Angiogenesis in Gynecological Cancers: Role of Neurotrophins

Maritza P. Garrido, Garrido MP, Torres I, Ignacio Torres, Vega M, Margarita Vega, Romero C, Carmen Romero
Frontiers in oncology · 2019 · vol. 9 , pp. 913 · doi:10.3389/fonc.2019.00913 · PMID:31608227 · PMC6761325 · W2972235392
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⚙ AI-generated summary by claude@2026-06, 2026-06-14 ⓘ

This review discusses how neurotrophins like NGF and BDNF stimulate tumor progression and angiogenesis, with an emphasis on their role in gynecological cancers.

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⚙ AI-generated deep summary by claude@2026-06, 2026-06-14 · read from full text ⓘ

This review examines how angiogenesis contributes to gynecological cancers (especially ovarian and cervical) and focuses on the angiogenic roles of VEGF versus neurotrophins (NGF and BDNF). It describes tumor-associated VEGF signaling under hypoxia, summarizes experimental angiogenesis assays (in vivo and in vitro), and reports evidence that NGF and BDNF can directly stimulate endothelial proliferation, migration, tube formation, invasion, and vascular permeability in multiple cell and animal models, partly through TRK receptor–activated pathways (PI3K/AKT, MAPK/ERK, PLCγ/PKC). A key limitation explicitly implied by its review format is that it synthesizes findings across heterogeneous models, which can complicate direct comparison and definitive attribution relative to VEGF-based therapies such as bevacizumab, shown to have only modest results. Relevance to endometriosis: the paper discusses angiogenic regulation in female reproductive tissues, including uterine and endometrial contexts where VEGF and related factors are active, providing mechanistic background that overlaps with angiogenesis in endometrium-dependent disease processes, though it does not directly study endometriosis or adenomyosis.

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Abstract

Angiogenesis, or generation of new blood vessels from other pre-existing, is a key process to maintain the supply of nutrients and oxygen in tissues. Unfortunately, this process is exacerbated in pathologies such as retinopathies and cancers with high angiogenesis as ovarian cancer. Angiogenesis is regulated by multiple systems including growth factors and neurotrophins. One of the most studied angiogenic growth factors is the vascular endothelial growth factor (VEGF), which is overexpressed in several cancers. It has been recently described that neurotrophins could regulate angiogenesis through direct and indirect mechanisms. Neurotrophins are a family of proteins that include nerve growth factor (NGF), brain-derived growth factor (BDNF), and neurotrophins 3 and 4/5 (NT 3, NT 4/5). These molecules and their high affinity receptors (TRKs) regulate the development, maintenance, and plasticity of the nervous system. Furthermore, it was recently described that they display essential functions in non-neuronal tissues, such as reproductive organs among others. Studies have shown that several types of cancer overexpress neurotrophins such as NGF and BDNF, which might contribute to tumor progression and angiogenesis. Besides, in recent years the FDA has approved the use of pharmacologic inhibitors of pan-TRK receptors in patients with TRKs fusion-positive cancers. In this review, we discuss the mechanisms by which neurotrophins stimulate tumor progression and angiogenesis, with emphasis on gynecological cancers.
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Role

Cervical cancer is the fourth most frequent cancer in women. Approximately 90% of deaths from cervical cancer occur in low-income and middle-income countries, in which strategies of prevention, early diagnosis, effective screening, and treatment programs are less common ( 116 ). In the context of cervical cancer, BDNF/TRKB are perhaps the best studied NTs. It has been described that BDNF and TRKB expression are significantly higher in cervical cancer tissues than in normal tissues and that their presence is higher in advanced stages of this neoplasm ( 6 , 7 ). In addition, BDNF levels are positively associated with lymph node metastasis ( 7 ) in cervical cancer patients. In cervical cancer cell lines, BDNF/TRKB increases cell proliferation ( 7 , 117 ), apparently involving ERK and AKT signaling pathways ( 118 ). TRKB downregulation in cervical cancer cells suppress the activation of epithelial mesenchymal transition (EMT) by downregulation of N-cadherin and vimentin, among other proteins, and strongly diminishes cell proliferation, migration and invasion ( 117 , 118 ). Considering that the activation of ERK signaling pathway by BDNF/TRKB was associated with an increase of VEGF expression in osteoblasts ( 93 ), and given that TRKB can activate PI3K and ERK signaling pathways which regulate VEGF expression in several models ( 119 – 121 ), it is plausible that the VEGF expression could be increased by TRKB in cervical cancer, similarly to ovarian cancer. There is no direct evidence that overexpression of NTs and its receptors are involved in the physiopathology of endometrial cancer. However, antecedents suggest that NTs could contribute to this pathology, since their expression increase in endometriosis ( 122 – 124 ), a condition that has been associated with higher risk of ovarian and endometrial cancer ( 125 – 127 ). The endometriosis is an estrogen-dependent inflammatory disease, characterized by the presence of endometrial-like tissue outside the uterine cavity ( 128 ). An important characteristic of this pathology is that angiogenesis is deregulated. In endometriosis, the VEGF expression is increased and promotes the spreading of new blood vessels at the endometriotic lesions and surroundings, which contributes to the survival of lesions ( 129 ). A recent study has shown that drospirenone, a drug used for endometriosis treatment, significantly decreases inflammatory cytokines and NGF expression, as well as VEGF expression in human endometriotic stromal cells ( 130 ). Similarly, Ginsenoside (a ginseng-derivate extract) decreases both VEGF and BDNF in rat endometriotic implants ( 131 ). These antecedents suggest that NTs could contribute not only to the pelvic chronic pain typical of endometriosis, but also to pathological angiogenesis, probably by the increase of VEGF levels.

Vegf

There are many known angiogenic factors, among which VEGF is the most widely studied in the context of cancer. VEGF genes include VEGF-A to VEGF-E and another related gen, placental growth factor (PLGF) ( 47 – 50 ). VEGF-A (from now referred as VEGF) has the most important effect in the formation of blood vessels during development or in pathological conditions as cancer ( 51 ). At the same time, VEGF undergoes alternative exon splicing ( 52 , 53 ), leading to several transcripts that include VEGF 121 , VEGF 145 , VEGF 165 , VEGF 189 , and VEGF 206 , which give origin to VEGF peptides of 121, 145, 165, 189 and 206 amino acids, respectively ( 54 ). Besides, VEGF 121 is totally secreted and VEGF 165 is partially secreted from cells ( 55 , 56 ). In ovarian, endometrial and cervical cancers, VEGF 121 and VEGF 165 are the most dominantly expressed ( 57 – 60 ).

Tumor

Tumor growth has two phases: an avascular stage (when tumors are constrained at diameters of 1–2 mm) and a posterior vascular stage ( 25 ), in which tumor cells need to secrete soluble factors to promote an increase of angiogenesis and continued growing ( 26 ). In the normal vasculature, endothelial cells are stable; rarely they sprout or divide and they are associated to mural cells (pericytes) in a basal membrane. However, in the case of the tumor vasculature several chromosomal abnormalities arise ( 27 – 29 ), as well as variations of size and thickness, irregular shape, and big trans-cellular holes and fenestrae ( 30 , 31 ). These characteristics produce a decrease of blood flow and drug delivery, and increase the interstitial fluid pressure, the extravasation of blood components and the intravasation of tumor cells ( 30 , 32 ). Particularly in gynecologic neoplasms, angiogenesis plays a key role, since the ovary and uterus cyclically regulate the angiogenesis during the ovarian cycle involving blood vessel growth and regression, with a fine regulation ( 33 – 35 ). Therefore, angiogenesis is undoubtedly crucial in gynecological cancers, but this process is uncontrolled. Given that angiogenesis is a complex process that involves different cell types, in vivo experiments constitute the ideal condition to evaluate it. Some examples of in vivo assays are: the chick embryo chorioallantoic membrane (CAM) assay ( 36 ), zebrafish embryo assay ( 37 , 38 ), corneal micropocket assay ( 39 , 40 ), and matrigel plug assays ( 41 ). Moreover, there are some experimental approaches in vitro to evaluate the angiogenic potential of cells, which may have some advantages, such as the reproducibility and low cost to perform these assays ( 42 ). However, it is considered that in vitro assays evaluate vasculogenesis or de novo formation of vasculature-like structures and usually involve only endothelial cells and extracellular matrix. Examples of this are tubular formation assays in matrigel ( 43 , 44 ) and the recently developed microfluidic cell culture systems ( 45 ). Nevertheless, in vitro assays are widely used, because they are a cheap and reproducible method to evaluate the angiogenic potential ( 46 ).

Author

MG, IT, and CR: conceptualization. MG: writing original draft. MV and CR: writing, review, and editing. The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Conclusions

NGF/TRKA and BDNF/TRKB are the main NTs studied in the context of cancer. These NTs and their receptors are over-expressed in gynecological neoplasms, such as ovarian and cervical cancers, in which they promote the progression of these diseases. Furthermore, NTs are involved in uterine pathologies such as endometriosis, which suggests that they could contribute to endometrial cancer progression, however this has not been elucidated yet. NTs are indirect angiogenic factors, acting through the induction of VEGF expression in ovarian cancer cells; besides, it is possible that NTs could display the same effect in other cancer cells such as cervical and endometrial. In addition, NTs exhibit a direct angiogenic role, mainly studied in endothelial cells that express NTs receptors, and respond by increasing endothelial cell proliferation, migration and differentiation. Moreover, NTs increases angiogenesis both in in vitro and in vivo models. Consequently, NTs and their receptors may be considered as important angiogenic factors, mostly in the context of anti-angiogenic therapy against VEGF, where overexpression of NTs could increase the angiogenesis independent of VEGF levels and contribute to therapy failure. Since NTs and TRK receptors are drivers of a wide variety of adult and pediatric cancers as gynecological neoplasms, the FDA has recently approved pan-TRK inhibitors for the treatment of TRK fusion-positive solid tumors. Because TRK fusion has been described in several gynecological cancers, the recently developed TRK inhibitors emerge as a new therapeutic approach for the treatment in this subtype of neoplasms. Given that angiogenesis is a key feature in gynecological neoplasms, and NTs acts as direct and indirect angiogenic factors, it may be relevant to study whether TRK inhibitors could improve the efficacy of anti-angiogenic drugs as bevacizumab, which was not elucidated yet.

Introduction

Gynecological neoplasms belong to a group of malignances that include ovarian, cervical, uterine, fallopian tubes, vulvar, vaginal cancer and gestational trophoblastic neoplasms. The following sections of this review will be focused on the first two types, which are the most frequent ( 1 ). Gynecological neoplasms are characterized by exacerbated angiogenesis (which is defined as the generation of new blood vessels from pre-existing ones) and vascular endothelial growth factor (VEGF) is the most widely studied angiogenic factor in the context of cancer. VEGF is secreted by most tumor cells, mainly in response to hypoxia and low nutrient concentrations ( 2 ), and promotes angiogenesis through its receptors expressed in endothelial cells. This antecedent has been crucial for the development of new drugs as bevacizumab, a humanized monoclonal antibody directed against human VEGF. Unfortunately, this drug has shown modest results ( 3 ), because ovarian and uterine cells may overexpress other molecules that can act as angiogenic factors, such as neurotrophins (NTs) and their receptors ( 4 – 7 ). NTs are a group of molecules widely present in the central and peripheral nervous system. They have a key role in developmental neurobiology, by regulating neuronal survival, differentiation, neurites growth, and synthesis of neurotransmitters ( 8 ). NTs not only display key roles in neuronal tissues, but also in several non-neuronal tissues, such as mammary glands ( 9 , 10 ) and gynecological organs ( 11 – 13 ). During the neoplastic processes, NTs and their receptors are overexpressed by tumoral cells, promoting progression and angiogenesis in several cancer models. For instance, the expression of NTs predicts poor survival rates in breast and ovarian cancer patients ( 14 – 16 ) and NTs have been proposed as potential therapeutic targets in these neoplasms ( 4 , 17 , 18 ). Angiogenesis is a key process to supply nutrients and oxygen to tumor cells, as well as a way for cells to leave or enter to the circulation ( 19 ). In fact, tumors that have a high microvascular density could be more aggressive and generate distant metastasis ( 20 ). The term angiogenesis was first used by the British surgeon John Hunter in 1787; however, the study of vascular morphology in animal and human tumors began only in the first half of twentieth century ( 21 ). Endothelial cells, a baseline membrane and pericytes are the minimal components of vasculature. Endothelial cells form a barrier that controls the trans-endothelial flux of soluble components and most cell types ( 22 ). During angiogenesis, there are several important steps: a detection of humoral paracrine signals or angiogenic factors, resulting in the sprouting of endothelial cells, followed by an orchestrated increase of endothelial cell proliferation, migration, and differentiation ( 23 ). Activation of endothelial cells is accompanied by pericytes detachment, proliferation, and migration into the vessel interstitium to envelop the surface of the vascular tube. In addition, fibroblasts and endothelial cells build and remodel the new extracellular matrix ( 23 , 24 ). All of these changes are necessary to generate new capillary vessels.

Pharmacologic

Since the TRK receptors (TRKA, TRKB, and TRKC) are implicated in the progression of different kind of neoplasms, several drugs have been developed to target tumors that overexpress TRK receptors or present chromosomal rearrangements of TRK genes. For instance, in 2018, the Food and Drug Administration (FDA) approved Larotrectinib (Vitrakvi) for treatment of adult and pediatric patients with solid tumors that have TRK gene fusions ( 132 ). This was based in promissory results of 3 clinical trials ( NCT02122913 , NCT02637687 , and NCT02576431 ) with Larotrectinib that showed an objective response rate of 75% in pediatric patients, with good tolerability and safety ( 133 , 134 ). Larotrectinib is a small molecule that binds to NTs receptors, thereby preventing neurotrophin-TRK interaction and TRK activation, which results in the induction of cellular apoptosis and the inhibition of cell growth ( 135 ). It is important to point out that Larotrectinib was one of the first “tissue-agnostic drug” approved by FDA, concept that refers to a substance to treat cancer based on genetic and molecular features of tumor cells, regardless of the cancer type or origin ( 136 ). Additionally, Entrectinib (Rozlytrek), a potent and selective ATP-competitive inhibitor, was approved by the FDA in 2019 for adults and pediatric patients above 12 years old with solid tumors (as ovarian cancer) that have a TRK fusion without a known acquired resistance mutation ( 137 ). The first results of phase I/II studies show promising results: for example, an objective response rate of 57.4% was obtained in 54 adults with advanced or metastatic TRK fusion-positive solid tumors ( 138 ). Unfortunately, some patients have reported resistance to TRK inhibition with this drug considered as first generation of TRK inhibitors ( 139 ), probably due to mutations in TRK domain ( 140 , 141 ). To improve this aspect, a next-generation TRK-targeted agent is under study. For example, Loxo-195 is a recently developed drug, which phase 1/2 of the study started in 2017 in patients with TRK-positive solid tumors and TRK fusion-positive cancers (clinical trials NCT03215511 and NCT03206931 ). This drug could become an alternative treatment for tumors with acquired resistance to first-generation TRK-targeted agents ( 142 ). VMD-928 is another specific TRK inhibitor which is under phase 1 of the study since 2018 for treatment of advanced adult solid tumors or lymphoma ( NCT03556228 ). Because TRK overexpression is present in gynecological cancers, and particularly TRK fusion has been described in cervical and uterine cancer ( 143 , 144 ), the use of TRK inhibitors could be beneficial in these kinds of neoplasms. However, it is necessary to continue the studies to determine their effectiveness in gynecological cancers.

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