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Review
. 2024 Sep 26:14:1477610.
doi: 10.3389/fonc.2024.1477610. eCollection 2024.

The role of extracellular vesicles in the pathogenesis of gynecological cancer

Affiliations
Review

The role of extracellular vesicles in the pathogenesis of gynecological cancer

Madhura Chatterjee et al. Front Oncol. .

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.

Keywords: biomarkers; cancer progression; extracellular vesicles; gynecological cancer; therapeutic potential.

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Conflict of interest statement

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.

Figures

Figure 1
Figure 1
Different types of gynecological cancer, their epidemiology, and etiology. Cervical cancer is the fourth most common type of gynecological cancer which is caused by HPV infection. Endometrial cancer, the sixth most common type of gynecological cancer, is caused by estrogen. Ovarian cancer, the eighth most common type of gynecological cancer is caused by genetic damage. Vaginal cancer, which is very rare, is also caused by HPV infection. Uterine sarcoma is also rare and caused by radiation, EBV infection, estrogen, and tamoxifen. GTD and vulval cancer are also rare types of gynecological cancer whose etiology includes genetic and HPV, respectively. GTD, gestational trophoblastic disease; HPV, human papilloma virus; EBV, Epstein-Barr virus.
Figure 2
Figure 2
Biogenesis and uptake of different types of EVs. EVs comprise of MVs, EXs, and ApoBDs. MVs, 100-1000 nm in size, are produced by plasma membrane outward budding. EXs are 30-150 nm in size and of endocytic origin. Invagination of plasma membrane forms early endosomes. Invagination of early endosomal membrane generates EXs which mature into MVB. MVB fuses with the plasma membrane to release the EXs outside the cells. ApoBDs are generated from apoptotic cells having varying size (50-5000 nm). EVs are taken up by the recipient cells either by direct fusion with the plasma membrane or by endocytosis. In both the mechanisms, eventually, the contents (such as mRNAs, miRNAs, proteins, etc.) of the EVs are released into the cytosol of the recipient cells, thereby altering the phenotypes of the EVs fused recipient cells.
Figure 3
Figure 3
The role of EVs in cervical cancer. 1. HPV oncoproteins lead to the release of Wnt7b mRNA-enriched EVs from cervical cancer cells which promote proliferation and angiogenesis of endothelial cells. (black arrows) 2. HPV-infected cervical cancer cell-derived EVs promote replication of HIV-1 in macrophages (red arrows) 3. Cervical cancer cell-derived EVs transfer MCM3AP-AS1 to endothelial cells to promote angiogenesis (green arrows) 4. hBMSC-EVs transfer miR-144-3p to cervical cancer cells and down-regulate their proliferation, migration, and invasion. (yellow arrows) 5. hBMSC-EVs also release miR-331-3p-enriched EVs which inhibit the growth of cervical cancer cells. (blue arrows). Green upward arrows indicate up-regulation; Red downward arrows indicate down-regulation. HPV, human papilloma virus; EV, extracellular vesicle; CYP, cytochrome P450; 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; miR, microRNA.
Figure 4
Figure 4
The role of EVs in endometrial cancer. 1. EV-mediated transfer of TC0101441 from H-ECSC to L-ECSC contributes to endometriosis migration and invasion. (black arrows) 2. Endometrial cancer cell-derived EVs are enriched with LGALS3BP which helps in secondary colonization of the tumor. (red arrows) 3. hUCMSC-EVs, enriched with miR-302a, inhibit the proliferation and invasion of the endometrial cancer cell. (green arrows) 4. CAF, overexpressed with miR-320a, tends to release miR-320a enriched EVs which down-regulate endometrial tumor cell proliferation and migration. (violet arrows) 5. Carboplatin and paclitaxel loaded MSC-EVs enhance apoptosis and inhibit migration and invasion of endometrial cancer cells. (sky arrows). Green upward arrows indicate up-regulation; Red downward arrows indicate down-regulation. H-ECSC, TC0101441 high expressing endometriotic cyst stromal cell; EVs, extracellular vesicles; L-ECSC, TC0101441 low expressing endometriotic cyst stromal cell; LGALS3BP, galectin-3-binding protein; hUCMSC, human umbilical cord mesenchymal stem cell; miR, microRNA; CAF, cancer-associated fibroblast; MSC, mesenchymal stem cell.
Figure 5
Figure 5
The role of EVs in ovarian cancer. 1. Ovarian cancer cell-derived EVs transfer MMP-1 mRNA to mesothelial cell, leading to mesothelial apoptosis, thereby augmenting cancer metastasis. (black arrows) 2. Cisplatin-treated ovarian cancer cell-derived EVs promote invasion and impart cisplatin resistance to bystander cells. (blue arrows) 3. FAPhighα-SMAlow CAF-EVs promote proliferation, migration, invasion, and adhesion of ovarian cancer cells via the transfer of SLPI. (red arrows) 4. MSC-EVs transfer miR-18a-5p to ovarian cancer cells, thereby down-regulating cancer proliferation, migration, invasion, and chemoresistance. (green arrows) 5. MSC-EVs also transfer miR-424 to ovarian cancer cells, and hence perturbing cancer proliferation, migration, invasion, and angiogenesis. (sky arrows). Green upward arrows indicate up-regulation; Red downward arrows indicate down-regulation. EVs, extracellular vesicles; FAP, fibroblast activation protein-α; α-SMA, α smooth muscle cell actin; CAF, cancer-associated fibroblast; SLPI, secretory leukocyte protease inhibitor; MSC, mesenchymal stem cell; miR, microRNA.
Figure 6
Figure 6
The role of EVs in vaginal cancer. 1. bEVs from G. vaginalis and M. mulieris induce inflammation of vaginal epithelial cells, thereby leading to adverse reproductive outcomes. (black arrows) 2. Lactobacillus spp.-derived bEVs are enriched with several unique proteins and metabolites which prevent the attachment and entry of HIV-1 to CD4+ T-cells. (green arrows) 3. Vaginal fibroblasts release TIMP-2, TGFβ, and ABCC4-enriched EVs which down-regulate the collagen content, proliferation, and migration of normal fibroblasts. (sky arrows). Green upward arrows indicate up-regulation; Red downward arrows indicate down-regulation. bEVs, bacterial extracellular vesicles; 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.
Figure 7
Figure 7
The role of EVs in uterine sarcoma and vulval cancer. (A) EVs released from ULMS cell lines or patient’s sera and tissues are enriched with miR-369-3p and miR-654-3p which convert normal fibroblasts into CAFs. (B) CAF-EVs are shown to be enriched with UCA1 which confers VSCC cells resistance against cisplatin. ULMS, uterine leiomyosarcoma; EVs, extracellular vesicles; miR, microRNA; CAF, cancer-associated fibroblast; UCA1, urothelial cancer-associated 1; VSCC, vulvar squamous cell carcinoma.

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Grants and 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.

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