Abstract
Advanced ovarian cancer usually spreads to the visceral adipose tissue of the omentum. However, the omental stromal cell-derived molecular determinants that modulate ovarian cancer growth have not been characterized. Here, using next-generation sequencing technology, we identify significantly higher levels of microRNA-21 (miR21) isomiRNAs in exosomes and tissue lysates isolated from cancer-associated adipocytes (CAAs) and fibroblasts (CAFs) than in those from ovarian cancer cells. Functional studies reveal that miR21 is transferred from CAAs or CAFs to the cancer cells, where it suppresses ovarian cancer apoptosis and confers chemoresistance by binding to its direct novel target, APAF1. These data suggest that the malignant phenotype of metastatic ovarian cancer cells can be altered by miR21 delivered by exosomes derived from neighbouring stromal cells in the omental tumour microenvironment, and that inhibiting the transfer of stromal-derived miR21 is an alternative modality in the treatment of metastatic and recurrent ovarian cancer.
Highlights
Advanced ovarian cancer usually spreads to the visceral adipose tissue of the omentum
We demonstrate that specific miRNAs are directly transferred, through exosomes, from cancer-associated fibroblasts (CAFs) and cancer-associated adipocytes (CAAs) to ovarian cancer cells, and we identify the molecular mechanisms by which miRNAs modulate the malignant phenotypes in ovarian cancer cells
CAF and CAA exosomes have higher miR21 copy number. miRNAs that transfer between living cells that are involved in cell–cell communication are frequently encapsulated in exosomes, which facilitate their targeted exchange[14]
Summary
Advanced ovarian cancer usually spreads to the visceral adipose tissue of the omentum. Functional studies reveal that miR21 is transferred from CAAs or CAFs to the cancer cells, where it suppresses ovarian cancer apoptosis and confers chemoresistance by binding to its direct novel target, APAF1. The tumour microenvironment has been shown to directly affect cell growth, migration and differentiation through secreted proteins, cell–cell interactions and matrix remodelling[2]. As it can promote the tumour initiation of normal epithelial cells and facilitate the progression of malignant cells, the tumour microenvironment presents a unique opportunity to discover ways to better diagnose, understand and treat cancer. We demonstrate that specific miRNAs are directly transferred, through exosomes, from CAFs and CAAs to ovarian cancer cells, and we identify the molecular mechanisms by which miRNAs modulate the malignant phenotypes in ovarian cancer cells
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