Exosomes promote pre-metastatic niche formation in ovarian cancer

Abstract

Ovarian cancer is one of the most common gynecological malignancies. Upon initial diagnosis, the majority of patients present with widespread metastatic growth within the peritoneal cavity. This metastatic growth occurs in stages, with the formation of a pre-metastatic niche occurring prior to macroscopic tumor cell invasion. Exosomes released by the primary ovarian tumor are small extracellular vesicles which prepare the distant tumor microenvironment for accelerated metastatic invasion. They regulate intercellular communication between tumor cells and normal stroma, cancer-associated fibroblasts, and local immune cells within the tumor microenvironment. In this review, we highlight the emerging roles of ovarian cancer exosomes as coordinators of pre-metastatic niche formation, biomarkers amenable to liquid biopsy, and targets of chemotherapy.

Keywords: Exosome; Metastasis; Ovarian cancer; Pre-metastatic niche.

Fig. 1

a. The biogenesis of exosomes and the mechanisms involved in intercellular communication. The exosome is an intraluminal vesicle (ILV) formed by the inward budding of the endosomal membrane during the maturation of the multivesicular endosomes (MVEs) and then secreted after fusing with the cell surface. Uptake by recipient cells occurs via a three step processes: 1. membrane fusion with target cells; 2. endocytosis; 3. activation of surface receptors and signaling. b. Schematic diagram of the exosome. The exosome is a disk-shaped membranous vesicle with a diameter 30–100 nm, and carries a parental cell cargo including lipids, metabolites, proteins, nucleic acids (DNA fragments, mRNA, miRNA, etc.)

Fig. 2

Impact of ovarian cancer-exosomes on target cells during pre-metastatic niche formation. a. Ovarian cancer-exosomes induce apoptosis of dendritic cells, increase secretion of IL-6, and inhibit function of T cells and NK cells. b. Ovarian cancer-exosomes with their cargo, such as ATF2, MTA1, sE-cad, and CD147, which acts on human vein endothelial cells, inducing angiogenesis and vascular permeability. c. Ovarian cancer-exosomes convert fibroblasts to CAFs. d. Ovarian cancer-exosomes deliver miRNAs to macrophages and elicit M2 macrophage polarization by regulating the suppressor of cytokine signaling (SOCS)4/5/ STAT3 pathway in macrophages. e. Phenotypic conversion and apoptosis of PMCs, induced by ovarian cancer-exosomes, clears the mesothelial cell barrier of the peritoneum and omentum. OC ovarian cancer, NK natural killer, ATF2 Activating transcription factor 2, MTA1 Metastasis-associated protein 1, sE-cad soluble E-cadherin, SOCS Suppress cytokine signaling, STAT3 Signal transducer and activator of transcription 3, PMC Peritoneal mesothelial cell, CAF cancer-associated fibroblast

Fig. 3

Two main methods of ovarian cancer metastasis within the peritoneal cavity, direct implantation and hematogenous spread. a Distribution of ovarian cancer nests in the peritoneal cavity. b Mechanisms of ovarian cancer-exosome establishment of the pre-metastatic niche before metastasis. c After the formation of pre-metastatic niche, tumor cells home to the metastatic site then colonize and support vessel budding. OC: ovarian cancer; NK: natural killer; HUVECs: Human umbilical vein endothelial cells; TAM: tumor-associated macrophages; PMC: Peritoneal mesothelial cell; CAF: cancer-associated fibroblasts.