Exosomal transfer of stroma-derived miR21 confers paclitaxel resistance in ovarian cancer cells through targeting APAF1

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.

Cell‐to‐cell communication: microRNAs as hormones

“…Moreover, it has been shown that exosomes can be secreted by CAFs and taken up by cancer cells, as isolated exosomes from primary CAFs transfected with labeled miR‐21 successfully entered ovarian cancer cells (Au Yeung et al ., 2016). They confirmed transfer of miR‐21 from primary CAFs to ovarian cancer cells by co‐culturing CAFs transfected with labeled miR‐21 with ovarian cancer cells (Au Yeung et al ., 2016). In addition, miR‐21 was frequently upregulated in CAFs from both human pancreatic ductal adenocarcinoma samples and primary cell cultures, and higher expression of miR‐21 was significantly correlated with decreased overall survival in pancreatic ductal adenocarcinoma patients (Donahue et al ., 2014; Kadera et al ., 2013).…”

Extracellular vesicles swarm the cancer microenvironment: from tumor–stroma communication to drug intervention

“…Further characterization of the feedback loops initiated by EVs on tumor cells and the stromal environment might provide critical missing pieces in this picture. In a different context CAF EVs with increased levels of miRNA-21 profoundly impact ovarian cancer growth by suppressing apoptosis through binding to its novel target, APAF1 7 . Finally, as discussed above CAF-derived EVs directly participate in metabolic reprogramming.…”

Cancer-associated fibroblasts regulate endothelial adhesion protein LPP to promote ovarian cancer chemoresistance

“…Cancer-associated fibroblasts (CAFs), one of the primary stromal cell types in ovarian tumor tissues (6), secrete CAF-specific proteins, cytokines, and growth factors and produce an extracellular matrix (ECM) that supports tumor cell growth and angiogenesis and confers chemoresistance (7)(8)(9)(10)(11). However, the mechanisms by which CAFs promote angiogenesis in ovarian cancer remain poorly understood.…”