Unraveling the extracellular vesicle network: insights into ovarian cancer metastasis and chemoresistance

Abstract

Ovarian cancer (OC) is one of the most prevalent and lethal gynecological malignancies, with high mortality primarily due to its aggressive nature, frequent metastasis, and resistance to standard therapies. Recent research has highlighted the critical role of extracellular vesicles (EVs) in these processes. EVs, secreted by living organisms and carrying versatile and bioactive cargoes, play a vital role in intercellular communication. Functionally, the transfer of cargoes orchestrates multiple processes that actively affect not only the primary tumor but also local and distant pre-metastatic niche. Furthermore, their unique biological properties position EVs as novel therapeutic targets and promising drug delivery systems, with potential profound implications for cancer patients.This review summarizes recent progress in EV biology, delving into the intricate mechanisms by which EVs contribute to OC metastasis and drug resistance. It also explores the latest advances and therapeutic potential of EVs in the clinical context of OC. Despite the progress made, EV research in OC remains in its nascent stages. Consequently, this review presents existing research limitations and suggests avenues for future investigation. Altogether, the review aims to elucidate the critical roles of EVs in OC and spotlight their promising potential in this field.

Keywords: Chemotherapy resistance; Extracellular vesicles; Metastasis; Ovarian cancer.

Fig. 1

Biogenesis of extracellular vesicles. Exosomes are produced via the endosomal pathway. The plasma membrane invaginates to form early endosomes, which can exchange materials with the Golgi apparatus or fuse with each other to form late endosomes. These late endosomes transition into multivesicular bodies (MVBs). MVBs can fuse with lysosomes for degradation or with the plasma membrane to release exosomes. Apoptotic bodies, large oncosomes, and ectosomes are formed through cell budding. Migrasomes are vesicular structures generated at the tips or branches of contractile fibers during cell migration. Released extracellular vesicles (EVs) can directly bind to the cell surface, fuse with the cell membrane to release their contents into the cytoplasm, or be internalized by cells through endocytosis

Fig. 2

Metastatic process of ovarian cancer. In situ ovarian cancer can metastasize via blood and lymphatic vessels. However, due to the lack of anatomical barriers between the peritoneal cavity and ovaries, cancer cells can directly shed and implant within the peritoneum, the most common site of metastasis. EVs can travel with ascites, impacting the peritoneum and promoting the formation of pre-metastatic niches, thereby facilitating further OC spread

Fig. 3

The composition of EVs and their roles in ovarian cancer metastasis. The surface of EVs is composed of a phospholipid bilayer adorned with a variety of membrane proteins, including transmembrane proteins, transporters, antigen-presenting proteins, and receptors. Within these EVs are various bioactive cargos, such as lipids, proteins, DNA, and a range of RNA molecules, both coding and non-coding, like lncRNA, circRNA, and miRNA, all of which are essential for intercellular communication. The transfer of these EV components is crucial in the metastatic process of ovarian cancer, where they enhance the dissemination potential of primary tumor cells, support the formation of PMN, and orchestrate multiple pathophysiological processes such as immune regulation, angiogenesis, and EMT