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REVIEW ARTICLE
Year : 2021 | Volume
: 5
| Issue : 2 | Page : 97-106
Insights into the pathogenesis of preeclampsia based on the features of placentation and tumorigenesis
Yun-Qing Zhu1, Xing-Yu Yan2, Hua Li3, Cong Zhang4
1 Shandong Provincial Key Laboratory of Animal Resistance Biology, College of Life Sciences, Shandong Normal University, Ji'nan, Shandong 250014, China
2 School of Medicine, Xiamen University, Xiamen, Fujian 361102, China
3 Department of Gynecology and Obstetrics, Ji'nan Maternity and Child Care Hospital, Ji'nan, Shandong 250000, China
4 Shandong Provincial Key Laboratory of Animal Resistance Biology, College of Life Sciences, Shandong Normal University, Ji'nan, Shandong 250014; Center for Reproductive Medicine, School of Medicine, Ren Ji Hospital, Shanghai Jiao Tong University; Shanghai Key Laboratory for Assisted Reproduction and Reproductive Genetics, Shanghai 200135, China
Correspondence Address:
Cong Zhang
Shandong Provincial, Key Laboratory of Animal Resistance Research, College of Life Science, Shandong Normal University, 88 East Wenhua Road, Ji'nan, Shandong 250014
China
Source of Support: None, Conflict of Interest: None
DOI: 10.4103/2096-2924.320886
Placentation and tumorigenesis have many common features. Human placentation builds a maternal–fetal connection, circumvents maternal immune rejection of the fetus, and utilizes mechanisms that support tumorigenesis, such as proliferation, invasion, angiogenesis, and immune tolerance. Trophoblasts of the human placenta mimic the behavior of malignant cells, proliferating and invading the uterine decidua until reaching the myometrium and remodeling the spiral arteries that establish a new vascular system and escape the maternal immune response. These processes are under precise temporal and spatial regulation, and their dysregulation is associated with different pregnancy syndromes, including preeclampsia (PE), a pregnancy syndrome that is the leading cause of maternal and perinatal mortality and morbidity. At present, the precise mechanisms underlying the development of PE remain unclear. Here, we summarize and dissect the features between physiological placentation and pathological tumorigenesis to explore the pathogenesis of PE – which we believe to be the result of insufficient placentation, compared to the overaggression of tumorigenesis – to provide novel strategies to prevent and treat PE.
Keywords: Pathogenesis; Placentation; Preeclampsia; Tumorigenesis
Preeclampsia (PE) is a multisystem disease that affects 3%–5% of primiparas and is the leading cause of maternal and perinatal mortality and morbidity.[1],[2] Clinically, maternal symptoms include hypertension, proteinuria, kidney and liver dysfunction, and edema. PE is also responsible for increased risk of intrauterine growth restriction (IUGR), iatrogenic preterm birth, and placental abruption.[3] In addition, both mothers and children are likely to be affected by long-term cardiovascular complications.[4] Since these symptoms disappear with the stripping of placental tissue during delivery, it has been proposed that the placenta, under pathological conditions, may be the leading cause of PE pathogenesis.[5]
In several studies, a two-stage model has been proposed to explain the pathogenesis of PE [Figure 1]. The first stage involves abnormal placentation during early gestation.[6] During this stage, shallow interstitial trophoblast invasion is the main pathological manifestation, and endovascular extravillous trophoblasts (enEVT) are insufficient for remodeling spiral arteries.[7],[8] Therefore, placental development falls behind the fetal need for nutrients and oxygen. The second stage generally involves the maternal response to abnormal placentation, wherein maternal release factors (e.g., antiangiogenesis factors, pro-inflammatory factors, and autoantibodies) lead to systemic endothelial dysfunction, which is considered the main manifestation of PE. Subsequently, maternal hypertension, proteinuria, and other symptoms gradually develop.[9] After in-depth research on the pathogenesis of PE, Redman posited that the “two-stage model” did not fully reflect the pathogenesis of PE, and accordingly, they proposed a more detailed “six-stage model” in 2014.[10] The first stage lasts from fertilization to embryo implantation. In this relatively short period, the mother has poor immune tolerance to the paternal genes of the embryo. The second stage lasts from the 8th to 18th week of pregnancy, a critical period for placentation; abnormal placenta formation is considered a fuse that triggers PE. During this period, trophoblasts begin to invade the uterine spiral artery. Once the placenta is abnormally formed, it enters the third stage of PE, and a stress response occurs. The fourth stage is in the second half of pregnancy; at this stage, various placenta-derived injury factors are released into the maternal blood circulation. Once clinical symptoms such as high blood pressure appear, PE can be diagnosed in the fifth stage. Less than half of patients with PE enter the sixth stage. During this period, the condition rapidly worsens, the spiral artery rapidly develops atherosclerosis, and placental perfusion is further reduced, inducing spiral artery thrombosis and placental infarction. The more detailed time division of the “six-stage model” provides a solid theoretical foundation for studying the key molecular mechanisms of the mother–fetal dialog and temporal and spatial specificity of energy conversion, and it can better explain both early- and late-onset PE (clinical signs before or after 34 weeks of gestation). Early-onset PE has been linked to poor placentation, while late-onset PE is suggested to result from maternal factors.[11] Currently, our first challenge in confronting PE is to understand its precise pathogenesis, optimize prenatal detection, and obtain effective drugs without side effects on fetal development. In this review, we evaluated abnormal placentation in the pathogenesis of PE combined with mechanisms that are similar to tumor proliferation, invasion, angiogenesis, and immune tolerance during normal placental development.
Figure 1: A two-stage model illustrating the pathogenesis of preeclampsia. In the first stage, a defective placenta is caused by abnormalities or insufficiency in proliferation, invasion, angiogenesis, and mechanisms involved in immune tolerance. In the second stage, insufficient placental perfusion results in the release of maternal factors into the circulation, leading to systemic endothelial dysfunction as well as the induction of maternal hypertension, proteinuria, and other symptoms. Placentation and Tumorigenesis Placentation and tumorigenesis, like birth and death, appear to be two opposite processes, but they share many physiological mechanisms of progression. Human pregnancy begins with the attachment of a blastocyst to the decidua, rather than the fertilization of an oocyte.[12] In humans, before attachment occurs, the endometrium transforms into specialized secretory decidua, a process known as decidualization. Decidualization begins near the spiral artery and gradually extends to the entire endometrium. This process is regulated by various cytokines and hormones, and it is essential for embryo implantation, placental implantation, and maintenance of pregnancy. Meanwhile, primitive cytotrophoblasts (CTBs) of the trophectoderm of the blastocyst have proliferative and undifferentiated properties that produce differentiated trophoblasts in two ways. First, mononuclear CTBs are fused into multinucleated syntrophoblasts (STBs) that cover the surface of floating villi immersed in maternal blood. STBs are responsible for the secretion of pregnancy-related hormones (e.g., human chorionic gonadotropin and progesterone) as well as the exchange of nutrients and metabolic waste between the maternal and fetal circulation. In addition, STBs play an important role in preventing maternal immune rejection of the fetus. Second, CTBs continue to proliferate to form anchored villi attached to the uterine wall.[13],[14] After the villi are anchored to the maternal decidua, where invasion and migration are initiated, CTBs that detach from placental villi invade the decidua and are called extravillous trophoblasts (EVTs).
A subset of EVTs invades the deep layers of the endometrium until reaching one-third of the myometrium; these cells are called interstitial EVTs (iEVTs). enEVT is another type of EVT with endothelial-like characteristics, which replaces the vascular endothelial cells (VECs) and vascular smooth muscle cells (VSMCs) of spiral arteries. Several trophoblasts form trophoblast plugs and block the spiral arterial ostium to prevent maternal blood from entering the interstitial space, thereby maintaining the hypoxic environment that is required for villus growth.[15] After 12–13 weeks of pregnancy, the arteries open and maternal blood flows into the intervillous spaces to establish maternal–fetal circulation. Establishment of open blood circulation is completed after 20–22 weeks of pregnancy, and the spiral artery is transformed into low-resistance, high-capacity arteries, thereby ensuring the nutrition required for fetal growth.[16] Notably, although the fetus constitutes a semi-allograft of the maternal immune system, trophoblasts can escape maternal immune detection.[17] Ultimately, a cascade of these processes leads to placental development.
In general, the development of solid tumors occurs in three stages: initiation, promotion, and progression, all of which are accompanied by complex and dynamic cellular events.[18] The initiation stage involves the stimulation of oncogenic factors, leading to genetic and epigenetic changes in tissue-specific stem cells or somatic cells. These changes can affect oncogenes, tumor suppressor genes, and genes associated with DNA repair mechanisms, which transform tissue-specific stem cells or somatic cells into cancer stem cells (CSCs). CSCs self-renew and differentiate into tumor cells.[19] As the disease progresses, tumor cells continue to proliferate and form new blood vessels from the original tumor site, thereby promoting tumor development. Subsequently, the tumor microenvironment provides signals that support tumor growth. At this point, tumors are no longer limited to local tissues; they search for new tissues to initiate new tumor sites through metastasis to fulfill their growing need for survival.[20]
Tumor cells proliferate uncontrollably, invade normal tissues, establish a new vascular network, and evade the immune response of the host. Interestingly, the tumor microenvironment encounters a situation similar to that found at the maternal–fetal interface, namely, hypoxia and lack of blood supply. Although the placenta is considered “a normal tissue,” trophoblasts are defined as “pseudo-malignant.”[21] Trophoblasts of the placenta and malignant tumor cells have similar features, including high proliferation, invasion, angiogenesis, and immune tolerance [Figure 2].[22],[23] Therefore, in pathophysiological processes, comparable molecular mechanisms can be evaluated between placentation and tumorigenesis to explore the pathogenesis of PE.
Figure 2: Schematic illustration of the common features shared by placentation and tumorigenesis. During placentation, trophoblasts proliferate, invade the uterine decidua and myometrium, remodel the spiral artery, and escape maternal immune rejection at the maternal–fetal interface. This series of physiological processes is similar to the pathological processes that tumor cells use to proliferate, invade host tissues, accomplish angiogenesis through vascular mimicry, and evade host immune rejection in the tumor microenvironment during tumorigenesis. EVTs: Extravillous trophoblasts; iEVTs: Interstitial extravillous trophoblasts; enEVTs: Endovascular extravillous trophoblasts; VECs: Vascular endothelial cells; VM: Vascular mimicry. Proliferation During placental development, CTBs continue to proliferate to form anchoring villi and provide adequate cells to form STBs. The underlying CTBs update and supplement aged nonproliferative STBs through continuous proliferation and fusion.[24] In addition, CTB proliferation leads to the formation of anchored villi that attach blastocysts to the decidua. Before tumor formation, various carcinogenic factors cause tissue-specific stem cells or somatic cells to lose their normal growth regulation at the gene level and transform into CSCs. CSCs proliferate to form local lesions, which ultimately leads to tumorigenesis. The mechanisms of proliferation of CTBs in the placenta as well as malignant tumor cells are strikingly similar.
During placentation and tumorigenesis, both trophoblasts at the maternal–fetal interface and tumor cells in the tumor microenvironment are in a hypoxic environment. In response to low oxygen levels, cells upregulate hypoxia-inducible factor (HIF) expression and activate the vascular endothelial growth factor (VEGF)-VEGFR1 signaling pathway to promote cell proliferation.[25] Insulin-like growth factor (IGF) pathways contribute to the proliferation of both CTBs and malignant cells through the MAPK and PI3K pathways. Under normal physiological conditions, IGF levels are strictly regulated by IGF-binding proteins.[26] Depletion of binding proteins may lead to a malignant phenotype and subsequently initiate tumor formation.[27] Studies have also confirmed low IGF-1 expression and high IGF-2 and IGFBP-3 levels in the placental tissue of PE patients.[28] These findings may reveal abnormalities in the proliferation of placental trophoblasts. In addition to these pathways, in this review, we mainly discuss telomerase activity, survivin overexpression, and the Warburg effect.
Telomerase
Tumor cells have an infinite life span and continue to divide until their host dies, compared to normal human cells, the proliferative capacity of which is limited. Both telomeres and telomerases play an important role in this process.[29] Telomeres are DNA–protein complexes present at the end of chromosomes of eukaryotic cells, and they maintain chromosome stability and control cell division. Telomerase, a basic nuclear protein reverse transcriptase, is responsible for telomere elongation.[30] Telomerase activity is undetectable in normal somatic cells, whereas increased telomerase activity is observed in most human cancers. Intracellular telomerase concentration often reflects cellular proliferative capacity.[31] During pregnancy, telomerase activity changes with placental development; it is the highest in early pregnancy and decreases with placental maturation.[32] Studies have shown a reduction in telomerase content and shortened telomeres in trophoblasts from patients with PE and IUGR.[33],[34]
Survivin
Survivin is an apoptosis inhibitor located on the mitochondrial membrane. Survivin is overexpressed in many tumors to regulate tumor cell proliferation.[35] It is also upregulated in trophoblasts.[36],[37] Inhibition of survivin expression in vitro, i.e., in cultured trophoblasts and tumor cells, decreases their proliferation.[38] Several studies have shown that survivin levels in late pregnancy are significantly lower in a PE pathological placenta than in a normal placenta.[39] This may explain the large number of apoptotic STBs entering the maternal circulation, leading to endothelial cell activation and consequently triggering PE.[40]
Warburg effect
Normal cells rely on mitochondrial oxidative phosphorylation to provide energy. However, most tumor cells perform aerobic glycolysis to provide energy to meet their proliferation needs. This phenomenon is known as the Warburg effect.[41] The Warburg effect produces a large amount of lactic acid, which is stored in the biomass through the pentose phosphate pathway and is used as a substance required for cell proliferation.[42] The Warburg effect occurs not only in tumorigenesis but also in decidualization and placentation. Decidualization refers to the differentiation of endometrial stromal cells into enlarged and round-shaped decidual cells, and this process plays a vital role in embryo implantation and placental development.[43] Although decidualization involves mainly cell differentiation, it also requires the storage of biomass. Previous studies have shown that many genes and factors related to aerobic glycolysis are induced during decidualization, revealing that the process of decidualization requires the Warburg effect to provide energy.[44] In the early stages of human pregnancy, the maternal–fetal interface in a hypoxic environment induces HIF1α expression. Subsequently, HIF1α induces the expression of various glycolytic-related genes in trophoblasts, including GLUT1, PDK1, LDHA, and MCT4.[45],[46] During a pathological pregnancy, maternal decidualization defects often trigger PE.[47],[48] Specifically, abnormal energy metabolism affects decidualization and is thus involved in PE development.[49] In addition, defective placentation is involved in the pathogenesis of PE. HIF1α is highly expressed in the placenta of PE patients, and it upregulates the expression of LDHA and MCT4 in the placenta, ultimately leading to excessive plasma lactate levels in these patients.[46] Studies have also shown that an excessive Warburg effect during mid-pregnancy will increase the uptake of maternal glucose in the placenta, leading to fetal hypoglycemia and impaired fetal development,[50] and increase their metabolic rates as well as glucose uptake to maintain their proliferation.
InvasionDuring physiological placentation, EVTs shedding from the placental anchored villi invade the decidua.[51] Interstitial extravillous trophoblasts (iEVTs) migrate to the deeper layers of the maternal endometrium and even into the inner third of the myometrium. Endovascular trophoblasts (enEVTs) remodel the spiral artery, which we will discuss in the “Angiogenesis” section. In pathological tumorigenesis, tumor cell invasion occurs at the primary tumor site through the endothelial barrier; tumor cells penetrate the blood vessel, enter the circulation, and then transform into malignant cells in distant tissues to form new tumor sites.[52] Thus, in placentation and tumorigenesis, two different types of cells utilize similar strategies.
Epithelial–mesenchymal transition
Epithelial–mesenchymal transition (EMT) refers to the transformation of epithelial cells into mesenchymal cells, which changes cell activity from cell adhesion to invasion. EMT has previously been observed in physiological and pathological processes, including tumorigenesis, embryonic development, and tissue repair. The EMT process involves many changes in gene expression, including the suppression of epithelial genes and induction of mesenchymal genes.[53] EMT is used by both tumor cells and trophoblasts to promote invasion.[54],[55] In the placenta, E-cadherin mediates strong intercellular interactions between CTBs.[56] When EVTs invade decidual endometrial tissue, E-cadherin expression is gradually reduced and N-cadherin expression is increased, achieving a balance in order to meet the needs of invasion. This pattern has also been observed in most epithelial cancer cells. In fact, E-cadherin is an inhibitor of invasion and metastasis of epithelial cancer cells, and its elimination represents the ability to acquire invasion and metastasis.[57] During pregnancy, dysregulation of trophoblast EMT events results in poor trophoblast invasion.[58] Previous studies have also shown that expression of the epithelial marker E-cadherin was increased, and the mesenchymal marker N-cadherin was decreased, in the placental tissue of PE patients.[59] Furthermore, inadequate EVT invasion usually results in the shallow placental implantation associated with PE.[60] Together, these findings suggest that EMT of trophoblasts occurs in PE.
Extracellular matrix and proteases
The extracellular matrix (ECM) is a dynamic network of macromolecules (including collagen and glycoproteins) that play a vital role in cell invasion. Trophoblast invasion and malignant tumor cell invasion are complex processes that include the attachment of trophoblasts and tumor cells to the ECM, and the subsequent degradation of the ECM.[61] Interestingly, trophoblasts and malignant cells share similar enzymatic mechanisms during invasion.[21],[62],[63] Matrix metalloproteinases (MMPs) exhibit proteolytic activity and are involved in the invasive efficiency of trophoblasts and tumor cells. Among the MMP family members, MMP-2 and MMP-9 are important in tumor cell invasion and metastasis and are also involved in trophoblast invasion.[64] During invasion and metastasis, urokinase-type plasminogen activator (uPA) is highly expressed in many metastatic tumors.[65] Trophoblasts also produce uPA to degrade the endometrial ECM, thereby ensuring successful implantation of embryos.[66] The expression of MMP-2 and MMP-9 in the placenta of PE patients is lower than in the normal placenta,[67] which may weaken the invasion of trophoblasts.[68] Interfering with MMP-9 expression using miRNAs destroys the invasion of trophoblasts.[69] Moreover, MMP-9 deficiency results in an abnormal placenta and similar PE symptoms in mice.[70] In addition, dysfunctional uPA/uPAR leads to abnormal trophoblast invasion and contributes to the development of PE.[71]
Integrin
Integrins are the main cell adhesion receptors. They consist of 24 αβ heterodimer members generated from a combination of 18α integrin and 8β integrin subunits. Integrins contribute to cell–ECM interactions and extracellular signal transduction during physiological development and pathological processes.[72] During embryonic development, wound healing, or angiogenesis, cell movement increases, and the expression profiles of integrins also change. In tumorigenesis, highly aggressive tumor cells also show altered integrin expression patterns, commonly referred to as integrin switching.[73] Different integrins can bind to the same ligand to activate different signal transduction pathways in cells. Therefore, the expression patterns of integrins on the cell surface under the influence of the microenvironment are the key to determining cell behavior.[74]
The expression patterns of integrins also change with trophoblast invasion. Interleukin (IL)-1β, tumor necrosis factor-alpha, and interferon-γ have been reported as integrin regulatory signaling molecules in the process of invasion in placentation and tumorigenesis.[75],[76] These signaling molecules that act on EVTs downregulate α6β4 integrin (a receptor for epithelial laminin) and initiate the expression of fibronectin receptor α5β1 integrin during invasion.[77] When EVTs enter the uterine wall, they express α1β1 integrin (a receptor for laminin and type IV collagen), which endows EVTs with an invasive phenotype.[78] Altered integrin expression patterns have also been observed during tumor cell invasion.[79],[80] In particular, both CTBs and certain types of metastatic tumors express αV integrin, which contributes to both invasion and metastasis.[77] In PE, EVTs in the decidua fail to downregulate integrin α6β4 or upregulate integrin α1, which are important features during normal placentation.[56] These findings emphasize the importance of an altered integrin phenotype in PE pathogenesis.
Vessel RemodelingAngiogenesis, the formation of new blood vessels based on original blood vessels, is required for a wide variety of physiological and pathological processes.[81] In adults, angiogenesis occurs during wound healing and, under strict regulation, in the female reproductive system.[82] During a physiological pregnancy, fetal growth requires increased uterine blood flow perfusion to achieve nutrient and oxygen exchange. This process involves remodeling of the spiral artery, in which enEVTs invade the spiral arterial wall, then destroy the matrix, and replace VECs and VSMCs, transforming the spiral artery into a low-resistance, high-capacity blood vessel.[83] Under pathological conditions, tumorigenesis, tumor growth, and metastasis are dependent on angiogenesis.[84] During placentation, angiopoietin and VEGF family members play an important role in spiral artery remodeling, and the same molecules are employed during tumor angiogenesis.[85] Clinically, antiangiogenic drugs are commonly used to treat malignant tumors. The drugs that inhibit the classical angiogenic VEGF-VEGFR pathway can cause side effects such as hypertension and proteinuria in cancer patients.[86] These side effects during cancer treatment are also the main symptoms of PE. These findings may extend our understanding of insufficient angiogenesis in PE.
Vasculogenic mimicry
During tumorigenesis, tumor cells invade surrounding tissues and further differentiate and display a vascular phenotype to participate in the process of neovascularization, a process that is termed vasculogenic mimicry (VM).[87] Coincidently, when EVTs invade maternal spiral arteries, they also differentiate and display a vascular phenotype to accomplish spiral artery remodeling.[88],[89] It has previously been confirmed that VM mimics the embryonic vascular network model and supplies a sufficient amount of blood to tumor tissues.[90] Glycan-binding proteins galectin-1 and galectin-3, which are highly expressed in both EVTs and malignant tumor cells, are involved in the formation of VM and contribute to the process of angiogenesis.[91],[92],[93],[94] In addition, expression of MIG-7 is associated with cancer cells and enEVTs in VM.[95] In previous studies, it was reported that interfering with galectin-1-mediated angiogenesis in mice led to the onset of PE symptoms, determined by damage to decidual angiogenesis and spiral artery remodeling.[96] Taken together, these findings show that the formation of vascular structures may be affected in patients with PE.
Adhesion molecules
Adhesion molecules are responsible for the interaction between cells and the extracellular environment and form a normal tissue structure. Adhesion molecules include five families: cadherins, catenins, integrins, immunoglobulin superfamily, and nonclassical adhesion molecules.[97] Cadherins are important adhesion molecules that mediate cell–cell adhesion, and among them, the most intensely studied is E-cadherin. Catenin includes α-catenin, β-catenin, γ-catenin, and δ-catenin. Integrin is involved in the interaction between cells and ECM. The participation of cadherins, catenin, and integrin in the invasion process has been described earlier. In this section, we focus on the immunoglobulin superfamily, which includes vascular endothelial cadherin (VE-cadherin), vascular cell adhesion molecules (VCAM-1), platelet endothelial cell adhesion molecules (PECAM-1), and nerve cell adhesion molecules (NCAM). During the process of spiral artery remodeling, the expression patterns of adhesion molecules change. Trophoblasts tend to express vascular endothelial molecules instead of epithelial-type molecules.[98] VE-cadherin maintains tight junctions between endothelial cells[99] and is upregulated in enEVTs during remodeling of the spiral artery.[88] It has also been confirmed that aggressive melanoma cells intensively express VE-cadherin during tumor angiogenesis.[100] In addition, expression of VCAM-1 and PECAM-1 also increases with differentiation of EVTs into enEVTs.[56] Similarly, during tumor angiogenesis, expression of VE-cadherin and PECAM-1 also changes.[101],[102] During angiogenesis, tumor cells and trophoblasts have similar expression patterns of some adhesion molecules. Surprisingly, inappropriate expression of specific adhesion molecules has also been implicated in the pathogenesis of PE. It has previously been shown that CTBs fail to express proper adhesion molecules, such as VE-cadherin, VCAM, PECAM, and nerve cell adhesion molecules, which affect remodeling of the spiral artery.[88]
Immune TolerancePregnancy is a complex physiological process in which the maternal immune system undergoes a series of changes to maintain immune tolerance to the fetus. Tumor cells also evade host immune rejection when invading the host tissues. Studies have revealed that the immune tolerance mechanisms that sustain trophoblasts in placentation and malignant cells in tumorigenesis are similar.[103] Specifically, key immune cell types are similar when residing at the maternal–fetal interface and in the tumor microenvironment. In addition, immunosuppressive patterns are parallel in trophoblasts during placentation and tumor cells during tumorigenesis. Previous investigations have often applied this similarity to oncology to understand tumor progression from an immunological perspective. However, these mechanisms are rarely used to identify immune disorders in PE. A deeper understanding of this similarity may extend our understanding of immunodeficiency in the pathogenesis of PE.
Immune cells at the maternal–fetal interface and in the tumor microenvironment
The maternal–fetal interface is the contact surface between the uterine decidua and the extraembryonic tissue of a developing conceptus.[104] The tumor microenvironment is the cellular environment where the tumor is located and is composed of related cells and extracellular components.[105] The maternal–fetal interface and the tumor microenvironment both demonstrate hypoxia and insufficient blood supply during placentation and tumorigenesis. The main immune cell types participating in the immune response, which reside at the maternal–fetal interface and in the tumor microenvironment, are also similar, including natural killer (NK) cells, macrophages, regulatory T-cells, and dendritic cells. In humans, uterine NK cells at the maternal–fetal interface account for approximately 70% of all immune cells. It is generally believed that uterine NK cells are recruited from peripheral blood. They are distinct from peripheral blood NK cells because of their CD56+ CD16− cell surface phenotype.[106] High infiltration of CD56+ CD16− NK cells was also observed in tumors. Tumor-associated NK cells are similar to uterine NK cells in terms of cytokine production and reduced cytotoxic activity.[107] Previous studies have shown that an imbalance between cytotoxicity and regulatory NK cells may trigger PE.[108] Macrophages are the second most abundant immune cell population (approximately 20% of total immune cells). Macrophages at the maternal–fetal interface can phagocytose apoptotic CTBs and secrete IL-10 and indoleamine-2,3-dioxygenase to promote the immune environment of Th2-resistance. Moreover, tumor-associated macrophages are characterized by inflammatory and immunosuppressive properties and promote Th1–Th2 polarization via the NF-κB pathway.[109] Regulatory T-cells and dendritic cells also play important roles in pregnancy and tumor tolerance. Regulatory T-cells express CD4 and CD25 in both the decidua and peripheral blood.[110] Regulatory T-cells are also implicated in impaired antitumor immunity and suppression of effector T-lymphocyte proliferation. During normal pregnancy, a reduction in lymphocyte subsets is associated with spontaneous abortion and PE.[111] The role of dendritic cells in pregnancy is extremely complex. Ablation of uterine dendritic cells leads to abnormal decidualization and embryo absorption in mice.[112]
Immunosuppressive pattern
In addition to similar immune cell types regulating immune tolerance at the maternal–fetal interface and the tumor microenvironment, trophoblasts and tumor cells actively participate in immune regulation. To circumvent the immune regulation of T-cells, trophoblasts fail to express major histocompatibility complex (MHC) class I molecules. Similarly, malignant tumor cells downregulate MHC I to escape T-cell immune responses.[113] Moreover, trophoblasts reduce the expression of HLA class I cell surface proteins, but express nonclassical HLA, including HLA-C, HLA-E, and HLA-G, which are known as NK cell surface inhibitory receptors that transmit an inhibitory signal to reduce the cytotoxicity of NK cells.[114],[115] PE is implicated in immune tolerance imbalance, in which maternal immune responses to the fetus change from the condition of tolerance to inflammation. A prominent feature of patients with PE is that the expression of HLA-G protein in the placenta is lower than during a normal pregnancy. Defects of HLA-G can promote invasiveness and vascular formation at the maternal–fetal interface, which reveals a role for HLA-G in preventing the occurrence of PE.[116] In addition, trophoblasts and tumor cells express many immunosuppressive factors, including transforming growth factor-beta, IL-10, and VEGF, to suppress T-cell differentiation. This promotes tilting of the Th1–Th2 balance to Th2, as well as subsequent induction of specific immune tolerance.[117] In some mouse models of PE, the pathological placenta is often accompanied by a decrease in IL-10 levels and an increase in angiotensin II type I receptor agonistic autoantibodies.[118] In addition, Fas and FasL have a similar mechanism of regulating immune tolerance in trophoblasts and tumor cells. To induce apoptosis of immune cells and evade immune surveillance, it is important for tumor cells to downregulate the expression of Fas and upregulate the expression of FasL. Fas and FasL also participate in maternal immune cell apoptosis in the human and mouse trophectoderm.[119],[120] Clinical studies have shown that expression levels of FasL are lower in the placenta of IUGR and PE patients, revealing that a Fas/FasL imbalance contributed to the development of IUGR and PE.[121]
ConclusionAs a common reproductive disease, PE is often associated with abnormal placentation. Physiological placentation and pathological tumorigenesis share many molecular mechanisms. Identifying common features between placentation and tumorigenesis will improve our understanding of complex life phenomena. Several abnormal or insufficient processes initiate the pathological placentation of PE and the overaggressive growth of tumorigenesis; this is reflected mainly in the processes of proliferation, invasion, angiogenesis, and immune tolerance [Figure 3]. Downregulation of telomerase and survivin expression, in addition to abnormal energy metabolism (Warburg effect), affect the proliferation of trophoblasts. Abnormal expression patterns of proteases and integrins involved in EMT affect trophoblast invasion. In addition, pathological trophoblasts that fail to express the adhesion molecule, IgSF, affect the remodeling of spiral arteries. In addition to proliferation, invasion, and angiogenesis, immune tolerance disorders are also involved in the pathogenesis of PE, and abnormal expression of immune-related molecules affects maternal immune tolerance to the fetus. In previous studies, these comparable mechanisms have generally been applied to oncology studies, while studies of pregnancy disorders have been neglected. Therefore, considering that PE is a common and severe pregnancy syndrome, by comparing the mechanisms of pathological placenta formation and tumorigenesis, we provide a novel research idea by analyzing the pathogenesis of PE from the perspective of oncology, which may help us gain an in-depth understanding of PE.
Figure 3: Schematic summary of the pathogenesis of preeclampsia from the perspective of placentation and tumorigenesis. Compared with a normal pregnancy, preeclampsia is characterized mainly by shallow trophoblast invasion, insufficient remodeling of the spiral artery, and an abnormal immune tolerance environment, which leads to abnormal placentation. Among the common features of placentation and tumorigenesis, abnormal or insufficient physiological processes involved in proliferation, invasion, angiogenesis, and immune tolerance in normal pregnancy are known to trigger preeclampsia. EVTs: Extravillous trophoblasts; iEVTs: Interstitial extravillous trophoblasts; enEVTs: Endovascular extravillous trophoblasts; VECs: Vascular endothelial cells.Financial support and sponsorship
This study was supported by grants from the National Key R&D Program of China (2019YFA0802600 and 2017YFC1001403) and NSFC (31871512 and 31671199) to CZ. Support was also obtained by the Shanghai Commission of Science and Technology (17DZ2271100).
Conflicts of interest
There are no conflicts of interest.
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