Malignant extracellular vesicles carrying MMP1 mRNA facilitate peritoneal dissemination in ovarian cancer

Abstract

Advanced ovarian cancers are highly metastatic due to frequent peritoneal dissemination, resulting in dismal prognosis. Here we report the functions of cancer-derived extracellular vesicles (EVs), which are emerging as important mediators of tumour metastasis. The EVs from highly metastatic cells strongly induce metastatic behaviour in moderately metastatic tumours. Notably, the cancer EVs efficiently induce apoptotic cell death in human mesothelial cells in vitro and in vivo, thus resulting in the destruction of the peritoneal mesothelium barrier. Whole transcriptome analysis shows that MMP1 is significantly elevated in mesothelial cells treated with highly metastatic cancer EVs and intact MMP1 mRNAs are selectively packaged in the EVs. Importantly, MMP1 expression in ovarian cancer is tightly correlated with a poor prognosis. Moreover, MMP1 mRNA-carrying EVs exist in the ascites of cancer patients and these EVs also induce apoptosis in mesothelial cells. Our findings elucidate a previously unknown mechanism of peritoneal dissemination via EVs.

Ovarian cancer‐associated mesothelial cells induce acquired platinum‐resistance in peritoneal metastasis via the FN1/Akt signaling pathway

“…14 Furthermore, the surface of the peritoneum is histologically covered by a single layer of mesothelial cells (MCs), 15 which may have a key function in the development of the tumor microenvironment that supports peritoneal metastasis of OvCa. Moreover, recent studies have shown that activated MCs play an important role in the development of peritoneal metastasis; [16][17][18][19][20][21][22] these studies further demonstrated that MCs increase the adhesive and proliferative properties of OvCa cells. In fact, mesenchymal transition of MCs was reported to be induced by a variety of soluble factors in malignant ascites, 23 and modification of extracellular matrix (ECM) on the mesothelial cells also promoted peritoneal metastasis of OvCa.…”

Stilbenoid‐Mediated Epigenetic Activation of Semaphorin 3A in Breast Cancer Cells Involves Changes in Dynamic Interactions of DNA with DNMT3A and NF1C Transcription Factor

“…Hypermethylated ITGA7 belongs to the integrin family and is a newly identified tumor suppressor gene that decreases migration and invasion of cancer cells . On the other hand, hypomethylated MMP1 is a potent oncogene promoting metastasis and multi‐drug resistance, and hypomethylated PLEKHA5 facilitates metastasis to the brain . Hence, the functional role of differential methylation within those genes in response to RSV is unclear.…”

Exosomes play roles in sequential processes of tumor metastasis

“…A typical example reported a truncated and oncogenic form of the epidermal growth factor receptor (EGFR), known as EGFRvIII, can be transferred between glioma cells by intercellular oncosomes, a type of TDEs, leading to an increased anchorage‐independent growth capacity and expression of anti‐apoptotic genes . TDEs from highly metastatic ovarian cancer strongly induce metastatic behavior in moderately metastatic tumors via exosomal MMP1 mRNA . Similar results were discovered in hepatocellular carcinoma (HCC) in which oncogenic RNAs and proteins, like S100 family members and caveolins could be horizontal transferred to neighboring and distant hepatocytes through exosomes, enhancing the migratory and invasive abilities .…”