Abstract
Gynecological cancer, the most common form of cancers in women worldwide, initiates in the reproductive organs of females. More often, the common treatment measures, i.e. surgery, radiation, and medical oncology are found to be unsuccessful in the treatment of gynecological tumors. Emerging evidence indicates that extracellular vesicles (EVs) play a significant role in the pathogenesis of gynecological cancers by distinct mechanisms. The present review highlights how EVs contribute to the progression of different types of gynecological cancers such as cervical cancer, endometrial cancer, ovarian cancer, vaginal cancer, uterine sarcoma, gestational trophoblastic disease (GTD), and vulvar cancer. The primary focus is to understand how EVs’ cargo alters the phenotypic response of the recipient cells, thereby contributing to the progression of the disease, thus can be considered as a prognostic and diagnostic biomarker. A brief discussion on the role of EVs in the diagnosis and prognosis of different gynecological cancer types is also highlighted. Targeting the biogenesis of the EVs, their inside cargo, and EVs uptake by the recipient cells could be a potential therapeutic approach in the treatment of gynecological cancer beside conventional therapeutic means.
Introduction
Gynecological cancers are defined as cancers which begin in the reproductive organs of females such as cervix, endometrium, fallopian tubes, ovaries, uterus, and vagina (1). It is considered as the commonest form of cancers in women worldwide which impose significant public health issues (2). In developing countries like India, gynecological cancers account for ~25% of all cancer types diagnosed among women aged up to mid-sixties (3). In India, cervical cancer ranks second in terms of both incidence and mortality (4). The present review begins with a brief introduction of different types of gynecological cancers including their mortality rate worldwide. The main section of the review focuses on understanding how extracellular vesicles (EVs) play their part in the progression of gynecological cancers by different mechanisms. The final part of the review highlights the role of EVs as biomarkers in different types of gynecological cancers.
Types of gynecological cancers
Gynecological tumors can be categorized into cervical cancer, endometrial cancer, ovarian cancer, vaginal cancer, uterine sarcoma, gestational trophoblastic disease (GTD), and vulvar cancer. Table 1 briefly highlights the abundance, etiology, and cellular transformation mechanisms of different types of gynecological cancer. Figure 1 also summarizes different forms of gynecological cancers, their epidemiology, and etiology.
Table 1
| Gynecological cancer type | Rank | Etiology | Transformation mechanism | Reference/s |
|---|---|---|---|---|
| Cervical cancer | 4 | HPV | Viral E6 and E7 expression inactivates p53 and Rb of the host, promoting cellular transformation | (5) |
| Down-regulation of FHIT expression promotes p16 and c-myc over-expression, triggering cervical cancer progression | (6) | |||
| K-ras and H-ras mutations induce cervical cancer pathogenesis | (1) | |||
| RCAS1 overexpression is associated with cervical cancer invasiveness | (7) | |||
| Endometrial cancer | 6 | Estrogen | Loss of PTEN expression is associated with type I endometrial cancer progression | (8) |
| Mutations in K-ras and β-catenin also leads to type I endometrial cancer progression | (9) | |||
| Microsatellite instability results intype I endometrial cancer | (10) | |||
| Mutations in TP53 are associated with type II endometrial cancer | (11) | |||
| HER2 overexpression, p16 inactivation, and E-Cadherin down- regulation is also observed in a few type II endometrial cancers | (12, 13) | |||
| Ovarian cancer | 8 | Genetic damage | K-ras and BRAF mutations in the development of ovarian cancer | (14) |
| TP53 mutation and HER2, AKT2, and myc overexpression is associated with ovarian cancer development | (15, 16) | |||
| ~10% of ovarian cancer possesses mutations in BRCA1 and BRCA2 genes | (17) | |||
| HB-EGF promotes proliferation and metastasis of ovarian cancer | (18) | |||
| HB-EGF promotes proliferation and metastasis of ovarian cancer | (18) | |||
| Vaginal cancer | Rare | HPV | HPV infections lead to the development of vaginal cancer in younger women | (19) |
| The expression of DDX48, erb-B3 binding protein, and biliverdin reductase is altered in vaginal carcinoma, which may play a role in vaginal carcinogenesis | (20) | |||
| Uterine sarcoma | Rare | Radiation | RTK and HER2 have been shown to play a key role in carcinosarcoma pathogenesis | (21) |
| EBV | Rb-cyclin D plays an important role in leiomyosarcoma pathogenesis | (22) | ||
| Radiation, estrogen, tamoxifen | Wnt pathway and histone de/ acetylation plays a key role in ESS pathogenesis | (23, 24) | ||
| GTD | Rare | Genetic | NALP7 mutation is shown to be responsible for GTD | (25) |
| Vulval cancer | Rare | HPV | EGFR and p53 overexpression is associated with poor prognosis of vulval cancer | (26) |
| p73 overexpression is also observed in certain types of vulval cancer | (27) |
Different types of gynecological cancer; their rank according to the abundance, etiology, and cellular transformation mechanisms.
HPV, human papilloma virus; Rb, retinoblastoma; FHIT, fragile histidine triad; ras, rat sarcoma; RCAS1, receptor binding cancer antigen expressed on SiSo cells; PTEN, phosphatase and TENsin homolog; TP53, tumor protein p53; HER2, human epidermal growth factor receptor 2; BRAF, rapidly accelerated fibrosarcoma homolog B; BRCA, breast cancer; HB-EGF, heparin-binding EGF-like growth factor; DDX48, DEAD (Asp-Glu-Ala-Asp) box protein 48; erb-B3, erythroblastic oncogene B; RTK, receptor tyrosine kinase; EBV, Epstein-Barr virus; Wnt, wingless/integrated; ESS, endometrial stromal sarcoma; GTD, gestational trophoblastic disease; EGFR, extracellular growth factor receptor.
Figure 1
Cervical cancer
Cervical cancer, the malignant neoplasm, is originated from the cells in the uterine cervix which is further invaded into the female reproductive system (28). According to the World Health Organization (WHO), it is the fourth common cancer in women worldwide. The major causative agent for cervical cancer is human papilloma virus (HPV) (29). The 7,800 nucleotides long HPV DNA includes two open reading frames (ORFs), early- and late ORFs (30). Early ORFs codes for 7 proteins, named E1-7,which essentially control viral replication and host cell transformation (31). On the other hand, the late ORFs encoding proteins, L1 and L2 are the structural components of the virion (5). The integration of HPV DNA into the host genome leads to the expression of E6 and E7 which interact with host’ p53 and Rb, leading to their inactivation which ultimately results in cellular transformation (5). Therefore, the affinity of E6 and E7 to the host molecules determines the oncogenic potential of HPV, contributing to the pathogenesis of cervical cancer (32). However, emerging evidence indicates that the loss of chromosome 2q, -3p, and -11q as well as the addition of chromosome 1q and -3q are associated with the progression of cervical cancer (33). The fragile histidine triad gene (FHIT), located on chromosome 3p, is shown to be under-expressed in cervical cancer (34) which is accompanied by p16 and c-myc overexpression, thereby contributing to early progression of cervical cancer (6). Similarly, late events of cervical carcinogenesis are associated with mutations in K-ras and H-ras genes (1). On the other hand, a higher expression of RCAS1 is observed in invasive cervical carcinomas (7) which shows a positive correlation with cervical cancer progression.
Endometrial cancer
Endometrial cancer is a tumor which arises in the inner epithelial lining of the uterus (35). It is the sixth common cancer developed among women worldwide. Endometrial cancer is further classified as (1) estrogen-related or type I or endometrioid carcinoma and (2) non-estrogen-related or type II or non-endometrioid carcinoma (36). Uncontrolled exposure of estrogen to preneoplastic lesion hyperplasia forms such type I endometrial cancer (37). Mechanistically, loss of PTEN expression (8) and mutations in K-ras and β-catenin genes (9) are shown to be associated with the progression of type I endometrial cancer. Additionally, microsatellite instability (MSI) also results in type I endometrial cancer (10). In contrast to type I, type II endometrial carcinoma is developed from atrophic endometrium (36). In majority of cases, mutations in TP53 gene is associated with type II endometrial cancer (11); whereas overexpression of HER2, inactivation of p16, and down-regulation of E-Cadherin expression are also observed in a few type II endometrial cancers (12, 13).
Ovarian cancer
Ovarian cancer is defined as the malignancy of cells in the ovary (38). At present, it is the eighth most common cancer developed among women worldwide. The etiology of ovarian cancer includes damage to the genetic material (39). Mechanistically, mutations in K-ras and BRAF are shown to be associated with the development of ovarian cancer (14). In addition to these, mutations in TP53 and overexpression of AKT2, HER2 and myc also leads to ovarian cancer development (15, 16). However, ~10% of ovarian cancer has been reported to possess mutations in the genes, BRCA1 and BRCA2 (17), located in chromosomes 17q and 13q, respectively (40). Moreover, heparin-binding EGF (HB-EGF) plays a crucial role in the proliferation and metastasis of ovarian cancer (18), and HB-EGF inhibitors such as CRM197 may be used as a potential chemotherapeutic agent in the treatment of ovarian cancer (41).
Vaginal cancer
Vaginal cancer is defined as cancer of the vagina without the evidence of vulval or cervical cancer or their presence in the past five years (42). Unlike the other types of gynecological cancers, vaginal cancer is very rare. Due to its rarity, the etiology of vaginal cancer is not completely understood. However, emerging evidence indicate that HPV infections may lead to the development of vaginal cancer in younger women (19) although in majority of instances, vaginal cancer is observed in older postmenopausal women (19). The expression of three signature proteins, DDX48, erb-B3 binding protein, and biliverdin reductase is shown to be significantly altered in vaginal carcinomas which are believed to play a major role in the pathogenesis of vaginal carcinoma (20).
Uterine sarcoma
Uterine sarcomas are originated from the smooth muscles and connective tissues of the uterus (43). It accounts for ~1% of all gynecological cancers, therefore is also considered as a rare type of gynecological tumor (44). Uterine sarcomas have a few variants, carcinosarcoma, leiomyosarcoma, and endometrial stromal sarcoma (ESS) (45). The etiology of uterine sarcoma appears to be epigenetic. For example, radiation is the probable cause of carcinosarcoma (46). Receptor tyrosine kinase (RTK) and HER2 are shown to play a key role in carcinosarcoma pathogenesis and inhibitors against RTK and HER2 are found to be quite effective against carcinosarcoma (21). Epstein-Barr virus (EBV) infection has been shown to be associated with leiomyosarcoma (47). Mechanistically, ~90% of leiomyosarcoma cases have defects in the Rb-cyclin D pathway, which demonstrates the crucial role Rb-cyclin D pathway in the pathogenesis of leiomyosarcoma (22). Radiation and prolonged use of estrogen or tamoxifen have been shown to be the etiology for ESS (48). Mechanistically, the deregulation of Wnt signaling pathway is responsible for ESS pathogenesis (23). In another study, histone de/acetylation is shown to play a crucial role in the progression of ESS (24) and HDAC inhibitors could be used as potential therapeutics against ESS (23).
GTD
GTD is a rare form of gynecological cancer (49) with an incidence of 1 to 2 per 1000 pregnancies (50), resulted from abnormal fertilization (51). The etiology of GTD is shown to be genetic aberration. In this case, fertilization of an ovum without maternal chromosomes with a sperm forms the complete hydatidiform mole which constitutes all paternal chromosomes (52). Genes responsible for GTD are shown to be located in chromosome 19q13.3–13.4 (53), in which NALP7 mutation is predominantly observed (25).
Vulval cancer
Vulval cancer, the cancer of the vulva in postmenopausal women (54), is another type of rare gynecological cancer which accounts for 2-5% of all gynecological cancers (54). The most common subtype of vulval cancer is the squamous cell carcinoma (SCC) (54). HPV is the main causal agent of vulval cancer (55) although HPV-negative vulval cancer also exists (27). Overexpression of EGFR and p53 is shown to be associated with poor prognosis of vulval cancer (26). In addition, p73 overexpression is also observed in certain types of vulval cancer (27).
The role of EVs in gynecological cancer
EVs: a general overview
EVs are lipid bilayer enclosed, nano-sized particles which are released from almost every cell type into the extracellular environment (56). EVs represent a third mechanism of cell-to-cell communication beside the direct cell-to-cell contact and cellular secretary molecules (57). EVs transfer biomolecules such as DNA, RNA, microRNA (miRNA), long non-coding RNA (lncRNA), circular RNA, protein, lipid, metabolite etc. between the cells, thereby altering the phenotypes of the target recipient cells (58–65). EVs are abundantly found in biological fluids like blood, urine, saliva, breast milk, cerebrospinal fluid etc. and even in the interstitial spaces between the cells (66–70). EVs are readily taken up by the recipient cells either by direct fusion of EVs’ membrane with the recipient cells’ plasma membrane or by endocytic mechanism (60, 71). EVs can be broadly classified according to the biogenetic mechanism, size distribution, and function into microvesicles (MVs), exosomes (EXs), and apoptotic bodies (ApoBDs). Figure 2 briefly illustrates the biogenetic mechanism of different types of EVs and their fusion with target recipient cells.
Figure 2
MVs (also called microparticles; MPs or ectosomes) are produced by outward budding of the plasma membrane of a cell (61). Actomyosin reorganization is shown to play a crucial role in the biogenesis of MVs (61). Therefore, regardless of the originating cell, both cytosolic and membrane-associated proteins such as tetraspanins, integrins, cytoskeletal proteins, heat shock proteins, and proteins associated with post-translational modifications are often found abundantly in the MVs (69). MVs range in size from 100 nm to 1µm (70).
Unlike MVs, EXs have a diameter range of 30-150 nm (72). EXs are of endocytic origin (69); first the invagination of the plasma membrane forms large endosomes which are further invaginated to produce smaller EXs within the endosomes that are matured into multivesicular bodies (MVBs) (69). MVBs eventually fuse with the plasma membrane to release the EXs outside (69). Therefore, the endosomal sorting complexes required for the transport (ESCRT) pathway-associated proteins such as Alix, TSG101 etc. are abundantly found in the EXs (73, 74).
The other type of EVs, ApoBDs, having a broader diameter range between 50 nm to 5 µm, are generated from apoptotic cells (75). Apoptotic stimuli-induced cellular contraction generates a significant hydrostatic pressure which segregates the plasma membrane from the cytoskeleton, leading to the release of ApoBDs (76). Different cell organelle markers such as GRP78 for Golgi and endoplasmic reticulum, HSP60 for mitochondria, histones for nucleus are abundantly found in the ApoBDs (76).
EVs in gynecological cancer
Emerging evidence indicates that EVs play a crucial role in the development and progression of gynecological cancers. The present section briefly highlights how EVs contribute to the progression of different types of gynecological cancers. Table 2 summarizes EVs’ role in various gynecological tumors.
Table 2
| Gynecological cancer type | EV component | Mechanism | Reference/s |
|---|---|---|---|
| Cervical cancer | Wnt7b mRNA | E6 oncoproteins of HPV 16/18 induce Wnt7b mRNA in cervical cancer cells, leading to the release Wnt7b mRNA positive EVs which promote endothelial proliferation and angiogenesis. | (77) |
| Cytochrome P450 and HPV oncoproteins | HPV-infected cervical cancer cell-derived EVs induce replication of HIV-1 in macrophages via the transfer of cytochrome P450 and HPV oncoproteins | (78) | |
| MCM3AP-AS1 | Cervical cancer cell-derived EVs transfer MCM3AP-AS1 to endothelial cells, thereby inducing angiogenesis through binding miR-93 and inducing miR-93 target, p21 expression, further facilitating tumor growth | (79) | |
| miR-144-3p | hBMSC-EVs transfer miR-144-3p to cervical cancer cells and target CEP55, inhibiting proliferation, migration, and invasion of cancer cells while promoting invasion of cancer cells while promoting apoptosis | (80) | |
| miR-331-3p | hBMSC-EVs also transfer miR-331-3p to cervical cancer cells which targets DNMT3A and down-regulates the methylation of LIMS2 to inhibit the growth of cervical tumor | (81) | |
| Endometrial cancer | TC0101441 | TC0101441 is transferred from H-ECSCs to L-ECSCs via the EVs, promoting migration and/or invasion of the endometriosis | (82) |
| LGALS3BP | Endometrial tumor-derived EVs are enriched with LGALS3BP with epithelial-like properties which facilitate secondary colonization of the tumor | (83) | |
| hsa_circ_0001610 | M2-macrophage-derived EVs transfer hsa_circ_0001610 to the endometrial cells, thereby targeting miR-139-5p expression, leading to cyclin B1 expression and conferring tumor radio resistance | (84) | |
| miR-302a | hUCMSC-EVs are enriched with transfer hsa_circ_0001610 to the endometrial cells, thereby targeting miR-139-5p expression, leading to cyclin B1 expression and conferring tumor radio resistance | (84) | |
| miR-302a | hUCMSC-EVs are enriched with miR-302a which targets cyclin D and AKT pathway in endometrial cancer cells, thereby inhibiting tumor proliferation and migration | (85) | |
| miR-320a | miR320a over-expressed EVs from CAFs inhibit HIF-1α expression in endometrial cancer cells, thereby down-regulating VEGF-A expression and associated tumor proliferation | (86) | |
| carboplatin, paclitaxel | MSC-EVs, loaded with carboplatin and paclitaxel induce endometrial cancer cell apoptosis whereas inhibiting cell migration and invasion via down-regulating Rac1/NF-κB- dependent expression of MMP-2 | (87) | |
| Ovarian cancer | MMP-1 mRNA | Ovarian cancer cell-derived EVs transfer MMP-1 mRNA to mesothelial cells, leading to apoptosis, thereby facilitating peritoneal dissemination of metastatic ovarian cancer | (88) |
| Cisplatin-treated ovarian cancer cells release EVs which promote invasion and cisplatin-resistance to recipient bystander cells via the activation of p38 and JNK signaling pathway | (89) | ||
| SLPI | FAPhighα-SMAlow subpopulation of CAFs release SLPI-positive EVs which promote the proliferation migration, invasion, and adhesion of ovarian cancer cells via the activation of PI3K/AKT pathway | (90) | |
| miR-18a-5p | hMSC-EVs transfer miR-18a-5p to ovarian cancer cells and inhibit their proliferation, migration, invasion, and chemoresistance via targeting NACC1 | (91) | |
| miR-424 | MSC-EVs transfer miR-424 to ovarian cancer cells, leading to the downregulation of proliferation, migration, and invasion via targeting MYB. miR-424 of the MSC-EVs also suppress angiogenesis by reducing the expression of VEGF and VEGFR | (92) | |
| FasL, TRAIL | Ascites of ovarian cancer patients bear FasL- and TRAIL-positive EVs which trigger immune evasion by inducing apoptosis of immune cells | (93) | |
| ARG1 | ARG1 in ovarian cancer ascites-derived EVs suppresses peripheral T-cells, leading to immune evasion and promoting tumor growth | (94) | |
| circ-0001068 | circ-0001068 level in the serum EVs of ovarian cancer patients are significantly upregulated which is transferred to T-cells, leading to T-cell exhaustion and tumor immune evasion | (95) | |
| Vaginal cancer | EVs from G. vaginalis and M. mulieris promote TLR-2-specific inflammatory response to trigger adverse reproductive outcomes | (96) | |
| Unique proteins and metabolites | EVs from Lactobacillus spp. transfer unique proteins and metabolites to CD4+ T-cells, thereby preventing the attachment and entry of HIV-1 into the target cells | (97) | |
| TIMP-2, TGFβ, ABCC4 | Vaginal fibroblast-derived EVs of SUI patients down-regulate the collagen content, proliferation, and migration of normal fibroblasts via the transfer of TIMP-2, TGFβ, and ABCC4 | (98) | |
| Uterine sarcoma | miR-369-3p, miR-654-3p | The expression of miR-369-3p and miR-654-3p is up-regulated in the EVs derived from cell lines, tissues, and sera of ULMS patients which converts normal fibroblasts into CAFs | (98) |
| Vulval cancer | UCA1 | CAF-EVs transfer UCA1 to VSCC cells and confer cisplatin resistance through the regulation of miR-103a/ WEE1 axis | (99) |
The role of EVs in the progression of different types of gynecological cancers.
Wnt, wingless/integrated; HPV, human papilloma virus; EVs, extracellular vesicles; HIV-1, human immunodeficiency virus 1; MCM3AP-AS1, micro-chromosome maintenance protein 3-associated protein antisense RNA 1; hBMSC, human bone marrow mesenchymal stem cell; CEP55, centrosomal protein of 55 kDa; DNMT3A, DNA methyltransferase 3 alpha; LIMS2, LIM zinc finger domain containing 2; H-ECSC, TC0101441 high expressing endometriotic cyst stromal cell; L-ECSC, TC0101441 low expressing endometriotic cyst stromal cell; LGALS3BP, galectin-3-binding protein; hUCMSC, human umbilical cord mesenchymal stem cell; miR, microRNA; CAFs, cancer-associated fibroblasts; HIF-1α, hypoxia-inducible factor 1α; VEGF, vascular endothelial growth factor; hMSC, human mesenchymal stem cell; Rac1, Ras-related C3 botulinum toxin substrate 1; NF-κB, Nuclear factor kappa B; MMP, matrix metalloproteinase; JNK, Jun N-terminal kinase; FAP, fibroblast activation protein-α; α-SMA, α smooth muscle cell actin; SLPI, secretory leukocyte protease inhibitor; PI3K, phosphoinositide 3-kinase; NACC1, nucleus accumbens-associated protein 1; MYB, myeloblastosis viral oncogene homolog; VEGFR, VEGF receptor; TLR-2, Toll-like receptor 2; CD, cluster of differentiation; SUI, stress urinary incontinence; TIMP-2, tissue inhibitor of metalloproteinases 2; TGFβ, transforming growth factor-beta; ABCC4, ATP-binding cassette sub-family C member 4; ULMS, uterine leiomyosarcoma; UCA1, urothelial cancer-associated 1; VSCC, vulvar squamous cell carcinoma.
EVs in cervical cancer
Several studies delineate the active participation of EVs in the progression of cervical cancer. For example, E6 oncoproteins of HPV 16/18 are shown to induce the expression of Wnt7b mRNA in cervical cancer cells, resulting in the release of Wnt7b mRNA-enriched EVs (77). These EVs transfer Wnt7b mRNA to the endothelial cells leading to proliferation and angiogenesis by influencing β-catenin signaling (77). HPV-infected cervical cancer cell-secreted EVs are also shown to increase the replication of human immunodeficiency virus (HIV)-1 in infected macrophages through the transfer of cytochrome P450 (CYP) and HPV oncoproteins (78). In another study, cervical cancer cell-derived EVs are appeared to carry a long non-coding RNA (lncRNA), micro-chromosome maintenance protein 3-associated protein antisense RNA 1 (MCM3AP-AS1) which is transferred through the EVs to the recipient endothelial cells, leading to enhanced angiogenesis, via binding miR-93 and up-regulating its target, p21 expression (79). This in turn facilitates tumor growth (79). A bunch of studies also indicate that EVs often impede the progression of cervical cancer by various mechanisms. Human bone marrow mesenchymal stem cell (hBMSC)-derived EVs carry miR-144-3p to cervical cancer cells and target centrosomal protein of 55 kDa (CEP55), leading to the suppression of cancer cell proliferation, migration, and invasion while promoting apoptosis, ultimately inhibiting the progression of cervical cancer (80). hBMSC-EVs are also shown to deliver miR-331-3p to the cervical cancer cells and target DNA methyltransferase 3 alpha (DNMT3A) to reduce the methylation of LIM zinc finger domain containing 2 (LIMS2), thereby perturbing the growth of cervical tumors (81). Figure 3 briefly summarizes how EVs influence the progression of cervical cancer by different mechanisms.
Figure 3
EVs in endometrial cancer
EVs are also associated with the pathogenesis of endometrial cancer. For example, a lncRNA, TC0101441 is shown to be transferred from TC0101441 high expressing endometriotic cyst stromal cells (H-ECSCs) to TC0101441 low expressing ECSCs (L-ECSCs) through the EVs, thereby promoting endometriosis migration and/or invasion (82). Moreover, circulating endometrial tumor cell-derived EVs are found to be enriched with the adhesion protein, galectin-3-binding protein (LGALS3BP) which imparts the epithelial-like properties of the EVs, facilitating the secondary colonization of the tumor (83). miRNAs are often considered as predictive and diagnostic biomarkers for endometriosis (100). Gu et al. further demonstrated that M2-macrophage-derived EVs transfer circular RNA, hsa_circ_0001610 to endometrial cancer cells, leading to a downregulation of miR-139-5p expression, thereby inducing the expression of miR-139-5p target, cyclin B1 and thus conferring tumor radio resistance (84). Li et al. have demonstrated that human umbilical cord mesenchymal stem cell (hUCMSC)-released EVs are enriched with miR-302a which targets cyclin D1 and AKT signaling pathway in endometrial cancer cells, thereby inhibiting tumor proliferation and migration (85). Thus, miR-302a loaded EVs can be used as potential therapeutics in the treatment of endometrial cancer. In another study, miR-320a over-expressed EVs from cancer associated fibroblasts (CAFs) are shown to down-regulate hypoxia-inducible factor 1α (HIF-1α) in endometrial cancer cells, leading to the inhibition of vascular endothelial growth factor A (VEGF-A) expression and associated tumor proliferation (86). In a recent study by Ma et al., mesenchymal stem cell (MSC)-derived EVs loaded with therapeutic drugs, carboplatin and paclitaxel have been shown to induce apoptosis while perturbing endometrial cancer cell migration and invasion via Rac1/NF-κB-mediated down-regulation of matrix metalloproteinase 2 (MMP-2) expression (87). Figure 4 briefly illustrates how EVs influence the progression of endometrial cancer by different mechanisms.
Figure 4
EVs in ovarian cancer
A growing body of evidence identifies EVs to be a critical regulator in the development of metastasis and chemoresistance in epithelial ovarian cancer, mainly via augmenting epithelial to mesenchymal transition and tumor immune evasion (101). The study by Yokoi et al. indicates that EVs from ovarian cancer cells efficiently transfer MMP1 mRNA to mesothelial cells, leading to mesothelial apoptosis, which facilitates peritoneal dissemination of metastatic ovarian cancer (88). In a contemporary study, Samuel et al. have demonstrated that treatment of chemotherapeutic drug, cisplatin to ovarian cancer cells leads to the release of pro-cancerous EVs which not only induce invasion to the recipient bystander cells, but also confer cisplatin resistance through the activation of p38 and JNK signaling pathway (89). FAPhighα-SMAlow subpopulation of CAFs are shown to release secretory leukocyte protease inhibitor (SLPI) through the EVs which facilitates the proliferation, migration, invasion, and adhesion of ovarian cancer cells via the activation of PI3K/AKT pathway (90). In contrast, human MSC (hMSC)-derived EVs inhibit the proliferation, migration, invasion, and chemotherapy resistance of ovarian cancer cells via the transfer of miR-18a-5p and targeting nucleus accumbens-associated protein 1 (NACC1) (91). Similarly, MSC-EVs are also shown to transfer miR-424 to ovarian cancer cells, thereby down-regulating their proliferation, migration, and invasion, probably by targeting myeloblastosis viral oncogene homolog (MYB) (92). The study also delineates that miR-424 transfer through MSC-EVs reduce the expression of endothelial VEGF and VEGFR, thereby suppressing tumor angiogenesis (92). Emerging evidence indicates that genital microbiome plays a key role in genital dysbiosis and development of cervical- and endometrial cancer (102). However, understanding microbiome’s role in ovarian cancer development requires further investigations with robust methodologies which will aid in the development of novel preventive and therapeutic drugs (102). In this context, how the microbiome profile influencing the EVs population, and their characteristics can open a new therapeutic window in the treatment of ovarian cancer. A growing body of evidence also indicates that EVs actively carry immunosuppressors which aid evading host immune response and promoting progression of ovarian cancer. For example, ascites of ovarian cancer patients carries FasL- and TRAIL-positive EVs which facilitate immune evasion by inducing apoptosis of immune cells (93). Similarly, ARG1 in the EVs of ovarian cancer patients’ ascites suppresses peripheral T-cells, leading to immune evasion, thereby facilitating tumor growth (94). Moreover, the expression of circular RNA, circ-0001068 is shown to be significantly elevated in the serum EVs of ovarian cancer patients which induces the expression of PD-1 in T-cells, leading to T-cell exhaustion and promotion of tumor growth (95). In addition to the above, EV metabolites often result in the metabolic reprogramming of the recipient cells. For example, CAF-EVs are shown to carry amino acids and TCA cycle intermediates which are readily taken up by prostate cancer cells, leading to tumor growth and metastasis (103). However, EV-mediated metabolic reprogramming of gynecological cancers including ovarian cancer remains ill-defined. The reasons include difficulties in identifying EV metabolites for effective phenotypic alterations, different cell culture conditions often result in the enrichment of different metabolites into the EVs, the genetic variant associated with different metabolites enrichment into the EVs remains unexplored, and difficulties in EV isolation and purification for metabolites characterization (104). Figure 5 illustrates how EVs are associated with the progression of ovarian cancer.
Figure 5
EVs in vaginal cancer
A few instances report the active participation of the EVs in the pathogenesis of vaginal cancer. Bacteria such as Gardnerella vaginalis and Mobiluncus mulieris when colonized to the vaginal space, it leads to the development of bacterial vaginosis, preterm birth, and other sexually transmitted infections (STIs). A recent study indicates that bacterial EVs (bEVs) can be taken up by the vaginal epithelial cells and induce a Toll-like receptor 2 (TLR2)-dependent inflammatory response, leading to adverse reproductive outcomes (96). Another report delineates that vaginal symbiotic bacteria, Lactobacillus spp. release EVs, rich in unique proteins and metabolites, that protect CD4+ T-cells from HIV-1 infection probably by interfering with the viral attachment and entry into the target cells (97). Vaginal fibroblast-derived EVs of stress urinary incontinence (SUI) patients are shown to down-regulate the collagen content, proliferation, and migration of normal fibroblasts via the transfer of several differentially expressed proteins including tissue inhibitor of metalloproteinases 2 (TIMP-2), transforming growth factor-beta (TGFβ), and ATP-binding cassette sub-family C member 4 (ABCC4) (98). Figure 6 depicts how EVs from different sources are associated with vaginal cancer.
Figure 6
EVs in uterine sarcoma
Very limited studies report the role of EVs in the progression of uterine sarcoma. A recent study demonstrates that the expression of miR-369-3p and miR-654-3p is significantly up-regulated in the EVs derived from the cell lines as well as the sera and tissues of uterine leiomyosarcoma (ULMS) patients which converts normal fibroblasts into CAFs, thereby contributing to the progression of uterine sarcoma (98).
EVs in vulval cancer
A single study demonstrates that EVs play a crucial role in the progression of vulval cancer. CAF-derived EVs are shown to confer cisplatin resistance to vulvar squamous cell carcinoma (VSCC) through the transfer of lncRNA urothelial cancer-associated 1 (UCA1) and regulating miR-103a/WEE1 axis (99).
The role of EVs in the progression of GTD remains ill-defined. Figure 7 briefly illustrates how EVs influence the progression of uterine sarcoma (Figure 7A) and vulval cancer (Figure 7B).
Figure 7
EVs as biomarkers for gynecological cancer
A biomarker is defined as a medical sign that indicates the medical state of a patient which can be accurately measured and is reproducible (105). The present section highlights a brief examples of how EVs serve as biomarkers for different types of gynecological cancers. Table 3 also briefly delineates the role of EVs in different forms of gynecological cancers. For example, Zhou et al. have demonstrated that EVs from hypoxic cervical cancer cells are enriched with miR-152-3p which provides resistance against radiotherapy via targeting Kruppel-like factor 15 (KLF15) (106). As mentioned earlier, E6 oncoproteins of HPV 16/18 transfer Wnt7b mRNA from cervical cancer cells to endothelial cells through the EVs, thereby promoting endothelial proliferation and angiogenesis by β-catenin-dependent mechanisms, and thus can be considered as a potential biomarker for cervical cancer (77). Moreover, the expression of miR-125a-5p in the plasma EVs of cervical cancer patients is shown to be significantly lower as compared to the healthy individuals, thereby serving as a potential biomarker for cervical cancer diagnosis (107). A study by Ding et al. indicates that as compared to cervical intraepithelial neoplasia patients and normal controls, serum EVs of cervical cancer patients display a higher expression of lncRNA DLX6-AS1 which is positively correlated with lymph node metastasis, differentiation, shortened survival, and relapse (108). Therefore, lncRNA DLX6-AS1 in the serum EVs might serve as a promising marker for the prognosis and diagnosis of cervical cancer (108). Cervico-vaginal lavages of cervical cancer patients are shown to be enriched with EVs bearing signature lncRNAs, HOTAIR, MALAT1 and MEG3, making them early detection and diagnostic biomarkers for cervical cancer (109). By using ExoGAG, a highly efficient technology to enrich the EVs, Herrero et al. have demonstrated that endometrial cancer patients with high risk of recurrence exhibit higher expression of annexin A2 in the circulating EVs, thereby EVs’ annexin A2 level is considered as a prognostic biomarker for endometrial cancer (110). The expression of eight signature miRs, miR-383-5p, miR-10b-5p, miR-34c-3p, miR-449b-5p, miR-34c-5p, miR-200b-3p, miR-2110, and miR-34b-3p is shown to be dysregulated in the EVs isolated from pleural lavage of endometrial cancer patients as compared to EVs isolated from the ascitic fluid of control individuals, which marked them biomarkers for endometrial cancer (111). Moreover, miR-200c-3p expression in the urine EVs of endometrial cancer patients is significantly elevated as compared to EVs from patients without an established endometrial cancer which serve as a signature biomarker for endometrial cancer (112). Two signature circular RNAs, hsa_circ_0109046 and hsa_circ_0002577 are shown to be overexpressed in the serum EVs of endometrial cancer patients which is associated with the disease progression and considered as predictive biomarkers for endometrial cancer (113). Kuhlmann et al., by using next-generation sequencing (NGS)-based workflow, have identified miR-181a, miR-1908, miR-21, miR-486 and miR-223 to be over-expressed in the plasma EVs of platinum-resistant ovarian cancer patients, and thus designated these signature miRNAs as a promising biomarker for platinum-resistant ovarian cancer (114). In a cohort study, Lai et al. have demonstrated that three unique proteins, fibrinogen gamma gene (FGG), mucin 16 (MUC16), and apolipoprotein A4 (APOA4) are differentially expressed in the circulating EVs of ovarian cancer patients which can be used to screen patients with ovarian cancer (115). The complement C1r/C1s, Uegf, Bmp1 (CUB) domain-containing protein 1-positive (CDCP1+) EVs are shown to be significantly elevated in the ascites of ovarian cancer patients as compared to the benign counterparts, thereby CDCP1+ EVs is used as a biomarker for early response in ovarian cancer (116). Furthermore, epithelial ovarian cancer-released EVs are shown to transfer lncRNA, MALAT1 to endothelial cells, leading to angiogenesis, and thus considered as predictive biomarker for epithelial ovarian cancer (117). The expression of a circular RNA, circRNA051239 is significantly upregulated in the plasma EVs of epithelial ovarian cancer which targets miR-509-5p, leading to the induction of serine protease 3 (PRSS3), and promotion of cell proliferation and metastasis (118). Thus, EV-circRNA051239 can be considered as a diagnostic biomarker for metastatic epithelial ovarian cancer. As previously mentioned, EVs from cell lines, tissues, and sera of ULMS patients are enriched with miR-369-3p and miR-654-3p which transform normal fibroblasts into CAFs and hence EVs’ miR-369-3p and miR-654-3p can be used as prognostic and diagnostic biomarkers for ULMS (98).
Table 3
| Gynecological cancer type | EV component | Mechanism | Reference/s |
|---|---|---|---|
| Cervical cancer | miR-152-3p | EVs from hypoxia-triggered cervical cancer cells carry miR-152-3p which imparts cervical cancer resistance against radiotherapy via targeting KLF15 | (106) |
| Wnt7b mRNA | E6 oncoproteins of HPV 16/18 transfer Wnt7b mRNA from cervical cancer cells to the endothelial cells, inducing proliferation and angiogenesis by β-catenin-dependent pathway | (77) | |
| miR-125a-5p | The expression of miR-125a-5p in the plasma EVs of cervical cancer patients are significantly lower as compared to healthy individuals, serving as a potential biomarker for cervical cancer | (107) | |
| lncRNA DLX6-AS1 | Serum EVs of cervical cancer show an elevated expression of lncRNA DLX6-AS1 which is also associated with lymph node metastasis, differentiation, shortened survival, and relapse, hence, can be considered as a promising biomarker for cervical cancer | (108) | |
| lncRNA HOTAIR, MALAT1, MEG3 | The expression of HOTAIR, MALAT1, and MEG3 in the EVs derived from cervico-vaginal lavages of cervical cancer patients, are significantly upregulated, thereby considered as diagnostic biomarker for cervical cancer | (109) | |
| Endometrial cancer | annexin A2 | Annexin A2 in the circulating EVs of endometrial cancer patients is highly expressed which has the potential to be a prognostic biomarker for endometrial cancer | (110) |
| miR-383-5p, miR-10b-5p, miR-34c-3p, miR-449b-5p, miR-34c-5p, miR-200b-3p, miR-2110, miR-34b-3p | The expression of eight signature miRs in the pleural lavage EVs of endometrial cancer is shown to be dysregulated in endometrial cancer as compared to EVs isolated from the ascitic fluid of control individuals thereby considered as biomarkers for endometrial cancer | (111) | |
| miR-200c-3p | miR-200c-3p expression in the urine EVs of endometrial cancer patients is shown to be well-elevated as compared to urine EVs of patients without an established endometrial cancer, thus serving as a biomarker | (112) | |
| hsa_circ_0109046, hsa_circ_0002577 | Serum EVs of endometrial cancer patients are enriched with hsa_circ_0109046 and hsa_circ_0002577 which are considered as predictive biomarkers for endometrial cancer | (113) | |
| Ovarian cancer | miR-181a, miR-1908, miR-21, miR-486, , miR-223 | These five signature miRNAs are enriched in the plasma EVs of platinum-resistant ovarian cancer patients as compared to platinum- sensitive individuals and thus can be considered as promising biomarkers for platinum-resistant ovarian cancer | (114) |
| FGG, MUC16, APOA4 | Circulating EVs of ovarian cancer patients have differential expression of FGG, MUC16, and APOA4 which can be used to screen patients with ovarian cancer | (115) | |
| CDCP1 | As compared to the benign ascites, ascites of ovarian cancer patients show an elevated level of CDCP1+ EVs which is used as a biomarker of early response in ovarian cancer | (116) | |
| lncRNA MALAT1 | Epithelial ovarian cancer-derived EVs are shown to transfer MALAT1 to endothelial cells, thereby promoting angiogenesis, and thus considered as predictive biomarker for epithelial ovarian cancer | (117) | |
| circRNA051239 | Plasma EVs of epithelial ovarian cancer show an enhanced expression of circRNA051239 which promotes proliferation and metastasis of epithelial cancer by targeting miR-509-5p and thus, inducing PRSS3 expression | (118) | |
| Uterine sarcoma | miR-369-3p miR-654-3p | EVs from ULMS cells, tissues, and sera are enriched with miR-369-3p and miR-654-3p which transform normal fibroblasts into CAFs and thus, can be used as prognostic and diagnostic biomarkers for ULMS | (98) |
The role of EVs as biomarkers for different types of gynecological cancers.
KLF15, Kruppel-like factor 15; Wnt, wingless/integrated; lncRNA DLX6-AS1, long non-coding RNA distal-less homeobox 6 antisense RNA 1; EVs, extracellular vesicles; miR, microRNA; FGG, fibrinogen gamma gene; MUC16, mucin 16; APOA4, apolipoprotein A4; CDCP1, complement C1r/C1s, Uegf, Bmp1 (CUB) domain-containing protein 1; CAFs, cancer-associated fibroblasts; PRSS3, serine protease 3; ULMS, uterine leiomyosarcoma.
EVs in gynecological cancer diagnosis and prognosis
Early diagnosis and late follow-up become indispensable in the treatment of different types of cancer including gynecological cancer. In this regard, liquid biopsy of patients plays a significant role in the early diagnosis and prognosis of gynecological cancer. Emerging evidence has indicated that EVs released from the tumor cells often reside in body fluids like blood, urine, synovial fluid, saliva, breast milk etc. Therefore, analysis of EVs in the liquid biopsy of gynecological cancer patients often aids in the early diagnosis and prognosis of such cancer. In numerous occasions, it has been found that EVs themselves or their cargoes play a critical role in the diagnosis and prognosis of different types of gynecological tumors. A few examples are provided in the present section. For example, an increased expression of miR-21 and miR-146a is observed in the EVs collected from the cervicovaginal lavage fluid of cervical cancer patients as compared to normal subjects, hence these EV miRNAs can be used for diagnosing the cervical cancer (119). In another study, Zhang et al. have shown that three lncRNAs, Hox transcript antisense intergenic RNA (HOTAIR), maternally expressed gene 3 (MEG3), and MALAT1 (metastasis associated lung adenocarcinoma transcript 1) are enriched in the EVs derived from cervicovaginal lavages of cervical cancer patients which can be used for the detection and diagnosis of cervical cancer (109). Moreover, three signature miRNAs, miR-146a-5p, miR-151a-3p, and miR-2110 are over-expressed in the plasma EVs of cervical cancer patients and can be served as diagnostic and prognostic biomarkers for cervical cancer (120). A study by Herrero et al. has demonstrated that the expression of annexin A2 is significantly higher in the plasma EVs of endometrial cancer patients which is associated with disease recurrence and thus can be considered as a diagnostic and prognostic biomarker for endometrial cancer (110). In addition, miR-15a-5p, miR-106b-5p, and miR-107 are significantly enriched in the plasma EVs of endometrial cancer which is correlated with the disease progression, thus are considered as promising biomarkers for early diagnosis of endometrial cancer (121). An increased expression of miR-95 and decreased expression of miR-205 in the serum EVs of endometrial cancer renders them promising prognostic biomarkers for endometrial cancer (122). In ovarian cancer patients, a down-regulation of miR-1260a, miR-7977, and miR-192-5p expression is observed in the plasma EVs with the potential of considering as diagnostic and prognostic biomarkers for ovarian cancer (123). The expression of hepatocyte growth factor (HGF), signal transducer and activator of transcription 3 (STAT3), and interleukin-6 (IL-6) is shown to be significantly higher in the serum EVs of early stage high grade ovarian cancer as compared to benign and late stage tumor which can be used for early diagnosis of ovarian cancer (124). Moreover, claudin-4 is incorporated into the EVs derived from ovarian cancer cells which is retained in the peripheral blood, thereby likely to be used as a prognostic marker for ovarian cancer (125). In case of ULMS, the expression of miR-654-3p and miR-369-3p in the serum EVs is shown to be significantly higher as compared to myoma patients which can be used in the diagnosis and prognosis of ULMS (126). Table 4 briefly illustrates how EVs contribute to the early diagnosis and prognosis of various gynecological cancers.
Table 4
| Gynecological cancer type | EV origin | EV component | Reference/s |
|---|---|---|---|
| Cervical cancer | Cervicovaginal lavage fluid | miR-21, miR-146a  | (119) |
| Cervicovaginal lavage fluid | HOTAIR, MEG3, MALAT1 | (109) | |
| Plasma | miR-146a-5p, miR-151a-3p, miR-2110 | (120) | |
| Endometrial cancer | Plasma | Annexin A2 | (110) |
| Plasma | miR-15a-5p, miR- 106b-5p, miR-107 | (121) | |
| Serum | miR-95 miR-205  | (122) | |
| Ovarian cancer | Plasma | miR-1260a, miR- 7977, miR-192-5p | (123) |
| Serum | HGF, STAT3, IL-6 | (124) | |
| Peripheral blood | Claudin-4 | (125) | |
| ULMS | Serum | miR-654-3p, miR-369-3p | (126) |
The role of EVs in the diagnosis of different types of gynecological cancers.
miR, microRNA; HOTAIR, Hox transcript antisense intergenic RNA; MEG3, maternally expressed gene 3; MALAT1, metastasis associated lung adenocarcinoma transcript 1; HGF, hepatocyte growth factor; STAT3, signal transducer and activator of transcription 3; IL-6, interleukin 6. () indicates up-regulation; () indicates down-regulation
Conclusion and future direction
Gynecological cancer is considered as one of the major causes of cancer-related death among women worldwide. The treatment measures for gynecological cancer include surgery, radiation oncology, and medical oncology. However, despite advancement in the treatment measures, gynecological cancers continue to be the leading cause of morbidity and mortality of patients. The major reasons behind the increased mortality of gynecological cancers include the detection of tumors in the later stages, limited treatment options, and disease recurrence. Emerging evidence indicates that EVs play an important role in the progression of gynecological cancer by various mechanisms. The present review highlights how tumor cells communicate with other cells in the tumor microenvironment and vice versa through the release of EVs, thereby aiding in the progression of cancer. It has been shown in multiple occasions that EVs’ cargo plays an important role in the progression of gynecological cancer via modulating the phenotype of the EVs-fused recipient cells, and thus considered as prognostic and diagnostic biomarkers for gynecological cancer. Therefore, targeting EVs biogenesis, EVs’ cargo, and the uptake of EVs offer promising therapeutic strategies in restricting the progression of gynecological cancers. On top of this, due to easy uptake mechanism of the EVs, bioengineered EVs often show promising results in the treatment of different cancer types including gynecological cancer. Moreover, mesenchymal stem cell-derived EVs show anticancer properties in the context of gynecological tumors. Therefore, EVs can be used as a promising therapeutic machinery in gynecological cancer depending on the cellular origin. Moreover, EVs readily fuse with the recipient cells and are capable of avoiding host immune response. These trigger the use of EVs as a vehicle in which a therapeutic drug can be entrapped and efficiently transferred to the target recipient cells. In this regard, EV-mediated drug delivery can be an effective therapeutic approach in the treatment of various forms of gynecological tumors. However, a better understanding of EVs biogenesis, functions, and heterogeneity will facilitate the development of advanced EV-based therapeutic strategies against gynecological cancer.
Statements
Author contributions
MC: Data curation, Writing – original draft. SG: Data curation, Writing – review & editing. TM: Data curation, Writing – original draft. DP: Data curation, Methodology, Writing – original draft. UK: Conceptualization, Data curation, Writing – review & editing. AM: Conceptualization, Writing – review & editing. KD: Conceptualization, Methodology, Supervision, Writing – review & editing.
Funding
The author(s) declare that financial support was received for the research, authorship, and/or publication of this article. KD received the Ramalingaswami Re-entry Fellowship (Ref: BT/HRD/35/02/2006) from Department of Biotechnology, Government of India.
Acknowledgments
All the images in the manuscript were created with BioRender.com. We acknowledge that Bio Render provided us with the platform for the preparation of images.
Conflict of interest
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.
Publisher’s note
All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.
References
1
SpandidosDADokianakisDNKallergiGAggelakisE. Molecular basis of gynecological cancer. Ann N Y Acad Sci. (2000) 900:56–64. doi: 10.1111/j.1749-6632.2000.tb06216.x
2
PahwaSKaurA. Statistical analysis of gynecological cancer. Int J Reproduction Contraception Obstetrics Gynecology. (2022) 11:130–6. doi: 10.18203/2320-1770.ijrcog20215089
3
IyokeCAUgwuGO. Burden of gynaecological cancers in developing countries. World J Obstetrics Gynecology. (2013) 2:1–7. doi: 10.5317/wjog.v2.i1.1
4
SathishkumarKSankarapillaiJMathewANairRAGanganeNKhuraijamSet al. Survival of patients with cervical cancer in India – findings from 11 population based cancer registries under National Cancer Registry Programme. Lancet Regional Health - Southeast Asia. (2023) 24:100296. doi: 10.1016/j.lansea.2023.100296
5
BuckCBDayPMTrusBL. The papillomavirus major capsid protein L1. Virology. (2013) 445:169–74. doi: 10.1016/j.virol.2013.05.038
6
SamirRAsplundATotTPekarGHellbergD. High-risk HPV infection and CIN grade correlates to the expression of c-myc, CD4+, FHIT, E-cadherin, Ki-67, and p16INK4a. J Low Genit Tract Dis. (2011) 15:280–6. doi: 10.1097/LGT.0b013e318215170c
7
SonodaKKakuTKamuraTNakashimaMWatanabeTNakanoH. Tumor-associated antigen 22-1-1 expression in the uterine cervical squamous neoplasias. Clin Cancer Res. (1998) 4:1517–20.
8
OhgamiTKatoK. Current Approaches to Endometrial Cancer. pp. 18–32.
9
YeramianAMoreno-BuenoGDolcetXCatasusLAbalMColasEet al. Endometrial carcinoma: molecular alterations involved in tumor development and progression. Oncogene. (2013) 32:403–13. doi: 10.1038/onc.2012.76
10
MacDonaldNDSalvesenHBRyanAIversenOEAkslenLAJacobsIJ. Frequency and prognostic impact of microsatellite instability in a large population-based study of endometrial carcinomas. Cancer Res. (2000) 60:1750–2.
11
HechtJLMutterGL. Molecular and pathologic aspects of endometrial carcinogenesis. J Clin Oncol. (2006) 24:4783–91. doi: 10.1200/jco.2006.06.7173
12
HalperinRZehaviSHablerLHadasEBukovskyISchneiderD. Comparative immunohistochemical study of endometrioid and serous papillary carcinoma of endometrium. Eur J Gynaecol Oncol. (2001) 22:122–6.
13
HolcombKDelatorreRPedemonteBMcLeodCAndersonLChambersJ. E-cadherin expression in endometrioid, papillary serous, and clear cell carcinoma of the endometrium. Obstet Gynecol. (2002) 100:1290–5. doi: 10.1016/s0029-7844(02)02391-8
14
MayrDHirschmannALöhrsUDieboldJ. KRAS and BRAF mutations in ovarian tumors: a comprehensive study of invasive carcinomas, borderline tumors and extraovarian implants. Gynecol Oncol. (2006) 103:883–7. doi: 10.1016/j.ygyno.2006.05.029
15
O'NeillCJDeaversMTMalpicaAFosterHMcCluggageWG. An immunohistochemical comparison between low-grade and high-grade ovarian serous carcinomas: significantly higher expression of p53, MIB1, BCL2, HER-2/neu, and C-KIT in high-grade neoplasms. Am J Surg Pathol. (2005) 29:1034–41. doi: 10.1097/01.pas.0000166367.68459.7d
16
NoweeMSnijdersAMRockxDAPde WitRMKosmaVMHämäläinenKet al. DNA profiling of primary serous ovarian and Fallopian tube carcinomas with array comparative genomic hybridization and multiplex ligation-dependent probe amplification. J Pathol. (2007) 213:46–55. doi: 10.1002/path.2217
17
GeorgeSHShawP. BRCA and early events in the development of serous ovarian cancer. Front Oncol. (2014) 4:5. doi: 10.3389/fonc.2014.00005
18
YotsumotoFYagiHSuzukiSOOkiETsujiokaHHachisugaTet al. Validation of HB-EGF and amphiregulin as targets for human cancer therapy. Biochem Biophys Res Commun. (2008) 365:555–61. doi: 10.1016/j.bbrc.2007.11.015
19
BaralSKBiswasPKaiumMAIslamMADeyDSaberMAet al. A comprehensive discussion in vaginal cancer based on mechanisms, treatments, risk factors and prevention. Front Oncol. (2022) 12:883805. doi: 10.3389/fonc.2022.883805
20
HellmanKAlaiyaAABeckerSLomnytskaMSchedvinsKSteinbergWet al. Differential tissue-specific protein markers of vaginal carcinoma. Br J Cancer. (2009) 100:1303–14. doi: 10.1038/sj.bjc.6604975
21
PezzicoliGMoscaritoloFSilvestrisESilvestrisFCormioGPortaCet al. Uterine carcinosarcoma: An overview. Crit Rev Oncology/Hematology. (2021) 163:103369. doi: 10.1016/j.critrevonc.2021.103369
22
Dei TosAPMaestroRDoglioniCPiccininSLiberaDDBoiocchiMet al. Tumor suppressor genes and related molecules in leiomyosarcoma. Am J Pathol. (1996) 148:1037–45.
23
HrzenjakADieber-RothenederMMoinfarFPetruEZatloukalK. Molecular mechanisms of endometrial stromal sarcoma and undifferentiated endometrial sarcoma as premises for new therapeutic strategies. Cancer Lett. (2014) 354:21–7. doi: 10.1016/j.canlet.2014.08.013
24
HrzenjakAMoinfarFKremserMLStrohmeierBStaberPBZatloukalKet al. Valproate inhibition of histone deacetylase 2 affects differentiation and decreases proliferation of endometrial stromal sarcoma cells. Mol Cancer Ther. (2006) 5:2203–10. doi: 10.1158/1535-7163.Mct-05-0480
25
MurdochSDjuricUMazharBSeoudMKhanRKuickRet al. Mutations in NALP7 cause recurrent hydatidiform moles and reproductive wastage in humans. Nat Genet. (2006) 38:300–2. doi: 10.1038/ng1740
26
MantovaniGFragomeniSMInzaniFFagottiACorteLDGentileschiSet al. Molecular pathways in vulvar squamous cell carcinoma: implications for target therapeutic strategies. J Cancer Res Clin Oncol. (2020) 146:1647–58. doi: 10.1007/s00432-020-03226-6
27
O'NionsJBrooksLASullivanABellADunneBRozyckaMet al. p73 is over-expressed in vulval cancer principally as the Delta 2 isoform. Br J Cancer. (2001) 85:1551–6. doi: 10.1054/bjoc.2001.2138
28
GhoshSJayaramPKabekkoduSPSatyamoorthyK. Targeted drug delivery in cervical cancer: Current perspectives. Eur J Pharmacol. (2022) 917:174751. doi: 10.1016/j.ejphar.2022.174751
29
SchiffmanMCastlePEJeronimoJRodriguezACWacholderS. Human papillomavirus and cervical cancer. Lancet. (2007) 370:890–907. doi: 10.1016/s0140-6736(07)61416-0
30
BurkRDChenZVan DoorslaerK. Human papillomaviruses: genetic basis of carcinogenicity. Public Health Genomics. (2009) 12:281–90. doi: 10.1159/000214919
31
MoodyCALaiminsLA. Human papillomavirus oncoproteins: pathways to transformation. Nat Rev Cancer. (2010) 10:550–60. doi: 10.1038/nrc2886
32
MammasINSourvinosGGiannoudisASpandidosDA. Human papilloma virus (HPV) and host cellular interactions. Pathol Oncol Res. (2008) 14:345–54. doi: 10.1007/s12253-008-9056-6
33
HuangKFLeeWYHuangSCLinYSKangCYLiouCPet al. Chromosomal gain of 3q and loss of 11q often associated with nodal metastasis in early stage cervical squamous cell carcinoma. J Formos Med Assoc. (2007) 106:894–902. doi: 10.1016/s0929-6646(08)60059-5
34
GiarnieriEZanesiNBottoniAAlderisioMLukicAVecchioneAet al. Oncosuppressor proteins of fragile sites are reduced in cervical cancer. Cancer Lett. (2010) 289:40–5. doi: 10.1016/j.canlet.2009.07.017
35
MakkerVMacKayHRay-CoquardILevineDAWestinSNAokiDet al. Endometrial cancer. Nat Rev Dis Primers. (2021) 7:88. doi: 10.1038/s41572-021-00324-8
36
Matias-GuiuXPratJ. Molecular pathology of endometrial carcinoma. Histopathology. (2013) 62:111–23. doi: 10.1111/his.12053
37
BannoKYanokuraMIidaMMasudaKAokiD. Carcinogenic mechanisms of endometrial cancer: involvement of genetics and epigenetics. J Obstet Gynaecol Res. (2014) 40:1957–67. doi: 10.1111/jog.12442
38
HennessyBTColemanRLMarkmanM. Ovarian cancer. Lancet. (2009) 374:1371–82. doi: 10.1016/S0140-6736(09)61338-6
39
LandenCNJr.BirrerMJSoodAK. Early events in the pathogenesis of epithelial ovarian cancer. J Clin Oncol. (2008) 26:995–1005. doi: 10.1200/jco.2006.07.9970
40
PowellSNKachnicLA. Roles of BRCA1 and BRCA2 in homologous recombination, DNA replication fidelity and the cellular response to ionizing radiation. Oncogene. (2003) 22:5784–91. doi: 10.1038/sj.onc.1206678
41
YagiHYotsumotoFSonodaKKurokiMMekadaEMiyamotoS. Synergistic anti-tumor effect of paclitaxel with CRM197, an inhibitor of HB-EGF, in ovarian cancer. Int J Cancer. (2009) 124:1429–39. doi: 10.1002/ijc.24031
42
AdamsTSCuelloMA. Cancer of the vagina. Int J Gynecology Obstetrics. (2018) 143:14–21. doi: 10.1002/ijgo.12610
43
BužinskienėDMikėnasSDrąsutienėGMongirdasM. Uterine sarcoma: a clinical case and a literature review. Acta Med Litu. (2018) 25:206–18. doi: 10.6001/actamedica.v25i4.3931
44
SaitHKAnfinanNMSayedMEEAlkhayyatSSGhanemATAbayazidRMet al. Uterine sarcoma. Clinico-pathological characteristics and outcome. Saudi Med J. (2014) 35:1215–22.
45
KobayashiHUekuriCAkasakaJItoFShigemitsuAKoikeNet al. The biology of uterine sarcomas: A review and update. Mol Clin Oncol. (2013) 1:599–609. doi: 10.3892/mco.2013.124
46
SinghR. Review literature on uterine carcinosarcoma. J Cancer Res Ther. (2014) 10:461–8. doi: 10.4103/0973-1482.138197
47
DuffaudFRay-CoquardISalasSPautierP. Recent advances in understanding and managing leiomyosarcomas. F1000Prime Rep. (2015) 7:55. doi: 10.12703/p7-55
48
AkaevIYeohCCRahimiS. Update on endometrial stromal tumours of the uterus. Diagnostics (Basel). (2021) 11:429. doi: 10.3390/diagnostics11030429
49
NganHYSSecklMJBerkowitzRSXiangYGolfierFSekharanPKet al. Diagnosis and management of gestational trophoblastic disease: 2021 update. Int J Gynecology Obstetrics. (2021) 155:86–93. doi: 10.1002/ijgo.13877
50
HorowitzNSEskanderRNAdelmanMRBurkeW. Epidemiology, diagnosis, and treatment of gestational trophoblastic disease: A Society of Gynecologic Oncology evidenced-based review and recommendation. Gynecologic Oncol. (2021) 163:605–13. doi: 10.1016/j.ygyno.2021.10.003
51
GoldsteinDPBerkowitzRSHorowitzNS. Abeloff's Clinical Oncology. Sixth Edition. NiederhuberJEet al, editors. Elsevier (2020) p. 1544–1559.e1543.
52
FisherRANewlandsES. Gestational trophoblastic disease. Molecular and genetic studies. J Reprod Med. (1998) 43:87–97.
53
MoglabeyYBKircheisenRSeoudMMogharbelNEVeyverIVDSlimRet al. Genetic mapping of a maternal locus responsible for familial hydatidiform moles. Hum Mol Genet. (1999) 8:667–71. doi: 10.1093/hmg/8.4.667
54
RogersLJCuelloMA. Cancer of the vulva. Int J Gynecology Obstetrics. (2018) 143:4–13. doi: 10.1002/ijgo.12609
55
PretiMRotondoJCHolzingerDMichelettiLGallioNMcKay-ChopinDet al. Role of human papillomavirus infection in the etiology of vulvar cancer in Italian women. Infect Agent Cancer. (2020) 15:20. doi: 10.1186/s13027-020-00286-8
56
DasKPaulSMukherjeeTGhoshASharmaAShankarPet al. Beyond macromolecules: extracellular vesicles as regulators of inflammatory diseases. Cells. (2023) 12:1963. doi: 10.3390/cells12151963
57
DasKMukherjeeTShankarP. The role of extracellular vesicles in the pathogenesis of hematological Malignancies: interaction with tumor microenvironment; a potential biomarker and targeted therapy. Biomolecules. (2023) 13:897. doi: 10.3390/biom13060897
58
DasKKeshavaSMukherjeeTRaoLVM. A potential mechanism for the cytoprotective effects of activated protein C-released endothelial extracellular vesicles. Blood. (2024) 143:1670–5. doi: 10.1182/blood.2023023518
59
DasKKeshavaSKolesnickRPendurthiURRaoLVM. MicroRNA-10a enrichment in factor VIIa-released endothelial extracellular vesicles: potential mechanisms. J Thromb Haemost. (2024) 22:441–54. doi: 10.1016/j.jtha.2023.10.021
60
DasKKeshavaSPendurthiURRaoLVM. Factor VIIa suppresses inflammation and barrier disruption through the release of EEVs and transfer of microRNA 10a. Blood. (2022) 139:118–33. doi: 10.1182/blood.2021012358
61
DasKPrasadRSinghABhattacharyaARoyAMallikSet al. Protease-activated receptor 2 promotes actomyosin dependent transforming microvesicles generation from human breast cancer. Mol Carcinog. (2018) 57:1707–22. doi: 10.1002/mc.22891
62
DasKPrasadRRoySMukherjeeASenP. The protease activated receptor2 promotes rab5a mediated generation of pro-metastatic microvesicles. Sci Rep. (2018) 8:7357. doi: 10.1038/s41598-018-25725-w
63
DasKPaulSSinghAGhoshARoyAAnsariAAet al. Triple-negative breast cancer-derived microvesicles transfer microRNA221 to the recipient cells and thereby promote epithelial-to-mesenchymal transition. J Biol Chem. (2019) 294:13681–96. doi: 10.1074/jbc.RA119.008619
64
ParasharDMukherjeeTGuptaSKumarUDasK. MicroRNAs in extracellular vesicles: A potential role in cancer progression. Cell Signal. (2024) 121:111263. doi: 10.1016/j.cellsig.2024.111263
65
DasKRaoLVM. The role of microRNAs in inflammation. Int J Mol Sci. (2022) 23:15479. doi: 10.3390/ijms232415479
66
DasKKeshavaSAnsariSAKondreddyVEsmonCTGriffinJHet al. Factor VIIa induces extracellular vesicles from the endothelium: a potential mechanism for its hemostatic effect. Blood. (2021) 137:3428–42. doi: 10.1182/blood.2020008417
67
DasKPendurthiURManco-JohnsonMMartinEJBrophyDFRaoLVM. Factor VIIa treatment increases circulating extracellular vesicles in hemophilia patients: Implications for the therapeutic hemostatic effect of FVIIa. J Thromb Haemost. (2022) 20:1928–33. doi: 10.1111/jth.15768
68
DasKKeshavaSMukherjeeTWangJMagisettyJKolesnickRet al. Factor VIIa releases phosphatidylserine-enriched extracellular vesicles from endothelial cells by activating acid sphingomyelinase. J Thromb Haemost. (2023) 21:3414–31. doi: 10.1016/j.jtha.2023.08.025
69
DasKPaulSGhoshAGuptaSMukherjeeTShankarPet al. Extracellular vesicles in triple-negative breast cancer: immune regulation, biomarkers, and immunotherapeutic potential. Cancers (Basel). (2023) 15:4879. doi: 10.3390/cancers15194879
70
RaposoGStoorvogelW. Extracellular vesicles: exosomes, microvesicles, and friends. J Cell Biol. (2013) 200:373–83. doi: 10.1083/jcb.201211138
71
MulcahyLAPinkRCCarterDR. Routes and mechanisms of extracellular vesicle uptake. J Extracell Vesicles. (2014) 3:24641. doi: 10.3402/jev.v3.24641
72
KowalJTkachMThéryC. Biogenesis and secretion of exosomes. Curr Opin Cell Biol. (2014) 29:116–25. doi: 10.1016/j.ceb.2014.05.004
73
GéminardCDe GassartABlancLVidalM. Degradation of AP2 during reticulocyte maturation enhances binding of hsc70 and Alix to a common site on TFR for sorting into exosomes. Traffic. (2004) 5:181–93. doi: 10.1111/j.1600-0854.2004.0167.x
74
van NielGPorto-CarreiroISimoesSRaposoG. Exosomes: a common pathway for a specialized function. J Biochem. (2006) 140:13–21. doi: 10.1093/jb/mvj128
75
BorgesFTReisLASchorN. Extracellular vesicles: structure, function, and potential clinical uses in renal diseases. Braz J Med Biol Res. (2013) 46:824–30. doi: 10.1590/1414-431x20132964
76
WickmanGJulianLOlsonMF. How apoptotic cells aid in the removal of their own cold dead bodies. Cell Death Differ. (2012) 19:735–42. doi: 10.1038/cdd.2012.25
77
QiuJ-JSunS-GTangX-YLinY-YHuaK-Q. Extracellular vesicular Wnt7b mediates HPV E6-induced cervical cancer angiogenesis by activating the β-catenin signaling pathway. J Exp Clin Cancer Res. (2020) 39:260. doi: 10.1186/s13046-020-01745-1
78
RanjitSKodidelaSSinhaNChauhanSKumarS. Extracellular vesicles from human papilloma virus-infected cervical cancer cells enhance HIV-1 replication in differentiated U1 cell line. Viruses. (2020) 12:239. doi: 10.3390/v12020239
79
MoYLiangZLanLXiongXZhangCLiuWet al. Extracellular vesicles derived from cervical cancer cells carrying MCM3AP-AS1 promote angiogenesis and tumor growth in cervical cancer via the miR-93/p21 axis. Exp Cell Res. (2023) 428:113621. doi: 10.1016/j.yexcr.2023.113621
80
MengQZhangBZhangYWangSZhuX. Human bone marrow mesenchymal stem cell-derived extracellular vesicles impede the progression of cervical cancer via the miR-144-3p/CEP55 pathway. J Cell Mol Med. (2021) 25:1867–83. doi: 10.1111/jcmm.15573
81
YangSWangLGuLWangZWangYWangJet al. Mesenchymal stem cell-derived extracellular vesicles alleviate cervical cancer by delivering microRNA-331-3p to reduce LIM zinc finger domain containing 2 methylation in tumor cells. Hum Mol Genet. (2022) 31:3829–45. doi: 10.1093/hmg/ddac130
82
QiuJ-JLinYYTangXYDingYYiXFHuaKQ. Extracellular vesicle-mediated transfer of the lncRNA-TC0101441 promotes endometriosis migration/invasion. Exp Cell Res. (2020) 388:111815. doi: 10.1016/j.yexcr.2020.111815
83
MariscalJFernandez-PuentePCalamiaVAbaloASantacanaMMatias-GuiuXet al. Proteomic characterization of epithelial-like extracellular vesicles in advanced endometrial cancer. J Proteome Res. (2019) 18:1043–53. doi: 10.1021/acs.jproteome.8b00750
84
GuXShiYDongMJiangLYangJLiuZ. Exosomal transfer of tumor-associated macrophage-derived hsa_circ_0001610 reduces radiosensitivity in endometrial cancer. Cell Death Dis. (2021) 12:818. doi: 10.1038/s41419-021-04087-8
85
LiXLiuLLYaoJLWangKAiH. Human Umbilical Cord Mesenchymal Stem Cell-Derived Extracellular Vesicles Inhibit Endometrial Cancer Cell Proliferation and Migration through Delivery of Exogenous miR-302a. Stem Cells Int. (2019) 2019:8108576. doi: 10.1155/2019/8108576
86
ZhangNWangYLiuHShenW. Extracellular vesicle encapsulated microRNA-320a inhibits endometrial cancer by suppression of the HIF1α/VEGFA axis. Exp Cell Res. (2020) 394:112113. doi: 10.1016/j.yexcr.2020.112113
87
MaJZhangJLiuSGaoSXiHWangZ. Dual-drug-loaded MSCs-derived exosomal vesicles inhibit endometrial cancer cell proliferation by promoting apoptosis through the migration and invasion of Rac1/NF-κB/MMP2 signalling pathway. Biotechnol Bioprocess Eng. (2024) 29:551–63. doi: 10.1007/s12257-024-00088-4
88
YokoiAYoshiokaYYamamotoYIshikawaMIkedaSIKatoTet al. Malignant extracellular vesicles carrying MMP1 mRNA facilitate peritoneal dissemination in ovarian cancer. Nat Commun. (2017) 8:14470. doi: 10.1038/ncomms14470
89
SamuelPMulcahyLAFurlongFMcCarthyHOBrooksSAFabbriMet al. Cisplatin induces the release of extracellular vesicles from ovarian cancer cells that can induce invasiveness and drug resistance in bystander cells. Philos Trans R Soc B: Biol Sci. (2018) 373:20170065. doi: 10.1098/rstb.2017.0065
90
SunLKeMWangXYinMWeiJXuLet al. FAPhigh α-SMAlow cancer-associated fibroblast-derived SLPI protein encapsulated in extracellular vesicles promotes ovarian cancer development via activation of PI3K/AKT and downstream signaling pathways. Mol Carcinogenesis. (2022) 61:910–23. doi: 10.1002/mc.23445
91
WangXJiangLLiuQ. miR-18a-5p derived from mesenchymal stem cells-extracellular vesicles inhibits ovarian cancer cell proliferation, migration, invasion, and chemotherapy resistance. J Trans Med. (2022) 20:258. doi: 10.1186/s12967-022-03422-7
92
LiPXinHLuL. Extracellular vesicle-encapsulated microRNA-424 exerts inhibitory function in ovarian cancer by targeting MYB. J Trans Med. (2021) 19:4. doi: 10.1186/s12967-020-02652-x
93
PengPYanYKengS. Exosomes in the ascites of ovarian cancer patients: origin and effects on anti-tumor immunity. Oncol Rep. (2011) 25:749–62. doi: 10.3892/or.2010.1119
94
Czystowska-KuzmiczMSosnowskaANowisDRamjiKSzajnikMChlebowska-TuzJet al. Small extracellular vesicles containing arginase-1 suppress T-cell responses and promote tumor growth in ovarian carcinoma. Nat Commun. (2019) 10:3000. doi: 10.1038/s41467-019-10979-3
95
WangXYaoYJinM. Circ-0001068 is a novel biomarker for ovarian cancer and inducer of PD1 expression in T cells. Aging (Albany NY). (2020) 12:19095–106. doi: 10.18632/aging.103706
96
JosephAAntonLGuanYFergusonBMirroIMengNet al. Extracellular vesicles from vaginal Gardnerella vaginalis and Mobiluncus mulieris contain distinct proteomic cargo and induce inflammatory pathways. NPJ Biofilms Microbiomes. (2024) 10:28. doi: 10.1038/s41522-024-00502-y
97
PalominoRANVanpouilleCLaghiLParolinCMelikovKBacklundPet al. Extracellular vesicles from symbiotic vaginal lactobacilli inhibit HIV-1 infection of human tissues. Nat Commun. (2019) 10:5656. doi: 10.1038/s41467-019-13468-9
98
SunXZhuHLiWZhaoLLiWLiXet al. Small extracellular vesicles secreted by vaginal fibroblasts exert inhibitory effect in female stress urinary incontinence through regulating the function of fibroblasts. PloS One. (2021) 16:e0249977. doi: 10.1371/journal.pone.0249977
99
GaoQFangXChenYLiZWangM. Exosomal lncRNA UCA1 from cancer-associated fibroblasts enhances chemoresistance in vulvar squamous cell carcinoma cells. J Obstet Gynaecol Res. (2021) 47:73–87. doi: 10.1111/jog.14418
100
RonsiniCFumientoPIavaroneIGrecoPFCobellisLFranciscisPD. Liquid biopsy in endometriosis: A systematic review. Int J Mol Sci. (2023) 24. doi: 10.3390/ijms24076116
101
LucidiABucaDRonsiniCTinariSBolognaGBucaDet al. Role of extracellular vesicles in epithelial ovarian cancer: A systematic review. Int J Mol Sci. (2020) 21:8762. doi: 10.3390/ijms21228762
102
CapozziVAIncognitoGGScarpelliEPalumboMRandazzoGLPinoAet al. Exploring the relationship between ovarian cancer and genital microbiota: A systematic review and meta-analysis. J Pers Med. (2024) 14:351. doi: 10.3390/jpm14040351
103
ZhaoHYangLBaddourJAchrejaABernardVMossTet al. Tumor microenvironment derived exosomes pleiotropically modulate cancer cell metabolism. Elife. (2016) 5:e10250. doi: 10.7554/eLife.10250
104
KumarSMittalSGuptaPSinghMChaluvally-RaghavanPPradeepS. Metabolic reprogramming in tumor-associated macrophages in the ovarian tumor microenvironment. Cancers. (2022) 14:5224. doi: 10.3390/cancers14215224
105
StrimbuKTavelJA. What are biomarkers? Curr Opin HIV AIDS. (2010) 5:463–6. doi: 10.1097/COH.0b013e32833ed177
106
ZhouJLeiNTianWGuoRGaoFFuHet al. Hypoxic tumor cell-derived small extracellular vesicle miR-152-3p promotes cervical cancer radioresistance through KLF15 protein. Radiat Oncol. (2023) 18:183. doi: 10.1186/s13014-023-02369-3
107
LvATuZHuangYLuWXieB. Circulating exosomal miR−125a−5p as a novel biomarker for cervical cancer. Oncol Lett. (2021) 21:54. doi: 10.3892/ol.2020.12316
108
DingXZZhangSQDengXLQiangJH. Serum exosomal lncRNA DLX6-AS1 is a promising biomarker for prognosis prediction of cervical cancer. Technol Cancer Res Treat. (2021) 20:1533033821990060. doi: 10.1177/1533033821990060
109
ZhangJLiuSCLuoXHTaoGXGuanMYuanHet al. Exosomal long noncoding RNAs are differentially expressed in the cervicovaginal lavage samples of cervical cancer patients. J Clin Lab Anal. (2016) 30:1116–21. doi: 10.1002/jcla.21990
110
HerreroCFuenteADLCasas-ArozamenaCSebastianVPrietoPArrueboMet al. Extracellular vesicles-based biomarkers represent a promising liquid biopsy in endometrial cancer. Cancers (Basel). (2019) 11:2000. doi: 10.3390/cancers11122000
111
Roman-CanalBMoiolaCPGatiusSBonninSRuiz-MiróMGonzálezEet al. EV-associated miRNAs from peritoneal lavage are a source of biomarkers in endometrial cancer. Cancers. (2019) 11:839. doi: 10.3390/cancers11060839
112
SrivastavaAMoxleyKRuskinRDhanasekaranDNZhaoYDRameshR. A non-invasive liquid biopsy screening of urine-derived exosomes for miRNAs as biomarkers in endometrial cancer patients. AAPS J. (2018) 20:82. doi: 10.1208/s12248-018-0220-y
113
XuHGongZShenYFangYZhongS. Circular RNA expression in extracellular vesicles isolated from serum of patients with endometrial cancer. Epigenomics. (2018) 10:187–97. doi: 10.2217/epi-2017-0109
114
KuhlmannJDCheboutiIKimmigRBuderathPReuterMPuppelSHet al. Extracellular vesicle-associated miRNAs in ovarian cancer – design of an integrated NGS-based workflow for the identification of blood-based biomarkers for platinum-resistance. Clin Chem Lab Med (CCLM). (2019) 57:1053–62. doi: 10.1515/cclm-2018-1048
115
LaiHGuoYTianLWuLLiXYangZet al. Protein panel of serum-derived small extracellular vesicles for the screening and diagnosis of epithelial ovarian cancer. Cancers. (2022) 14:3719. doi: 10.3390/cancers14153719
116
KongLXuFYaoYGaoZTianPZhuangSet al. Ascites-derived CDCP1+ extracellular vesicles subcluster as a novel biomarker and therapeutic target for ovarian cancer. Front Oncol. (2023) 13:1142755. doi: 10.3389/fonc.2023.1142755
117
QiuJJLinXJTangXYZhengTTLinYYHuaKQ. Exosomal metastasis−Associated lung adenocarcinoma transcript 1 promotes angiogenesis and predicts poor prognosis in epithelial ovarian cancer. Int J Biol Sci. (2018) 14:1960–73. doi: 10.7150/ijbs.28048
118
MaRYeXChengHCuiHChangX. Tumor-derived exosomal circRNA051239 promotes proliferation and migration of epithelial ovarian cancer. Am J Transl Res. (2021) 13:1125–39.
119
LiuJSunHWangXYuQLiSYuXet al. Increased exosomal microRNA-21 and microRNA-146a levels in the cervicovaginal lavage specimens of patients with cervical cancer. Int J Mol Sci. (2014) 15:758–73. doi: 10.3390/ijms15010758
120
MaGSongGZouXShanXLiuQXiaTet al. Circulating plasma microRNA signature for the diagnosis of cervical cancer. Cancer biomark. (2019) 26:491–500. doi: 10.3233/cbm-190256
121
ZhouLWangWWangFYangSHuJLuBet al. Plasma-derived exosomal miR-15a-5p as a promising diagnostic biomarker for early detection of endometrial carcinoma. Mol Cancer. (2021) 20:57. doi: 10.1186/s12943-021-01352-4
122
ZhengWYangJWangYLiuX. Exosomal miRNA-93 and miRNA-205 expression in endometrial cancer. J King Saud Univ - Sci. (2020) 32:1111–5. doi: 10.1016/j.jksus.2019.10.006
123
ChenLWangKLiLZhengBZhangQZhangFet al. Plasma exosomal miR-1260a, miR-7977 and miR-192-5p as diagnostic biomarkers in epithelial ovarian cancer. Future Oncol. (2022) 18:2919–31. doi: 10.2217/fon-2022-0321
124
DorayappanKDPGardnerMLHiseyCLZingarelliRASmithBQLightfootMDSet al. A microfluidic chip enables isolation of exosomes and establishment of their protein profiles and associated signaling pathways in ovarian cancer. Cancer Res. (2019) 79:3503–13. doi: 10.1158/0008-5472.Can-18-3538
125
LiJSherman-BaustCATsai-TurtonMBristowRERodenRBMorinPJ. Claudin-containing exosomes in the peripheral circulation of women with ovarian cancer. BMC Cancer. (2009) 9:244. doi: 10.1186/1471-2407-9-244
126
NagaoYYokoiAYoshidaKKitagawaMAsano-InamiEKatoTet al. Uterine leiomyosarcoma cell-derived extracellular vesicles induce the formation of cancer-associated fibroblasts. Biochim Biophys Acta Mol Basis Dis. (2024) 1870:167103. doi: 10.1016/j.bbadis.2024.167103
Summary
Keywords
gynecological cancer, extracellular vesicles, biomarkers, therapeutic potential, cancer progression
Citation
Chatterjee M, Gupta S, Mukherjee T, Parashar D, Kumar U, Maitra A and Das K (2024) The role of extracellular vesicles in the pathogenesis of gynecological cancer. Front. Oncol. 14:1477610. doi: 10.3389/fonc.2024.1477610
Received
08 August 2024
Accepted
09 September 2024
Published
26 September 2024
Volume
14 - 2024
Edited by
Stefano Restaino, Ospedale Santa Maria della Misericordia di Udine, Italy
Reviewed by
Carlo Ronsini, Università degli Studi della Campania “Luigi Vanvitelli”, Italy
Sudhir Kumar, Emory University, United States
Updates
Copyright
© 2024 Chatterjee, Gupta, Mukherjee, Parashar, Kumar, Maitra and Das.
This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
*Correspondence: Kaushik Das, kd3@nibmg.ac.in; Arindam Maitra, am1@nibmg.ac.in; Umesh Kumar, umeshkumar82@gmail.com
Disclaimer
All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.