1095537 research-article2022 WHE0010.1177/17455057221095537Women’s HealthEspañol et al. Review Women’s Health Neural plasticity of the uterus: Volume 18: 1­–13 © The Author(s) 2022 Article reuse guidelines: New targets for endometrial cancer? sagepub.com/journals-permissions DOI: 10.1177/17455057221095537 https://doi.org/10.1177/17455057221095537 journals.sagepub.com/home/whe Pia Español1,2 , Rocio Luna1,2, Cristina Soler1,2, Pablo Caruana1, Amanda Altés-Arranz1, Francisco Rodríguez1, Oriol Porta1,2, Olga Sanchez3,4, Elisa Llurba2,3,4, Ramón Rovira1,2* and María Virtudes Céspedes1,5* Abstract Endometrial carcinoma is the most common gynecological malignancy in Western countries and is expected to increase in the following years because of the high index of obesity in the population. Recently, neural signaling has been recognized as part of the tumor microenvironment, playing an active role in tumor progression and invasion of different solid tumor types. The uterus stands out for the physiological plasticity of its peripheral nerves due to cyclic remodeling brought on by estrogen and progesterone hormones throughout the reproductive cycle. Therefore, a precise understanding of nerve- cancer crosstalk and the contribution of the organ-intrinsic neuroplasticity, mediated by estrogen and progesterone, of the uterine is urgently needed. The development of new and innovative medicines for patients with endometrial cancer would increase their quality of life and health. This review compiles information on the architecture and function of autonomous uterine neural innervations and the influence of hormone-dependent nerves in normal uterus and tumor progression. It also explores new therapeutic possibilities for endometrial cancer using these endocrine and neural advantages. Keywords autonomic nervous system, endometrial cancer, nerve-cancer, nerve plasticity, neuroreceptor, neurotherapy, neurotransmitter, sex hormones signaling Date received: 12 November 2021; revised: 28 March 2022; accepted: 1 April 2022 Introduction 1  ynecology and Oncology Peritoneal Group, Institut d’Investigacions G Nerve-cancer interaction was first described in the pain Biomèdiques Sant Pau, Hospital de la Santa Creu i Sant Pau, Barcelona, process associated with cancer progression1 and perineu- Spain 2 Department of Obstetrics and Gynecology, Hospital de la Santa Creu ral invasion (PNI), which cancer cells use as a track to i Sant Pau, Barcelona, Spain disseminate.2 Over recent decades, nerve-cancer cross- 3 Women and Perinatal Health Research Group, Obstetrics and talk as a contributor to the tumor microenvironment has Gynaecology Department, Hospital Sant Pau and Universitat come to be seen as an important key-player. It is where Autònoma de Barcelona, Barcelona, Spain 4 activated downstream signaling pathways stimulate can- Maternal and Child Health and Development Network, Instituto Salud Carlos III, Madrid, Spain cer cells to grow and migrate.3 5 CIBER de Bioingeniería, Biomateriales y Nanomedicina (CIBER-BBN), Tumors interplay with nerves to stimulate and main- Barcelona, Spain tain nerve infiltration through a paracrine mechanism *Ramón Rovira and María Virtudes Céspedes provided equal co-author involving the secretion of growth factors driving to neu- contribution. rogenesis.4 Reciprocally, cancer cells use nerves to acti- vate angiogenesis and contribute to immune modulation Corresponding authors: María Virtudes Céspedes, Gynecology and Oncology Peritoneal Group, and to tumor dissemination through the release of cat- Institut d’Investigacions Biomèdiques Sant Pau, Hospital de la Santa echolamines like noradrenaline, epinephrine, dopamine, Creu i Sant Pau, 08041 Barcelona, Spain. acetylcholine, and neurotrophic factors induced by can- Email: mcespedes@santpau.cat cer and stromal cells.5,6 Pia Español, Department of Obstetrics and Gynecology, Hospital de la The active crosstalk between nerves and tumor cells was Santa Creu i Sant Pau, 08025 Barcelona, Spain. first demonstrated in prostate7 and gastric8 cancers, and Email: pia.espanol.lloret@gmail.com Creative Commons Non Commercial CC BY-NC: This article is distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 License (https://creativecommons.org/licenses/by-nc/4.0/) which permits non-commercial use, reproduction and distribution of the work without further permission provided the original work is attributed as specified on the SAGE and Open Access pages (https://us.sagepub.com/en-us/nam/open-access-at-sage). 2 Women’s Health recently extended to other types of cancer. In cancer, the the autonomic nervous system (Figure 1(a)). actions of the sympathetic and parasympathetic nervous Macroscopically, the uterus can be divided into the body or systems seem complementary and not in opposition, a well- corpus and the cervix. Laterally, it is connected to the ova- known and accepted relationship in human physiology.3 For ries by the fallopian tubes. The uterine corpus is composed example, the sympathetic nerves stimulate the early stages of three main tissue layers. The endometrium is the inner of cancer progression while the parasympathetic nerves lining that goes through morphologic and functional activate cancer cell dissemination at later stages.7 changes during the hormonal cycle. Two different stratums Furthermore, it is known that the density of sympathetic and can be distinguished. The basal one that is adhered to the parasympathetic nerves infiltrating the microenvironment is myometrium and the functional layer that proliferates and greater in prostate, colorectal, and breast tumors. Moreover, then sheds during the menstrual cycle. Moreover, the it has been associated with tumor aggressiveness, poor clini- endometrium plays an important role during embryo cal outcomes as well as decreased patient survival.9–11 implantation in pregnancy.17 The second layer, the myo- Parallel to the prognostic relevance of endometrial can- metrium, is composed of smooth muscle cells (myocytes) cer (EC), the therapeutic implication of neural control distributed in longitudinal fibers in the outer position and emerges as a new paradigm for treatment and cancer pre- circular or oblique fibers in the internal part. Finally, the vention. Denervation of the primary tumor by the destruc- outer layer is known as the serosa and is composed of epi- tion of both the sympathetic (adrenergic) and parasympathetic thelial cells. Regarding vascularization, arcuate vessels (cholinergic) nerves, surgically or pharmacologically, originating from anastomoses of uterine and ovarian ves- resulted in a significant decrease in cancer growth in experi- sels penetrate the myometrium in a spiral-shape and branch mental models of prostate, gastric, pancreatic cancers, and into radial arteries that traverse the myometrium to arrive basal cell carcinomas.7,8,12,13 at the endometrium as spiral arteries18 (Figure 1(b)). The morphology of the uterus is characterized by a Sympathetic (SNS) and parasympathetic (PSNS) divi- physiological plasticity of the peripheral nerves due to its sions of the autonomic nerve system are essential to con- cyclical remodeling throughout the reproductive cycle necting organs to the central nervous system (CNS).19 under the influence of estrogen and progesterone.14 As a Depending on the nature of the stimuli transmitted, auton- consequence, understanding nerve-crosstalk in EC is a omous innervation has both afferent and efferent compo- challenge considering the complex relationship between nents. The afferent component conducts somatic and hormone levels and nerve plasticity. Among uterine can- visceral sensory stimuli from the periphery to the CNS, cers, endometrial carcinoma is the most common gyneco- while the efferent component, also known as the motor logical malignancy in Western countries, and its incidence branch, sends impulses to activate the smooth muscle, car- rate is expected to increase due to a rise in the index of diac muscle, and glands.20 obesity along with prolonged life expectancy.15 Despite Anatomically, the sympathetic pre-ganglionic neurons the highest survival rate of all gynecological cancers, the innervating the uterus are in the intermediolateral cell survival rate is poor with only 15% of women surviving column of the spinal cord at the T12-L2 level. Their pre- for 5 years when EC is diagnosed at the latest stage (IV).16 ganglionic fibers pass through the sympathetic chain, exit Regarding the neural system as a recent and interesting in the lumbar nerves, and synapse with the post-gangli- cancer progression contributor, an understanding of the onic neurons inside the inferior mesenteric ganglion. mechanisms could lead clinicians to uncovering interest- After that, the sympathetic fibers are carried into the pel- ing information for the prognosis and management of EC. vis as the right and left hypogastric nerves main trunks This review compiles information on the architecture from the superior hypogastric plexus.21 The post-gangli- and function of autonomous uterine neural innervations and onic fibers from these neurons pass through the inferior the influence of hormone-dependent nerves in normal uterus hypogastric plexus. They interact with fibers from the and tumor progression. Furthermore, it explores strong and PSNS and continue to the uterovaginal plexus to inner- weak points and exposes new therapeutic possibilities for vate the vagina and the uterus. In addition, distinct gan- EC using these endocrine and neural advantages to be glia selectively innervate restricted areas of the uterus, applied in the clinical management of this condition. thereby revealing region-specific control of uterine activ- ity.20 Finally, some pre-ganglionic fibers from the L1–L2 spinal segments directly descend in the sympathetic Autonomous innervation and nerve chain and synapse with post-ganglionic neurons in the plasticity of the uterus hypogastric plexus (Figure 1(a)). Sympathetic and parasympathetic nerves in the The parasympathetic pre-ganglionic neurons that inner- vate some locations of the female genital tract and the uterus uterus are placed in the intermediolateral cell column of To interpret the relationship between uterine innervation the sacral spinal cord at the S2–S4 level. Parasympathetic and EC, it is relevant to understand the anatomy of the fibers exit from the ventral roots of the spinal medulla and uterus and the physiological distribution of the fibers of travel through the pelvic splanchnic nerves. There, they Español et al. 3 Figure 1. Autonomic innervation in the uterus: (a) Autonomic innervation distribution in the uterus. (b) Uterus anatomy: layers, nerves, and vessels. Neural control of the uterus is provided mutually by SNS and PSNS fibers creating a visceral co-regulation. The origin of SNS pre-ganglionic fibers initiates from the thoracolumbar region [T10-L2] of the CNS. SNS ganglia, where synapse is produced, are mainly located along the paravertebral sympathetic chain that runs parallel to the spinal cord. The post-ganglionic fibers finally join the spinal nerves to innervate the uterus. PSNS comes from the craniosacral region [S2–S4]. The PSNS ganglia and origin nerve roots are situated close to the uterus where shorter fibers make up the pelvic splanchnic nerves that innervate the uterus (a). Red: sympathetic nervous system; Blue: parasympathetic nervous system; Green: visceral afferents; Continuous line: pre-ganglionic fibers; Dotted lines: post-ganglionic fibers. In detail, uterine anatomy is composed of three layers and an exceptional vessel network that interacts with the autonomic nervous system (b). pass through the inferior hypogastric plexus to reach the confirmed in humans and murine models where ectopic uterine tissue20 (Figure 1(a)). endometrium implants develop sympathetic, parasympa- Topographically, the autonomic nerve fibers are hetero- thetic, and sensory nerve fibers.25 Both layers of the endo- geneously distributed in the uterus, being higher in the metrium of women with endometriosis appear to be tubal end of the uterine horn (endometrial junction) and in densely innervated.26 Nevertheless, the identification of the cervix.22 Within the different uterine layers, nerve den- nerve fibers in the functional layer of non-pathological sity is moderate in the circular and longitudinal smooth endometrium is controversial, and it could be relationated muscle of the myometrium and abundant around the blood with hormonal changes of reproductive cycle.27 vessels of the arcuate and radial arteries in the vascular zone that is interposed between these two smooth muscle Neurotransmitters and neuroreceptors of the layers23,24 (Figure 1(b)). Innervation in the non-pathologi- cal endometrium has not been studied extensively. autonomic nervous system in the uterus According to initial literature,14 this layer may be poorly In the sympathetic branch, the pre-ganglionic fibers release innervated by autonomic fibers that would be located the neurotransmitter acetylcholine (ACh), which acts on around the vessels and restricted to the basal layer. The cholinergic receptors on the post-ganglionic cells (Figure 1). most interesting available information comes from These cells release mainly norepinephrine (NE) from sym- research into pathological situations like endometriosis. pathetic endings. Interestingly, sympathetic innervation in The presence of nerves in endometriotic tissue has been the uterus also makes up a complex system involving 4 Women’s Health Table 1. Neurotransmitters and their specific receptors in the neural control of uterine responses and endometrial cancer. Neural Healthy uterus Endometrial cancer signalinga Endometrium Myometrium Endothelium Endometrial cells Myocytes Endothelial cells Endometrial tumor cells Sympathetic NE; NE; NE; NE; β2 > β3 > β1; α1 > α2; α1 > α2; β2 > β3 > β1; Epithelial proliferation22,28,29 Contraction31,32 Vasoconstriction22,28 Epithelial proliferation33 NE; NE; β2 > β3 > β1; β1; Tocolysis31,32 Vasodilation22,28 Parasympathetic ACh; ACh; ACh; ACh; nAchR-α7; M3 > M2; M3 > M1 > M2; M3 > M1 > M2;35,36 MMP-9 secretion34 Contraction34,35 Vasodilation34 Dopaminergic DA; – DA; DA; DRD2;37 DRD1 > DRD2; DRD1 > DRD2; Antiangiogenic effect37 Antiangiogenic effect38,39 NE: noradrenaline; β: beta-adrenergic receptor; α: alpha-adrenergic receptor; Ach: acetylcholine; nAchR: nicotinic receptor; M: muscarinic receptor; DA: dopamine; DRD: dopamine receptor. a Neurotransmitter; receptor(s) ordered by expression and relevance; action in the uterus. several types of co-transmissions that consist of a whole cervical and isthmic area muscle contraction with little or range of other molecules belonging to the synaptic vesi- no effect on the uterine body35 (Table 1). cles.28 For example, NE along with adenosine triphosphate (ATP), chromogranin, hydroxylase, and other molecules Estrogen, progesterone, and uterine nerve with oxytocic and tocolytic effects are released from the sympathetic neurons through exocytosis.29 These com- plasticity pounds decrease the release of neurotransmitters from In a physiological endometrium environment, estrogen local nerve endings and can modulate smooth muscle cell induces proliferation of the glandular epithelium, stroma, activity via interaction with specific receptors located on and vessels. Progesterone prepares the endometrium for the membrane of the connective tissue cells, the endome- implantation, by overcoming the proliferative effect of trium, and the placenta.30 The isthmic uterine muscle cells estrogen and inducing differentiation of the glands, stroma, especially express type A α1 adrenergic receptors (α1AR) and vessels.40 Estrogen signaling is mediated by one of with a contractile effect,31 whereas those from the uterine two receptors: estrogen receptor alpha (ERα) and estrogen body mainly possess β2 adrenergic receptors (β2AR) that receptor beta (ERβ).41 Progesterone signaling is mediated induce tocolysis. β1 and β3 adrenergic receptors (β1AR- by the progesterone receptor (PR) of which two isoforms, β3AR) expression has also been described in myometrial PRA and PRB, have been identified.42 cells, both with a tocolytic effect32 (Table 1). Another remarkable function of estrogen and progester- On the contrary, the uterine parasympathetic fibers one is the capacity to remodel uterine innervation in mainly release ACh to modulate myometrial activity.34 response to their cyclic variations in circulating levels These cholinergic endings possess vesicles that contain from puberty onward to menopause, inclusive of preg- ACh that is stored together with ATP and proteoglycans.30 nancy.14 The proportion of neurons expressing ERα is ACh stimulates muscarinic acetylcholine receptors greater in the uterine-projecting neurons. That suggests (CHRs) on uterine myometrial cells. These receptors that they are selectively sensitive to the effects of estro- belong to the superfamily of G protein-coupled receptors, gen.43 Sympathetic nerves are the most susceptible while five CHMRs genes corresponding to subtypes M1, M2, parasympathetic and sensory nerves show no significant M3, M4, and M5 receptors have been identified. CHRM3 changes. Estrogen elicits a rapid degeneration of sympa- has been described as the most expressed in the uterus and thetic terminal axons in the myometrium and, conversely, mainly mediates uterine contractions.36 ACh administra- they regenerate under low-estrogen conditions.44 tion induces an increase in the frequency and intensity of Mechanistically, the myometrium produces proteins that myometrial contractile waves through the M3 receptor repel sympathetic axons, including BDNF, neurotrimin, with no significant change in tone. Although M3 receptors semaphorins, and pro-NGF, in the presence of the steroid are present on the membrane of all myometrial cells, cho- hormone.14 In addition, estrogen also affects neurotrophin linergic endings are mainly distributed in the cervical area receptor expression in sympathetic neurons, which favors and the isthmus as well as the rest of the uterus in small the pro-degenerative effects of the target tissue.44 It is also numbers. Therefore, parasympathetic stimulation causes an important modulator of the release of NE from the Español et al. 5 nerve terminals influencing the metabolism and turnover (CNH) (in association with p53 mutation and a worse of its neurotransmitter and its synthetic enzyme activity.14 prognosis).54 The Cancer Genome Atlas Research Network Concerning progesterone, it mediates neuronal plastic- (TCGA)55 molecular classification for EC offers the ity by altering the expression patterns of the corresponding opportunity to improve the current histological diagnosis A and B receptors in some neurological diseases. However, and classification system, specify the prognostic informa- its specific role in uterine nerve plasticity still remains tion of each patient, adapt the indication of adjuvant treat- uncertain.45 As this hormone is especially linked to preg- ments and assess the incorporation of therapies directed at nancy, several authors that have used experimental models certain types of targets or predict the response to them.38,56,57 in induced pregnancy states have described modifications The standard of care for the proper management of EC of NA levels46 accompanied by a degeneration of uterine is surgical treatment. Adjuvant treatment consisting of nerves.47,48 These findings shine a light on the complexity radiotherapy or chemotherapy with platinum-based cyto- of the neuroplasticity phenomenon. It involves multiple toxic drugs, or in combination is indicated depending on factors orchestrated by the estrogen and progesterone hor- factors that might impact on the recurrence and survival in mones in the reproductive organ. EC.58,59 The surgical extent is determined by the type of tumor (Type-I or Type-II), the histological grade and by Endometrial Cancer the suspicion of extension of the disease determined by means of imaging tests.60 Currently, in the initial stage of EC is the most common gynecological malignancy affect- the pathology in Type-I tumors, the standard surgery con- ing women in Western countries.49 The risk factors include sists of a total hysterectomy with double adnexectomy. genetic disorders, obesity, diabetes mellitus, high levels of The sentinel lymph node biopsy is normally considered for estrogen, and increasing age. The overall 5-year survival staging in patients with low and intermediate-risk disease rate for EC is around 80%, mainly because patients are to assess for the presence of pelvic nodal metastases as normally diagnosed at an early stage. Unfortunately, up to long as there is no extrauterine disease. In this group of 20% of the EC patients relapse and eventually die due to patients, lymphadenectomy is not currently recommended the tumor spreading beyond the uterus when the diagnosis since numerous studies have confirmed the validity of the comes up at an advanced stage.16 The most important sentinel node technique,61 which has less post-surgical prognostic factors comprise the tumor stage, histological morbidity. In the case of patients with type-II tumors or grade, stage of disease, depth of myometrial invasion, type-I tumors with suspected infiltration ⩾ 50% of the lymphovascular space involvement (LVSI), and cervical myometrium, grade III or from stage II by imaging tests, involvement.50 total hysterectomy with double adnexectomy should be combined with a pelvic and para-aortic lymphadenectomy. Histology, molecular classification, and current In tumors with a serous, carcinosarcoma or undifferenti- ated histology, infracolic omentectomy is recommended. treatments for endometrial carcinoma After the surgery, the requirement for chemotherapy or EC is traditionally classified into two types based on their radiotherapy is discussed in a tumor multidisciplinary etiology and prognosis.51 Type-I EC has a favorable prog- committee following clinical guidelines criteria.58,59 The nosis as it is often diagnosed at an early stage. It has an same occurs in cases of recurrence. endometrioid histological typology and often arises from Immunotherapy using immune checkpoint blocked tar- endometrial hyperplasia in a setting of unopposed estrogen geting, programmed death 1 (PD1) and programmed death ambience in peri- and post-menopausal women. It com- ligand 1 (PDL1) is also emerging as an exciting new treat- monly expresses high levels of ERα and PR.52 Type-II ment for EC based on tumor characteristics and the molec- tumors account for 10%–20% of ECs and often have a ular profile. Two drugs are currently approved by the EMA serous, papillary, or clear cell histology. They tend to be and/or FDA, pembrolizumab, and dostarlimab. composed of markedly atypical cells that grow in papil- Dostarlimab was granted accelerated approval for the lary, glandular, or solid patterns.52 Type-II tumors arise in treatment of patients with recurrent or advanced deficient the background of an atrophic post-menopausal endome- mismatch repair (dMMR) EC that has progressed or fol- trium independent of estrogen and may be preceded by lowing prior treatment with platinum-containing chemo- endometrial intraepithelial carcinoma (EIC). Type-II therapy.62 It is noted that the biomarkers MSI and PDL1 tumors have a poor prognosis as they tend to spread from expression that often predict the response to immunother- the site of origin early in the development of the dis- apy are not frequently seen in the most aggressive EC ease.52,53 In the last decade, molecular studies have gener- forms.63 These data confer less immunogenic profile than ated promising results. An outstanding example is the endometroid histology subtypes or early-stage serous ECs molecular classification that divides EC into four catego- to advanced serous subtypes. However, a recent phase-II ries: POLE-ultramutated (in association with a high histo- trial for the study of pembrolizumab in combination with logical grade and good prognosis), microsatellite instability lenvatinib (a multi-kinase inhibitor) has shown a 50% (MSI), copy number low (CNL), and copy number high response rate in women with advanced serous endometrial 6 Women’s Health disease.64 The progression-free survival (7.2 vs 3.8 months; insulin-like growth factor-1 (IGF-1), the expression of EGF HR 0.56) and the overall survival (OS: 18.3 vs 11.4 Receptor (EFGR), and the transcriptional factors c-fos and months; HR 0.62) were significantly improved with the c-myc, as well as the activation of the PI3K/Akt pro-sur- combination of both versus pembrolizumab monother- vival signaling pathway.74,75 Genomic alterations are also apy.65 Based on this study, pembrolizumab with lenvatinib observed, including transcriptional regulators that are linked was also approved in an accelerated manner by the FDA to estrogens signaling.76 Progesterone binds to nuclear PR to for patients with previously treated metastatic EC whose regulate varied signaling that leads to triggering transcrip- tumors were not MSI-H/dMMR.66 tional activity.40 That transcriptional activity is modulated On the contrary, recent findings related to uterine cancer by a variety of miRNAs and epigenetic factors as has been molecular drivers such as overexpression or amplification widely demonstrated in animal models.77 Estrogen signal- of the epidermal growth factor receptor 2 (HER2) in endo- ing is known as one of the most important risks for EC, metrial serous carcinoma has led the incorporation of sev- being ERα a key oncogene in EC.74 Type-I endometrial eral anti-HER2 therapies. That includes targeted therapeutic tumors express high levels of ER and are hormonally driven, trastuzumab, which is associated with improved survival while Type-II tumors are less likely to express ER.73 for women with advanced and recurrent HER2-positive As previously stated, neural regulation by estrogen and disease when added to conventional chemotherapy.65 progesterone in the uterus oscillates over a woman’s lifes- In the “ESGO/ESTRO/ESP guidelines for the manage- pan, depending mainly on the estrogen conditions. ment of patients with endometrial carcinoma” that was Particularly in EC, age-related neural plasticity does not updated in 2021,58 information and bibliographic refer- suffer specific changes because the mean age on diagnosis ences are provided for the current management of EC. of patients is 62 years old (menopausal state).78 This point differs from the changes in hormone levels during the tumor progression in comparison with the lack of hor- Perineural invasion as a new route of mones after the surgical treatment, including the double metastasis in Endometrial Cancer as new route adnexectomy discussed below (Figure 2(b)) of metastasis in EC An in-depth understanding of hormone influence in EC Distant metastasis is still the leading cause of death in has led to the selective application of hormonal therapy in EC.67 In addition to transcelomic invasion and lymphatic affected patients. Progestin therapies act by blocking and hematogenic spread, the most common metastatic estrogen-induced uterine growth and are indicated in routes, PNI is the fourth route of tumor dissemination. PNI young patients desiring uterine-sparing in the initial states has been defined as the infiltration of the perineural sheath of the disease.79 Despite this, its application to avoid tumor by tumor cells. It plays a crucial role in the progression of recurrence after the surgery or in treating metastatic several carcinomas,68 and it leads to a poor prognosis in patients presents variable responses and more studies are head and neck squamous cell carcinoma, pancreatic can- needed to improve the treatment indication. cer, and prostate cancer.69,70 The biological interactions between nerves and cancer cells are vital in this process. Neural influence in Endometrial However, the key drivers of PNI and its mechanisms are still largely unknown for the majority of cancers. In EC, Ti Cancer et al. have demonstrated, in in vitro neural invasion assays An influence of the innervation in tumor progression has and transwell cocultures systems, the role of the dorsal been described in several gynecological cancers as well as root ganglion neurons to promote perineural metastasis of in EC.3,36 We hypothesize that similar to the pathophysiol- EC cells via AMPA receptor 2 (GluR2) as this effect was ogy of endometriosis,14 there might be a redistribution of inhibited by both endogenous/exogenous knockdown of the endometrial layer nerve fibers in EC that creates an GluR2. Moreover, GluR2 was expressed in endometrial inflammatory tumor microenvironment (Figure 2). An cell lines and also in endometrial tissue, suggesting that overexpression of β-ADRs in tumor tissue relative to their GluR2 could be a predictor of perineural metastasis in this matching to normal tissue has been reported in EC. This is type of cancer.71 However, the prognostic value of PNI in especially true for β2-AR (IHC score normal vs cancer 0,0 EC is still unknown. vs 1,1), contrary to β1-AR and β3-AR (Table 1).33 β3-AR, which stimulated lipolysis in human fat cells in physio- Sexual hormones influence in Endometrial logic conditions,80 has been related to the metabolic syn- drome. A genetic analysis has shown that the prevalence of Cancer an allele of the Trp64Arg polymorphism in this receptor The lack of estrogen/progesterone balance normally domi- gene might contribute to the susceptibility to EC among nated by estrogens can develop in EC formation.72,73 obese people.81 Estrogen binds to nuclear ER resulting in the induction of The influence of adrenergic signaling in EC was found growth factors like epidermal growth factor (EGF) and indirectly through the evaluation of the stress response Español et al. 7 Figure 2. Nerve-cancer cell and sex hormone crosstalk: (a) Tumor progression. (b) Recurrence. Cancer cells can attract nerve fibers and stimulate nerve outgrowth by the paracrine secretion of neurotrophic factors (NF) in a process called neuroneogenesis. NFG contributes to the process and stimulates angiogenesis and inflammation. Tumor-associated macrophages also play an important role by secreting pro-inflamatory cytokines (IL-1, IL-6, IL-8, and TNF-α) that aid the tumor in circumventing antitumor responses. Conversely, nerve fibers secrete neurotransmitters (NE, E, ACh) that bind neuroreceptors in cancer and stromal cells (immune and endothelial cells) to stimulate tumor growth. Furthermore, estrogen has two effects, the induction of tumor growth by increasing estrogen signaling in cancer cells and the disruption of the sympathetic fibers, thereby giving prevalence to parasympathetic signaling (a). After surgical intervention, sex hormone levels are reduced and both sympathetic and parasympathetic signaling are active (b). where adrenergic signaling is increased. The stress- and lymphatic metastasis. This combination along with induced release of catecholamine can activate β-ADRs in other clinicopathological risk factors is a stronger prog- tumor cells and trigger increased expression of pro-angio- nostic model and has significant clinical value in targeted genic molecules like vascular endothelial growth factor therapy for endometrial carcinoma patients.36 (VEGF) in mouse model and cell lines.82,83 It results in Dopaminergic signaling is also active in ECs. enhanced tumor vascularization, more aggressive growth Dopamine receptor type-2 (DRD2) is highly expressed and the spread of malignant cells (Figure 2(a)). Several in aggressive EC types (CNH, serous histology) and is studies have analyzed the mechanisms and their relation- associated with grade, stage, and worse OS and progres- ship with clinical results. In EC, serum levels of VEGF sion-free survival (PFS).37 DRD2 antagonism with have been described as independent factors for poor prog- ONC201 potently inhibits cell proliferation in EC cell nosis.84 Moreover, a recent study that experimented on lines through the induction of apoptosis and increased cytokine array analysis in an adipose medium revealed that cellular stress. ONC201 might be a novel targeting agent VEGF protein expression is upregulated in visceral adi- for EC neurotherapy, particularly in more aggressive EC pose tissue in obese patients, which is correlated with types for which effective treatments are limited.37,39 increased tumor growth, vasculature promotion, and Another neural modulator described in EC is Substance mTOR activity in in vivo xenograft models of EC.85 P (SP). It is an undecapeptide that belongs to a family of Cholinergic fibers, besides providing an important tachykinins. SP is widely expressed in both the central input to the uterus, are also detected in infiltrating endo- and peripheral nervous systems and is also involved in metrial tumors. A study that assayed the immunohisto- endometrial carcinoma progression. SP preferentially chemical expression of CHRM3 in 257 endometrial binds to neurokinin-1 receptor (NK-1R) and induces the carcinoma patients has revealed that CHRM3 is highly expression of vascular endothelial growth factor (VEGF) expressed in advanced endometrial carcinoma and is and promotes cancer cell proliferation and metastasis in closely correlated with the FIGO stage, vascular invasion, endometrial adenocarcinoma.86 8 Women’s Health Neuronal elements are also necessary to create a Targeting neurotransmitters and their receptors tumor microenvironment. The innervation brought on by in cancer cancer cells is known to play an active role in tumor pro- gression and invasion in different tumor types.87 Among the neural targets, the neurotransmitters are highly Cholinergic and adrenergic fibers release neurotransmit- investigated molecules thanks to their capacity to enable ters that create a downstreaming signal to stimulate the communication between neurons. The use of repurposed corresponding receptors situated in immune cells (mac- drugs is supported by the results obtained in clinical trials rophages), stromal cells, and blood vessels. Multiple with patients taking beta-adrenergic antagonists for the processes such as migration, invasion, and angiogenesis treatment of cardiovascular disorders and anxiety. They involve pro-inflammatory cytokines, chemokines, and presented with increased OS in prostate, breast, and ovar- neurotrophic factors to promote tumor growth. ian cancers.95–97 Conversely, the main tumor promotes raised innervation Beta-adrenergic antagonists may mediate the inhibition by mechanisms like axonogenesis based on the secretion of the stimulatory effect of catecholamines released by of axon-guidance molecules and neurogenesis that stim- nerves in the tumor microenvironment through a mecha- ulate the novo stem cells.88 In the same tumor microen- nism that continues being investigated. Other evidence to vironment, estrogen and progesterone hormones support the use of the anti-neurogenic therapy is based on maintain paracrine connections with nerves terminals. data on stress-induced cancer development related to sur- Evidence indicates that changes in circulating estrogen gical stress, psychological stress, and depression.98 The mediated through ERα are determinant of variations in higher circulation levels of E and NE that favor tumor acti- uterine sympathetic innervation89 (Figure 2). vation can be prevented with the use of β-blockers. This Compared to other solid tumors, there is room for mechanism has been experimented with in mouse models unveiling the neural influence in EC and the mechanisms of pancreatic ductal adenocarcinoma.99 Furthermore, com- that neurotransmitters and neuroreceptors apply to acti- mon therapies for stress and anxiety disorders like benzo- vate oncogenic pathways. Autonomic nervous system diazepines and SSRIs also inhibit the proliferation and contribution has been widely studied in breast cancer migration of cancer cells in vitro.100 including the impact of stress on tumor progression.90,91 Currently, more than 20 clinical trials101 are ongoing to Breast cancer is a heterogeneous disease mainly charac- evaluate the therapeutic efficacy (alone or in combination) terized by the status of HER2, the estrogen receptor and of antagonists or agonists of adrenergic receptors. Although the progesterone receptor of the primary tumor. The clinical responses are pending assessment, mechanisms well-known biological effects of stress on breast tumor such as the decreased induction of neurites, a decline in progression may be because of its high incidence, as it is nerve-cancer interaction and less neurotrophin secretion the most common cancer in women, together with the have been proposed for tumor innervation inhibition extended experience in experimental models of this brought on by these treatments.3 The most used is propran- tumor.92 However, the role of the different adrenergic olol, a non-selective beta-adrenergic antagonist. It has receptors, especially β2AR, expressed in tumors and dif- been tested in the treatment of several gastrointestinal can- ferent stroma cells is still under research. Although a cers, prostate cancer, hepatocarcinoma, recurrent breast study demonstrated that there was a higher incidence of cancer, cutaneous melanoma, renal cell carcinoma and EC in patients with both estrogen receptor–positive or hemangioma.102 In addition, metoprofol and esmolol, –negative breast cancer than in the general population,93 selective β1-AR antagonists, have been accepted for the the influence of estrogen in the crosstalk between nerves treatment of solid tumors, hematological malignancies and and breast tumors has not yet been studied. Similar to intracranial tumors.103 Relative to uterine cancers, a recent EC, neural plasticity may be implicated. It would be an study that presented experimental data proved that pro- interesting area of study. pranolol can block the cGMP-PKG signaling pathway in cervical cancer cells.104 Neural therapy in cancer and Differently, the activation of dopaminergic signaling, and not the inhibition of adrenergic signaling, has an anti- perspectives for Endometrial Cancer tumor effect. It has also been associated with apoptosis Anti-neurogenic therapies have been applied extensively induction in breast cancer cells. Therefore, the use of for the treatment of pain, cardiovascular disorders, mental D2-agonists in dopamine receptor expressing tumors disorders, and anxiety. However, they also have been redi- seems to be a promising tool as a complementary therapy rected to oncology treatments under the so-called “drug in breast cancer.105 There are ongoing clinical trials to repurposing” policy. It implies testing for new indications evaluate cabergoline (D2 and D3 dopamine receptors) in of existing drugs using information on pharmacokinetics, metastatic and recurrent breast cancer.101 Regarding cho- safety, and the manufacturing of the medication. This linergic receptors, a muscarinic antagonist currently used would make it a very cost-efficient treatment strategy.94 in the treatment of the overactive bladder (e.g. darifenacin) Español et al. 9 seems to arrest tumor progression in small-cell lung carci- undergo in surgery influences the level of this hormone. noma.106 However, the potential therapeutic effects of cho- Low levels of estrogen given after surgical intervention linergic antagonists are still under investigation.107 might enhance sympathetic signaling that leads to a pro- tumorigenic response. It is known that the sympathetic nerves are a determinant factor in endometrial tumor pro- Targeting neurotrophins and their receptors in gression and recurrence (Figure 2(b)). Based on this cancer hypothesis, it would be interesting to investigate the rela- Nerve growth factor (NGF) plays a significant role in tionship between sympathetic innervation and sex hor- pain generation.94 Many strategies like blocking with mones in the early and late stages of EC to provide new antibodies, small pharmacologic inhibitors, and peptides information related to recurrences as well as new treat- have been designed to antagonize NGF and its receptors ments for EC patients. TrkA and p75NTR.108 Interestingly, a humanized mono- clonal antibody (tanezumab) that has been validated in Conclusion mouse models is already in clinical trials for its analgesic activity in chronic rheumatoid arthritis and back pain. In Patients affected by EC are diagnosed in the early stages it, anti-NGF antibodies have been shown to decrease the and have high rates of survival. However, these rates are pain caused by bone metastases from prostate cancer and reduced dramatically if regional or distant spread is to attenuate bone destruction.109 Beyond this role in the involved. Nerves have been reported to play an active role pain process, Pro-NGF and NGF, through their TrkA and in tumor progression and invasion, and they are associated p75NTR receptors, stimulate tumor cell growth and inva- with aggressiveness and a poor prognosis in several can- sion in breast110 and prostate cancer cells.111 Furthermore, cers. The status of estrogen and progesterone levels is one involvement has been seen in the proliferation in the stem of the major risk factors in developing EC and might influ- cell compartment.112 Other neurotrophin expressions like ences nerve innervations and subsequently EC progres- the brain-derived neurotrophic growth factor and its sion. Further studies should be done to evaluate the receptor TrkB strongly contribute to proliferation and relationship between hormonal status, nerve plasticity, and dissemination in gastric tumor cells.113 Altogether, the EC. This could lead to uncovering interesting information identification of neurotrophic factors like inductors of for the diagnosis, prognosis, and management of EC. tumor cell growth, the dissemination of many cancer Moreover, those studies might bring about new therapeutic cells as well as the drivers of nerve infiltration in tumors options (anti-neurogenic), alone or in combination with also support the use of these molecules as a new neuro- standard therapies to improve the health and quality-of-life therapeutic approach. of women. Author contribution(s) Anti-neurogenic treatment perspectives in Pia Español: Conceptualization; Data curation; Formal analysis; Endometrial Cancer Investigation; Methodology; Writing—original draft; Writing— Many patients undergoing surgery achieve clinical remis- review & editing. sion, but advanced-stage cancer is prone to recurrence.67 A Rocio Luna: Data curation; Formal analysis; Visualization; Writing—original draft. deeper understanding of nerve dependence can contribute Cristina Soler: Data curation; Formal analysis; Writing—origi- to the use of the targeted anti-neurogenic therapy presented nal draft. as a novel tool in the management of EC adjuvant to stand- Pablo Caruana: Investigation; Methodology; Resources; ard treatments. Writing—original draft. Anti-neurogenic therapy targeting sympathetic nerves Amanda Altés-Arranz: Investigation; Methodology; Writing— using adrenergic antagonists has been evaluated as a novel original draft. strategy to control tumor growth in other cancers. However, Francisco Rodriguez: Investigation; Methodology; Resources; in EC, contrary to others, the status of sympathetic inner- Writing—original draft. vation is variable and highly influenced by estrogen and Oriol Porta: Conceptualization; Formal analysis; Supervision; progesterone hormones. Until now, no prospective studies Writing—original draft. have evaluated possible anti-neurogenic therapies specifi- Olga Sanchez: Conceptualization; Data curation; Investigation; Writing—original draft. cally for EC. The linkage between EC survival and β- Elisa Llurba: Conceptualization; Formal analysis; Funding blockers was only evaluated in a UK population-based acquisition; Writing—review & editing. study without any significant results.114 The success of a Ramon Rovira: Conceptualization; Formal analysis; Writing— potential anti-adrenergic therapy may depend on the status review & editing. of residual sympathetic innervation and the levels of circu- María Virtudes Céspedes: Conceptualization; Data curation; lating estrogen and progesterone. The ovaries are the main Funding acquisition; Project administration; Writing—original productors of estrogen, and the bilateral oophorectomy draft; Writing—review & editing. 10 Women’s Health Declaration of conflicting interests 11. Pundavela J, Roselli S, Faulkner S, et al. Nerve fibers infil- trate the tumor microenvironment and are associated with The author(s) declared no potential conflicts of interest with nerve growth factor production and lymph node invasion in respect to the research, authorship, and/or publication of this breast cancer. Mol Oncol 2015; 9(8): 1626–1635. article. 12. Stopczynski RE, Normolle DP, Hartman DJ, et al. Neuroplastic changes occur early in the development of Funding pancreatic ductal adenocarcinoma. Cancer Res 2014; 74(6): The author(s) disclosed receipt of the following financial support 1718–1727. for the research, authorship, and/or publication of this article: 13. Peterson SC, Eberl M, Vagnozzi AN, et al. Basal cell carci- This work was supported by the Instituto de Salud Carlos III noma preferentially arises from stem cells within hair folli- (ISCIII) with co-funding from FEDER (PI17/00150 and cle and mechanosensory niches. 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