Exosomes in diagnostic and therapeutic applications of ovarian cancer

Abstract

Ovarian cancer accounts for more deaths than any other female reproductive tract cancer. The major reasons for the high mortality rates include delayed diagnoses and drug resistance. Hence, improved diagnostic and therapeutic options for ovarian cancer are a pressing need. Extracellular vesicles (EVs), that include exosomes provide hope in both diagnostic and therapeutic aspects. They are natural lipid nanovesicles secreted by all cell types and carry molecules that reflect the status of the parent cell. This facilitates their potential use as biomarkers for an early diagnosis. Additionally, EVs can be loaded with exogenous cargo, and have features such as high stability and favorable pharmacokinetic properties. This makes them ideal for tumor-targeted delivery of biological moieties. The International Society of Extracellular Vesicles (ISEV) based on the Minimal Information for Studies on Extracellular Vesicles (MISEV) recommends the usage of the term "small extracellular vesicles (sEVs)" that includes exosomes for particles that are 30-200 nm in size. However, majority of the studies reported in the literature and relevant to this review have used the term "exosomes". Therefore, this review will use the term "exosomes" interchangeably with sEVs for consistency with the literature and avoid confusion to the readers. This review, initially summarizes the different isolation and detection techniques developed to study ovarian cancer-derived exosomes and the potential use of these exosomes as biomarkers for the early diagnosis of this devastating disease. It addresses the role of exosome contents in the pathogenesis of ovarian cancer, discusses strategies to limit exosome-mediated ovarian cancer progression, and provides options to use exosomes for tumor-targeted therapy in ovarian cancer. Finally, it states future research directions and recommends essential research needed to successfully transition exosomes from the laboratory to the gynecologic-oncology clinic.

Keywords: Diagnostics; Drug delivery; Drug resistance; Exosomes; Extracellular vesicles; Gynecological cancers; Metastasis; Ovarian cancer; Tumor microenvironment.

Fig. 1

Number of exosome related publications available in PubMed. a graph showing number of articles obtained using the search terms “exosomes” and “cancer”, “exosomes” and “ovarian cancer” including review articles categorized year wise. Venn diagram information summarizing number of publications common to input search criteria organized as (b) “extracellular vesicles” and “ovarian cancer” v/s “exosomes” and ovarian cancer; (c) “exosomes” and “therapeutics” and “ovarian cancer”, “exosomes” and “diagnostics” and “ovarian cancer”, “exosomes” and “theranostics” and “ovarian cancer”. Additionally, the number of exosomes related publications obtained with search terms (d) “ovarian cancer” and “peritoneal cancers”; (e) “ovarian cancer” and “gynecological cancers” and (f) “ovarian cancer” and “peritoneal cancer” and “gynecological cancer” have been compiled. Numbers are reflective of both research and review articles available in the database. Intersection areas are exclusive to publications common under the different input criterion provided. Combining these search criterion gives a comprehensive dataset for a better understanding of number of exosomes related research articles available across multiple cancer types. Figure created with Biorender.com

Fig. 2

Relationship of exosomes and exosomal contents with ovarian cancer progression and metastasis, immune suppression and drug resistance. Image created with BioRender.com

Fig. 3

Role of exosomes in immune modulation in ovarian cancer. The antigen carried on the surface of the exosomes may activate an immune response, while different exosomal contents may suppress the immune system or help to evade immune recognition. Image created with BioRender.com

Fig. 4

Overview of conventional exosome isolation methods with its merits and demerits. Image created with BioRender.com

Fig. 5

Exosomes as nanocarriers offers several benefits and numerous exosomes-based therapeutics are being applied for treating ovarian cancer. Image created with BioRender.com

Fig. 6

Exosome-based combination therapy for melanoma. Anchor (BODIPY)-spacer (PEG)-targeting ligand (cyclic RGD peptide) functionalized exosomes loaded with doxorubicin for melanoma therapy. Image reproduced with permission from Kang et al. [272] copyright (2020) American Chemical Society

Fig. 7

Schematic representation of therapeutic and diagnostic applications of exosomes in ovarian cancer. Image created with BioRender.com