot L
      • et al.
      The HLA-G gene is expressed at a low mRNA level in different human cells and tissues.
      Targeting HLAG with a peptide-based vaccine strategy to develop a cytotoxic T-cell response against tumor cells bearing the molecule has proved feasible,
      • Komohara Y
      • Harada M
      • Ishihara Y
      • et al.
      HLA-G as a target molecule in specific immunotherapy against renal cell carcinoma.
      although much work remains before other methods of HLAG inhibition could lead to restoration of antitumor immunity.
      Other cell surface tolerance signals common between trophoblasts and cancer cells include CD200 (OX-2) and CEACAM-1. Trophoblast cells expressing CD200 can inhibit CD8+ T cytotoxic lymphocyte (CTL) generation and shift the cytokine balance toward TH2 in vitro.
      • Clark DA
      • Keil A
      • Chen Z
      • Markert U
      • Manuel J
      • Gorczynski RM
      Placental trophoblast from successful human pregnancies expresses the tolerance signaling molecule, CD200 (OX-2).
      Expression of CD200 is a negative prognostic factor in patients with multiple myeloma
      • Moreaux J
      • Hose D
      • Reme T
      • et al.
      CD200 is a new prognostic factor in multiple myeloma [published correction appears in Blood. 2007;109 (7):2717].
      and acute myeloid leukemia,
      • Tonks A
      • Hills R
      • White P
      • et al.
      CD200 as a prognostic factor in acute myeloid leukaemia [letter].
      and it has been shown to down-regulate TH1 cytokines in vitro in solid tumors, including melanomas, ovarian carcinomas, and renal cell carcinomas.
      • Siva A
      • Xin H
      • Qin F
      • Oltean D
      • Bowdish KS
      • Kretz-Rommel A
      Immune modulation by melanoma and ovarian tumor cells through expression of the immunosuppressive molecule CD200.
      As a potential cancer stem cell marker, CD200 may be a promising target for these cells that survive conventional chemotherapy.
      • Kawasaki BT
      • Farrar WL
      Cancer stem cells, CD200 and immunoevasion.
      CEACAM-1 (CD66a), expressed on both trophoblasts and IL-2-activated decidual leukocytes, plays a role in inhibiting NK-mediated cytolysis.
      • Gray-Owen SD
      • Blumberg RS
      CEACAM1: contact-dependent control of immunity.
      Colocalization of osteopontin on EVT cells is associated with an invasive phenotype important for successful placentation.
      • Briese J
      • Oberndörfer M
      • Pätschenik C
      • et al.
      Osteopontin is colocalized with the adhesion molecule CEACAM1 in the extravillous trophoblast of the human placenta and enhances invasion of CEACAM1-expressing placental cells.
      CEACAM-1 expression in cancer is associated with increased angiogenesis in non-small cell lung cancer
      • Dango S
      • Sienel W
      • Schreiber M
      • et al.
      Elevated expression of carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM-1) is associated with increased angiogenic potential in non-small-cell lung cancer.
      ; in melanoma, it has been shown to be predictive of the development of metastatic disease.
      • Thies A
      • Moll I
      • Berger J
      • et al.
      CEACAM1 expression in cutaneous malignant melanoma predicts the development of metastatic disease.
      Expression of other immunomodulatory molecules, including components of the extrinsic apoptotic pathway such as FAS, TNF superfamily receptors,
      • Phillips TA
      • Ni J
      • Hunt JS
      Death-inducing tumour necrosis factor (TNF) superfamily ligands and receptors are transcribed in human placentae, cytotrophoblasts, placental macrophages and placental cell lines.
      TRAIL,
      • Phillips TA
      • Ni J
      • Pan G
      • et al.
      TRAIL (Apo-2L) and TRAIL receptors in human placentas: implications for immune privilege.
      and B7 family members such as B7H1 (or programmed death ligand 1, PDL-1),
      • Petroff MG
      • Chen L
      • Phillips TA
      • Azzola D
      • Sedlmayr P
      • Hunt JS
      B7 family molecules are favorably positioned at the human maternal-fetal interface.
      is also common between trophoblast and cancer cells (Table 1).
      Chemokines and cytokines also play a role in promoting a tolerogenic environment in placentation and the tumor microenvironment. Implantation of the blastocyst occurs in a TH1-predominant (inflammatory) milieu, but the fetomaternal interface must transition to a TH2-polarized (immunologically tolerant) state for pregnancy to continue (for an excellent review, refer to van Mourik et al
      • van Mourik MS
      • Macklon NS
      • Heijnen CJ
      Embryonic implantation: cytokines, adhesion molecules, and immune cells in establishing an implantation environment.
      ). However, before implantation can occur, the endometrial lining must be receptive in the so-called window of implantation, in which many immunomodulatory genes are up-regulated monthly during the midsecretory phase of the menstrual cycle.
      • van Mourik MS
      • Macklon NS
      • Heijnen CJ
      Embryonic implantation: cytokines, adhesion molecules, and immune cells in establishing an implantation environment.
      Under the influence of progesterone, the endometrial epithelium up-regulates decay-accelerating factor and osteoponin expression, and the endometrial stroma increases IL-15 expression.
      • Kao LC
      • Tulac S
      • Lobo S
      • et al.
      Global gene profiling in human endometrium during the window of implantation.
      • Franchi A
      • Zaret J
      • Zhang X
      • Bocca S
      • Oehninger S
      Expression of immunomodulatory genes, their protein products and specific ligands/receptors during the window of implantation in the human endometrium.
      Expression of complement regulatory proteins (eg, decay-accelerating factor) is a well-established immunomodulatory mechanism used by many cancers to escape complement-mediated cell death and evade an immune response by inhibiting T-cell proliferation.
      • Spendlove I
      • Ramage JM
      • Bradley R
      • Harris C
      • Durrant LG
      Complement decay accelerating factor (DAF)/CD55 in cancer.
      Osteopontin has TH1 cytokine functions and is chemotactic for macrophages, T cells, and DCs, the last of which it induces to secrete IL-12 and tumor necrosis factor α (TNF-α).
      • Wang KX
      • Denhardt DT
      Osteopontin: role in immune regulation and stress responses.
      • Renkl AC
      • Wussler J
      • Ahrens T
      • et al.
      Osteopontin functionally activates dendritic cells and induces their differentiation toward a Th1-polarizing phenotype.
      Osteopontin is overexpressed in many cancers and is associated with metastatic potential.
      • Weber GF
      Molecular mechanisms of metastasis.
      Additionally, tissues that physiologically express high levels of osteopontin, such as bone, lung, and liver, may create a receptive microenvironment for metastasis via interaction with osteopontin receptor CD44 on the surface of cancer cells.
      • Weber GF
      • Ashkar S
      • Cantor H
      Interaction between CD44 and osteopontin as a potential basis for metastasis formation.
      RANTES (CCL5) is a chemokine produced by trophoblasts that may play a role in apoptosis of potentially harmful maternal CD3+ cells.
      • Fraccaroli L
      • Alfieri J
      • Larocca L
      • et al.
      A potential tolerogenic immune mechanism in a trophoblast cell line through the activation of chemokine-induced T cell death and regulatory T cell modulation.
      Melanoma cells can induce tumor-infiltrating lymphocytes to secrete RANTES and subsequently undergo apoptosis as another mechanism to evade an immune response.
      • Mellado M
      • de Ana AM
      • Moreno MC
      • Martínez C
      • Rodríguez-Frade JM
      A potential immune escape mechanism by melanoma cells through the activation of chemokine-induced T cell death.
      Trophoblast cells also secrete chemoattractant cytokines, such as GRO-α, MCP1, and IL-8, to actively recruit the CD14+ monocytes to the fetomaternal interface.
      • Fest S
      • Aldo PB
      • Abrahams VM
      • et al.
      Trophoblast-macrophage interactions: a regulatory network for the protection of pregnancy.
      GRO-α is an oncogenic and angiogenic cytokine driven by RAS, which is inappropriately activated in most cancers.
      • Ancrile BB
      • O'Hayer KM
      • Counter CM
      Oncogenic ras-induced expression of cytokines: a new target of anti-cancer therapeutics.
      Capable of inducing vascular permeability along with mononuclear cell recruitment, MCP1 is associated with angiogenesis and malignant pleural effusions.
      • Stathopoulos GT
      • Psallidas I
      • Moustaki A
      • et al.
      A central role for tumor-derived monocyte chemoattractant protein-1 in malignant pleural effusion.
      Inhibition of MCP1 can lead to reduced malignant angiogenesis and recruitment of tumor-associated macrophages in a mouse model of melanoma.
      • Koga M
      • Kai H
      • Egami K
      • et al.
      Mutant MCP-1 therapy inhibits tumor angiogenesis and growth of malignant melanoma in mice.
      Finally, the IL-8 pathway is well known to be a central immune and angiogenic factor within the tumor microenvironment and is important in stress-induced chemotherapeutic resistance.
      • Waugh DJ
      • Wilson C
      The interleukin-8 pathway in cancer.
      A tryptophan-catabolizing enzyme, IDO is important in promoting tolerance by inhibiting proliferation of lymphocytes both at the fetomaternal interface
      • von Rango U
      • Krusche CA
      • Beier HM
      • Classen-Linke I
      Indoleamine-dioxygenase is expressed in human decidua at the time maternal tolerance is established.
      and tumor microenvironment.
      • Katz JB
      • Muller AJ
      • Prendergast GC
      Indoleamine 2,3-dioxygenase in T-cell tolerance and tumoral immune escape.
      Tryptophan levels have been observed to decrease in pregnancy with a return to normal, nonpregnant levels in the puerperium,
      • Schröcksnadel H
      • Baier-Bitterlich G
      • Dapunt O
      • Wachter H
      • Fuchs D
      Decreased plasma tryptophan in pregnancy.
      possibly a result of tryptophan degradation by IDO-expressing trophoblast cells. Expression of HLAG on DCs can be induced by IDO, indicating potential cooperation in immune suppression between these 2 molecules.
      • López AS
      • Alegre E
      • LeMaoult J
      • Carosella E
      • González A
      Regulatory role of tryptophan degradation pathway in HLA-G expression by human monocyte-derived dendritic cells.
      Tumor-derived PGE2 secretion can increase IDO expression in local DCs.
      • von Bergwelt-Baildon MS
      • Popov A
      • Saric T
      • et al.
      CD25 and indoleamine 2,3-dioxygenase are up-regulated by prostaglandin E2 and expressed by tumor-associated dendritic cells in vivo: additional mechanisms of T-cell inhibition.
      Antigen-expressing cells and IDO-expressing tumor cells might also contribute to local immunosuppression in tumor-draining lymph nodes.
      • Munn DH
      Indoleamine 2,3-dioxygenase, tumor-induced tolerance and counter-regulation.
      Pharmacologic inhibitors of IDO are under development and in early-stage clinical trials as anticancer agents.
      • Katz JB
      • Muller AJ
      • Prendergast GC
      Indoleamine 2,3-dioxygenase in T-cell tolerance and tumoral immune escape.
      Induction of IDO can also be blocked in vitro by cyclooxygenase 2 inhibitors.
      • Sayama S
      • Yoshida R
      • Oku T
      • Imanishi J
      • Kishida T
      • Hayaishi O
      Inhibition of interferon-mediated induction of indoleamine 2,3-dioxygenase in mouse lung by inhibitors of prostaglandin biosynthesis.
      When murine breast cancer vaccine recipients received the oral cyclooxygenase 2 inhibitor celecoxib, an increase in tumor-specific CTLs was observed.
      • Basu GD
      • Tinder TL
      • Bradley JM
      • et al.
      Cyclooxygenase-2 inhibitor enhances the efficacy of a breast cancer vaccine: role of IDO.
      Trophoblast invasion and spiral artery remodeling are tightly controlled processes, likely kept in check both by molecular programming of trophoblast cells and by paracrine immune factors.
      • von Rango U
      Fetal tolerance in human pregnancy–a crucial balance between acceptance and limitation of trophoblast invasion.
      We have much to gain in terms of developing novel immunologic interventions for our patients with cancer by closely examining both the similarities and differences of the intimate cross-talk that occurs within the tumor and placental microenvironments.

      EVIDENCE FOR SYSTEMIC IMMUNE MODULATION

      Similar to the increasing antigenic burden of progressive cancer,
      • Anker P
      • Mulcahy H
      • Chen XQ
      • Stroun M
      Detection of circulating tumour DNA in the blood (plasma/serum) of cancer patients.
      fetal DNA can be found circulating in maternal blood by the second trimester in the height of the tolerogenic cytokine milieu.
      • Lo YM
      • Corbetta N
      • Chamberlain PF
      • et al.
      Presence of fetal DNA in maternal plasma and serum.
      Although its immunologic consequences have not been fully elucidated, this circulating DNA likely contributes to tolerance and eventual exhaustion of antigen-specific CTLs. This phenomenon is well described for the human immunodeficiency virus, chronic infection with which leads to progressive HIV-specific T cell dysfunction.
      • Jones RB
      • Ndhlovu LC
      • Barbour JD
      • et al.
      Tim-3 expression defines a novel population of dysfunctional T cells with highly elevated frequencies in progressive HIV-1 infection.
      In addition to circulating nucleic acids, cellular fragments, known as microparticles or exosomes, can be detected in the peripheral blood of pregnant women in the third trimester.
      • Taylor DD
      • Akyol S
      • Gercel-Taylor C
      Pregnancy-associated exosomes and their modulation of T cell signaling.
      Trophoblast-derived microparticles are proinflammatory, activate the coagulation system, can cause endothelial dysfunction, and are circulating at higher levels in pre-eclamptic vs normal pregnancies.
      • Redman CW
      • Sargent IL
      Microparticles and immunomodulation in pregnancy and pre-eclampsia.
      These microparticles are also involved in down-regulation of T-cell activity and deletion of activated T cells through interactions with FAS or TRAIL on the microparticle surface.
      • Théry C
      • Zitvogel L
      • Amigorena S
      Exosomes: composition, biogenesis and function.
      A similar phenomenon of cancer cell-derived microparticles contributing to the hypercoagulable state and impaired antitumor immunity of patients with cancer has been described (reviewed in Amin et al
      • Amin C
      • Mackman N
      • Key NS
      Microparticles and cancer.
      ). Microparticles derived from melanoma cells have been shown to express HLAG, likely contributing to their immunomodulatory properties.
      • Riteau B
      • Faure F
      • Menier C
      • et al.
      Exosomes bearing HLA-G are released by melanoma cells.
      Just as circulating tumor cells have been identified in patients with early-stage malignancies,
      • Alix-Panabières C
      • Riethdorf S
      • Pantel K
      Circulating tumor cells and bone marrow micrometastasis.
      intact trophoblast cells are also known to circulate in the maternal peripheral blood as early as the ninth week of pregnancy.
      • Mueller UW
      • Hawes CS
      • Wright AE
      • et al.
      Isolation of fetal trophoblast cells from peripheral blood of pregnant women.
      These fetally derived cells can engraft in the mother irrespective of HLA disparity and establish a long-term microchimerism that persists for decades after parturition.
      • Evans PC
      • Lambert N
      • Maloney S
      • Furst DE
      • Moore JM
      • Nelson JL
      Long-term fetal microchimerism in peripheral blood mononuclear cell subsets in healthy women and women with scleroderma.
      Rates of fetal microchimerism are decreased in female patients with cancer (34%) compared with healthy controls (57%), and the immunomodulatory implications of this decrease are unclear.
      • Gilmore GL
      • Haq B
      • Shadduck RK
      • Jasthy SL
      • Lister J
      Fetal-maternal microchimerism in normal parous females and parous female cancer patients.
      An increased number of fetal microchimeric cells in aggressive breast carcinoma
      • Dubernard G
      • Oster M
      • Chareyre F
      • et al.
      Increased fetal cell microchimerism in high grade breast carcinomas occurring during pregnancy.
      and melanoma
      • Nguyen Huu S
      • Oster M
      • Avril MF
      • et al.
      Fetal microchimeric cells participate in tumour angiogenesis in melanomas occurring during pregnancy.
      during pregnancy have been observed. Whether these cells were recruited to the tumor microenvironment by inflammation and behave as innocent bystanders or whether they participate in tumor progression by providing angiogenic or tolerogenic signals is unclear at this time.
      Many additional immunomodulatory proteins are secreted by trophoblast cells and can be found circulating in maternal peripheral blood. Among these molecules, soluble HLAG may be the most extensively studied.
      • Hunt JS
      • Jadhav L
      • Chu W
      • Geraghty DE
      • Ober C
      Soluble HLA-G circulates in maternal blood during pregnancy.
      Soluble HLAG impairs NK/DC cross-talk, promotes proinflammatory cytokine secretion from both uterine and peripheral blood mononuclear cells,
      • van der Meer A
      • Lukassen HG
      • van Cranenbroek B
      • et al.
      Soluble HLA-G promotes Th1-type cytokine production by cytokine-activated uterine and peripheral natural killer cells.
      and induces apoptosis of CD8+ cells through CD8 ligation
      • Contini P
      • Ghio M
      • Poggi A
      • et al.
      Soluble HLA-A,-B,-C and -G molecules induce apoptosis in T and NK CD8+ cells and inhibit cytotoxic T cell activity through CD8 ligation.
      and FAS-FASL interaction.
      • Puppo F
      • Contini P
      • Ghio M
      • Indiveri F
      Soluble HLA class I molecules/CD8 ligation trigger apoptosis of CD8+ cells by Fas/Fas-ligand interaction.
      Soluble HLAG has been well documented in malignancies,
      • Rebmann V
      • Regel J
      • Stolke D
      • Grosse-Wilde H
      Secretion of sHLA-G molecules in malignancies.
      including acute leukemia,
      • Gros F
      • Sebti Y
      • de Guibert S
      • et al.
      Soluble HLA-G molecules increase during acute leukemia, especially in subtypes affecting monocytic and lymphoid lineages.
      multiple myeloma,
      • Leleu X
      • Le Friec G
      • Facon T
      • Intergroupe Francophone du Myélome
      • et al.
      Total soluble HLA class I and soluble HLA-G in multiple myeloma and monoclonal gammopathy of undetermined significance.
      lymphoproliferative disorders,
      • Sebti Y
      • Le Friec G
      • Pangault C
      • et al.
      Soluble HLA-G molecules are increased in lymphoproliferative disorders.
      breast and ovarian carcinoma,
      • Kleinberg L
      • Flørenes VA
      • Skrede M
      • et al.
      Expression of HLA-G in malignant mesothelioma and clinically aggressive breast carcinoma.
      renal cell carcinoma,
      • Seliger B
      • Schlaf G
      Structure, expression and function of HLA-G in renal cell carcinoma.
      • Dunker K
      • Schlaf G
      • Bukur J
      • Altermann WW
      • Handke D
      • Seliger B
      Expression and regulation of non-classical HLA-G in renal cell carcinoma.
      lung cancer,
      • Urosevic M
      • Kurrer MO
      • Kamarashev J
      • et al.
      Human leukocyte antigen G up-regulation in lung cancer associates with high-grade histology, human leukocyte antigen class I loss and interleukin-10 production.
      gliomas,
      • Wiendl H
      • Mitsdoerffer M
      • Hofmeister V
      • et al.
      A functional role of HLA-G expression in human gliomas: an alternative strategy of immune escape.
      and melanoma.
      • Ugurel S
      • Rebmann V
      • Ferrone S
      • Tilgen W
      • Grosse-Wilde H
      • Reinhold U
      Soluble human leukocyte antigen–G serum level is elevated in melanoma patients and is further increased by interferon-α immunotherapy.
      Cancer cells can also trigger monocytes to release HLAG, further down-regulating antitumor immunity.
      • Morandi F
      • Levreri I
      • Bocca P
      • et al.
      Human neuroblastoma cells trigger an immunosuppressive program in monocytes by stimulating soluble HLA-G release.
      Whether HLAG can be targeted to break cancer-specific tolerance remains to be investigated.
      A search for other immunomodulatory molecules from conditioned media of placental tissue has yielded interesting results. Surprisingly, no interleukins were identified by either proteomic analysis or sensitive radioimmunoassays; rather, in addition to pregnancy-associated hormones, substances including PSG1, glycodelin, TGF-β2, thrombospondin-1, PEDF, MIF, and galectin 1 were identified as important immunoregulators in pregnancy.
      • Dong M
      • Ding G
      • Zhou J
      • Wang H
      • Zhao Y
      • Huang H
      The effect of trophoblasts on T lymphocytes: possible regulatory effector molecules–a proteomic analysis.
      Many of these substances have been identified in cancer as well. For example, PSGs may not be pregnancy specific at all. Pregnancy-specific glycoprotein 9 deregulation is an early event in colorectal carcinogenesis.
      • Salahshor S
      • Goncalves J
      • Chetty R
      • Gallinger S
      • Woodgett JR
      Differential gene expression profile reveals deregulation of pregnancy specific beta1 glycoprotein 9 early during colorectal carcinogenesis.
      Expressed frequently in lung carcinomas,
      • Boucher LD
      • Yoneda K
      The expression of trophoblastic cell markers by lung carcinomas.
      PSG1 is associated with estrogen receptor negativity and a higher risk of death in early-stage breast cancer.
      • Fagnart OC
      • Cambiaso CL
      • Lejeune MD
      • Noel G
      • Maisin H
      • Masson PL
      Prognostic value of concentration of pregnancy-specific β1 -glycoprotein (SP1) in serum of patients with breast cancer.
      Glycodelin may be involved in tumor angiogenesis by increasing VEGF release in many cell lines.
      • Song M
      • Ramaswamy S
      • Ramachandran S
      • et al.
      Angiogenic role for glycodelin in tumorigenesis.
      An inhibitor of TGF-β2 (overexpressed in many cancers) is in phase 1/2 cancer clinical trials.
      • Schlingensiepen KH
      • Fischer-Blass B
      • Schmaus S
      • Ludwig S
      Antisense therapeutics for tumor treatment: the TGF-beta2 inhibitor AP 12009 in clinical development against malignant tumors.
      Thrombospondin 1 is an endogenous angiogenesis inhibitor, although its expression in tumor stroma may render tumor cells insensitive to VEGF and help maintain tumor cell dormancy.
      • Kang SY
      • Watnick RS
      Regulation of tumor dormancy as a function of tumor-mediated paracrine regulation of stromal Tsp-1 and VEGF expression.
      Another endogenous angiogenesis inhibitor, PEDF, may have anti-invasive effects on tumor cells.
      • Fernandez-Garcia NI
      • Volpert OV
      • Jimenez B
      Pigment epithelium-derived factor as a multifunctional antitumor factor.
      MIF can stabilize HIF-1α, a factor central to cellular response to hypoxia.
      • Rendon BE
      • Willer SS
      • Zundel W
      • Mitchell RA
      Mechanisms of macrophage migration inhibitory factor (MIF)-dependent tumor microenvironmental adaptation.
      Galectin1 expression within tumors and the stromal tissues is positively correlated with cancer aggressiveness
      • Liu FT
      • Rabinovich GA
      Galectins as modulators of tumour progression.
      and a diminished T-cell response.
      • Rabinovich GA
      • Liu FT
      • Hirashima M
      • Anderson A
      An emerging role for galectins in tuning the immune response: lessons from experimental models of inflammatory disease, autoimmunity and cancer.
      Another soluble immunomodulator, soluble CD30, a member of the tumor necrosis superfamily of receptors and marker of TH2 polarization, is increased in women with normal pregnancies and reduced in those with preeclampsia and intrauterine growth retardation.
      • Kusanovic JP
      • Romero R
      • Hassan SS
      • et al.
      Maternal serum soluble CD30 is increased in normal pregnancy, but decreased in preeclampsia and small for gestational age pregnancies.
      In addition to being prognostic in patients with CD30+ classical Hodgkin lymphoma,
      • Casasnovas RO
      • Mounier N
      • Brice P
      • et al.
      Plasma cytokine and soluble receptor signature predicts outcome of patients with classical Hodgkin's lymphoma: a study from the Groupe d'Etude des Lymphomes de l'Adulte.
      soluble CD30 is a potential marker of chronic B cell hyperactivation and can predict those at risk of AIDS-associated non-Hodgkin lymphoma.
      • Breen EC
      • Fatahi S
      • Epeldegui M
      • Boscardin WJ
      • Detels R
      • Martínez-Maza O
      Elevated serum soluble CD30 precedes the development of AIDS-associated non-Hodgkin's B cell lymphoma.
      The identification of common immunomodulators helps expand the concept of tolerance in pregnancy and cancer beyond TH2 and toward a more complete understanding of chronic inflammation, angiogenesis, and immunologic privilege.

      IMPLICATIONS FOR CANCER THERAPEUTICS

      As a healthy pregnancy progresses toward parturition, several changes within the mother reflect a restoration of active, TH1-predominant immunity. Although Treg levels stay constant until the postpartum period,
      • Saito S
      • Sasaki Y
      • Sakai M
      CD4+CD25high regulatory T cells in human pregnancy.
      a gradual return of CD16+ NK cells is observed in late pregnancy.
      • Rukavina D
      • Podack ER
      • Rubesa G
      • Spanjol-Pandelo S
      • Randic L
      Down-regulated expression of perforin-positive/CD16+ cells in the peripheral blood lymphocytes in the first trimester of pregnancy and up-regulation at the end of pregnancy.
      Suppressed earlier in pregnancy, circulating cytotoxic γδ-T cells increase with the onset of labor.
      • Barakonyi A
      • Miko E
      • Varga P
      • Szekeres-Bartho J
      V-chain preference of gamma/delta T-cell receptors in peripheral blood during term labor.
      Interleukin 2 levels decrease while granulocyte macrophage colony—stimulating factor and interferon-γ increase through the third trimester and even more markedly at the onset of labor.
      • Vassiliadis S
      • Ranella A
      • Papadimitriou L
      • Makrygiannakis A
      • Athanassakis I
      Serum levels of pro- and anti-inflammatory cytokines in nonpregnant women, during pregnancy, labour and abortion.
      Increased expression of genes associated with acuteinflammation and neutrophil and monocyte influx has been observed in human fetal membranes at parturition.
      • Haddad R
      • Tromp G
      • Kuivaniemi H
      • et al.
      Human spontaneous labor without histologic chorioamnionitis is characterized by an acute inflammation gene expression signature.
      • Bollopragada S
      • Youssef R
      • Jordan F
      • Greer I
      • Norman J
      • Nelson S
      Term labor is associated with a core inflammatory response in human fetal membranes, myometrium, and cervix.
      Concomitant with an increase in the potent uterine contractile prostanoid PGF-2α, proinflammatory cytokines and MMPs prepare the uterus for labor.
      • Christiaens I
      • Zaragoza DB
      • Guilbert L
      • Robertson SA
      • Mitchell BF
      • Olson DM
      Inflammatory processes in preterm and term parturition.
      Markedly down-regulated at term compared with midgestation are genes involved in angiogenesis, such as angiopoietin 2.
      • Winn VD
      • Haimov-Kochman R
      • Paquet AC
      • et al.
      Gene expression profiling of the human maternal-fetal interface reveals dramatic changes between midgestation and term.
      Taken together, these changes support a transition from a TH2 to a TH1 polarity during the third trimester.
      In contrast, patients with advanced malignancies continue to experience a progressive failure of antitumor immunity, which has been associated with a TH2-polarization and VEGF-driven chronic inflammation.
      • Nevala WK
      • Vachon CM
      • Leontovich AA
      • Scott CG
      • Thompson MA
      • Markovic SN
      • Melanoma Study Group of the Mayo Clinic Cancer Center
      Evidence of systemic Th2-driven chronic inflammation in patients with metastatic melanoma.
      We have identified the expression of immunomodulatory genes known to be supportive of pregnancy in our own patients with metastatic melanoma via gene-expression profiling (unpublished data). We have also verified that these immunomodulatory genes are differentially expressed in melanoma vs benign melanocytic nevi in 2 independent publically available datasets from the National Center for Biotechnology Information/GenBank GEO database: GSE4587,
      • Smith AP
      • Hoek K
      • Becker D
      Whole-genome expression profiling of the melanoma progression pathway reveals marked molecular differences between nevi/melanoma in situ and advanced-stage melanomas.
      which was analyzed on the GeneChip Human Genome U133 Plus 2.0 Array platform (Affymetrix, Santa Clara, CA), and GSE3189,
      • Talantov D
      • Mazumder A
      • Yu JX
      • et al.
      Novel genes associated with malignant melanoma but not benign melanocytic lesions.
      which was analyzed on the GeneChip Human Genome U133 Array Set HG-U133A platform (Affymetrix). We selected approximately 70 immunomodulatory genes on the basis of our critical review of the obstetrics literature, log-transformed the raw data, and performed an analysis of variance on this gene set on Partek 6.4 software. A summary of results is listed in Table 2. Osteopontin and other important components of innate immunity such as TLR2 and TLR4 and PTX3 were significantly up-regulated in melanoma compared with benign nevi. Galectins 1 and 9 were also significantly up-regulated compared with nevi. Notably down-regulated in melanoma were genes known to be up-regulated in term placenta,
      • Winn VD
      • Haimov-Kochman R
      • Paquet AC
      • et al.
      Gene expression profiling of the human maternal-fetal interface reveals dramatic changes between midgestation and term.
      • Mikheev AM
      • Nabekura T
      • Kaddoumi A
      • et al.
      Profiling gene expression in human placentae of different gestational ages: an OPRU Network and UW SCOR Study.
      including LPL, FABP4, and FZD10 (a Wnt receptor). Overall, this pattern is supportive of our theory that tumor cells use similar mechanisms of immune escape as those cells of the developing placenta, although these similarities have not yet been studied in a systematic fashion. Given what we have learned about the similarities between the placenta and tumor microenvironment, we plan to next comprehensively evaluate changes in systemic immune homeostasis in pregnancy vs cancer in order to prioritize potential therapeutic targets. In particular, identifying immunologic distinctions between pregnancy and cancer will be critical for this process.
      TABLE 2Immunomodulatory Genes Differentially Expressed in Melanoma vs Benign Melanocytic Lesions
      IL-8 = interleukin 8. For expansion of all gene symbols, see Glossary to Genetics Terminology at the end of the article.
      Gene symbolGSE4587 fold change (melanoma vs benign nevi)P valueGSE3189
      GSE3189 used the Affymetrix HG-U133A GeneChip and therefore lacked some probes compared with the Affymetrix U133 Plus 2.0 array used by GSE4587.
      fold change (melanoma vs benign nevi)
      P value
      SPP177.4<.00120.3<.001
      IDO34.7<.001
      TIMP26.5<.0013.3<.001
      TLR26.0<.001
      MMP95.9.0032.5<.001
      IL-85.8.1363.7.007
      TLR46.0.018
      PTX34.4.037
        MIF4.1.0053.5<.001
      LGALS94.1.002
      LGALS13.7.0044.1<.001
        LPL1.4.752−3.2<.001
      FABP4−2.2.615−2.3.009
      FZD10−2.9.168−4.8<.001
      a IL-8 = interleukin 8. For expansion of all gene symbols, see Glossary to Genetics Terminology at the end of the article.
      b GSE3189 used the Affymetrix HG-U133A GeneChip and therefore lacked some probes compared with the Affymetrix U133 Plus 2.0 array used by GSE4587.

      CONCLUSION

      By comparing immunologic patterns throughout healthy pregnancies, and in particular the return to TH1-polarized immunity through the third trimester, with those patterns observed in advanced malignancies, we have an opportunity to learn potential mechanisms to overcome the burden of long-term antigenic exposure and immunologic exhaustion in patients with cancer. The challenge for investigators in this field will be to extend our observations beyond the TH1/TH2 paradigm in both pregnancy and cancer to a model that can both assess the status and guide treatment of malignancies in an individualized, rational, real-time manner. A critical need exists for the development of treatments aimed at all aspects of cancer: malignant proliferation, invasion, vasculogenic mimicry, angiogenesis, and immune privilege. Studying how all these aspects are orchestrated in the predictable, physiologic process of pregnancy can facilitate the search for novel cancer treatment strategies, from cytotoxic chemotherapy to biologic agents and immunologic adjuncts, in the often unpredictable and arduous fight against the pathologic process of cancer.

      Glossary of Genetics Terminology

      AKT
      v-akt murine thymoma viral oncogene homolog
      ALK
      anaplastic lymphoma receptor tyrosine kinase
      BCL2
      B cell chronic lymphocytic leukemia/lymphoma 2
      CDK
      cyclin dependent kinase
      CEACAM1
      carcinoembryonic antigen-related cell adhesion molecule 1 (biliary glycoprotein)
      CMET (also known as MET)
      met proto-oncogene (hepatocyte growth factor) receptor
      CSF
      colony-stimulating factor
      CSF1R
      CSF type 1 receptor
      CXCR4
      chemokine (C-X-C motif) receptor 4
      EGF
      epidermal growth factor (beta-urogastrone)
      ERK
      extracellular signal—related kinase
      FABP4
      fatty acid—binding protein 4
      FAK
      focal adhesion kinase
      FAS
      Fas (TNF receptor superfamily, member 6)
      FASL
      FAS ligand
      FCγIIIA
      FC gamma receptor III A
      FGF
      fibroblast growth factor
      FLT1
      fms-related tyrosine kinase 1 (vascular endothelial growth factor/vascular permeability factor receptor)
      FOXP3
      forkhead box P3
      FZD10
      frizzled homolog 10
      GRO-α
      growth-related oncogene α
      HGF
      hepatocyte growth factor
      HIF-1α
      hypoxia inducible factor 1α
      HSP27
      heat shock protein 27
      IDO
      indoleamine 2, 3 dioxygenase
      IGF
      insulinlike growth factor
      IGF1R
      IGF type 1 receptor
      ILT2
      Ig-like transcript 2
      JAK
      janus kinase
      LGALS1
      galactin 1
      LGALS9
      galactin 9
      LPL
      lipoprotein lipase
      MAPK
      mitogen-activated protein kinase
      MCP1
      monocyte chemoattractant protein 1
      MEK (also known as MAP2K)
      MAPK/ERK kinase
      MIF
      macrophage migration inhibitory factor
      Mig-7
      migration-induction protein 7
      MDM2
      mouse double minute 2
      MMP
      matrix metalloproteinase
      MTOR
      mammalian target of rapamycin
      MUC1
      mucin 1
      NF-κB
      nuclear factor κB
      p38
      tumor protein 38
      PAR1
      protease activated receptor 1
      PDGF
      platelet-derived growth factor
      PDGFR
      PDGF receptor
      PEDF
      pigment epithelial—derived factor
      PGE2
      prostaglandin E2
      PGF
      placental growth factor
      PI3K
      phosphoinositide-3 kinase
      PSG1
      pregnancy-specific glycoprotein 1
      PTX3
      pentraxin 3
      RANTES (also known as CCL5)
      regulated on activation, normal T-cell expressed and secreted
      RAF
      v-raf-1 murine leukemia viral oncogene homolog 1
      RAS
      rat sarcoma viral oncogene homolog
      SDF (also known as CXCL12)
      stromal-derived factor 1
      SPP1
      osteopontin
      STAT
      signal transducers and activator of transcription
      TGF
      transforming growth factor
      TIM3 (also known as HAVCR2)
      T cell immunoglobulin mucin 3
      TIMP2
      tissue inhibitor of metalloproteinase 2
      TLR
      toll-like receptor
      TNF
      tumor necrosis factor
      TRAIL
      TNF-related apoptosis-inducing ligand
      TRAILR
      TRAIL receptor
      uPA
      urokinase plasminogen activator
      VEGF
      vascular endothelial growth factor
      VEGFR
      VEGF receptor
      waf1/cip1 (also known as CDKN1A)
      cyclin-dependent kinase inhibitor 1A
      Wnt
      wingless/T-cell factor
      XIAP
      X-link inhibitor of apoptosis protein

      Author Interview

      Interview with Dr. Shernan Holtan

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