The influence of secreted factors and extracellular vesicles in ovarian cancer metastasis

Abstract

Ovarian cancer cells mainly metastasise within the peritoneal cavity, the lethal consequence of tumour progression in this cancer type. Classically, changes in tumour cells, such as epithelial to mesenchymal transition, involve the down-regulatinon of E-cadherin, activation of extracellular proteases and integrin-mediated adhesion. However, our current understanding of ovarian tumour progression suggests the implication of both intrinsic and extrinsic factors. It has been proposed that ovarian cancer metastases are a consequence of the crosstalk between cancer cells and the tumour microenvironment by soluble factors and extracellular vesicles. Characterisation of the alterations in both the tumour cells and the surrounding microenvironment has emerged as a new research field to understand ovarian cancer metastasis. In this mini review, we will summarise the most recent findings, focusing our attention on the role of secreted factors and extracellular vesicles in ovarian cancer metastasis.

Keywords: Cancer; Exosomes; Extracellular vesicles; Metastasis.

Fig. 1

Main mechanisms involved in ovarian cancer – adipose tissue communication during metastasis. Schematic representation of how the secretion of specific adipokines and pro-inflammatory cytokines from adipose tissue (leptin, adiponectin, IL-6, IL-8, fatty acids) influences ovarian cancer migration and metastasis. Soluble factors act as local players that mediate in primary tumour growth and metastasis (see text for more details). In ovarian cancer, obesity influences metastasis to the omentum due to the increase in cytokines (IL-6, IL-8, TIMP1, MCP1) and over-expression of specific markers (Ob-Rb, FABP4) in ovarian cancer cells. Specific pathways are activated in ovarian cancer cells due to the action of these factors (see text for more details). Tumour cells induce phenotypical changes in the surrounding adipocytes including delipidation and conversion towards cancer-associated adipocytes (CAA). In turn, mature adipocytes secrete free-fatty acids. Factors modulated are shown in yellow (adipocytes) and blue (ovarian cancer).

Fig. 2

Communication between CAFs and ovarian cancer cell during metastasis. Schematic representation of the main factors secreted by cancer-associated fibroblasts (MFAP5, TGF-β b, Versican, CXCL12, etc.). Secretion of these factors influences metastasis to the omentum due to signalling activation (integrins, Nf-κβ, FAK, STAT4, see text for more details). Factors modulated are shown in yellow (CAFs) and blue (ovarian cancer).

Fig. 3

Macrophages and other immune cells reinforce ovarian cancer metastasis. Schematic representation of how macrophages secreted soluble factors (e.g. VEGF, IL-6, IL-8) during ovarian cancer progression favouring invasion and metastasis. These factors promote the activation of specific pathways (e.g. NF-κβ, c-Jun) and the secretion of different extracellular factors (e.g. CCL2, CSF-1, IL-6, MIF, EMPRINN). Tie2-expressing monocytes secrete IGF-1 in response to Ang2 secreted by ovarian cancer cells. The formation of ovarian cancer cell spheroids is reinforced by interaction with macrophages that promote EGFR expression by specific integrins and adhesion molecules on their surface (ICAM, αMβ2 integrin). Cancer cell-related changes are shown in boxes. Factors modulated are shown in grey (macrophages), red (Tie2-expressing monocytes) and blue (ovarian cancer).

Fig. 4

Communication between micro-environment and ovarian cancer cells through secreted vesicles. Exosomes from AD-MSCs reduce tumour cell proliferation activating apoptosis signalling. In turn, exosomes derived from ovarian cancer cells induce a myofibroblastic cell phenotype in MSCs. Macrophages secrete miR-7 promoting down-regulation of EGFR, AKT and ERK1/2. CD44 is secreted in ovarian cancer exosomes reinforcing mesenchymal transition in mesothelial cells. Similarly, exosomes from ovarian cancer cells induce Treg and the secretion of immunomodulatory chemokines (IL10). Secreted exosomes are represented by asterisks in grey (macrophages), blue (ovarian cancer cells), green (AD-MSCs). Cancer-cell-related changes are shown in boxes.