The multifaceted role of extracellular vesicles in metastasis: Priming the soil for seeding (original) (raw)

2017, International Journal of Cancer

Extracellular vesicles (EVs), including exosomes, play a key role in inter and intracellular communication, promoting the proliferation and invasion of recipient cells to support tumor growth and metastasis. Metastasis comprises multiple steps that first include the detachment of tumor cells through epithelial to mesenchymal transition (EMT), allowing the physical dissemination to distant organs. Thereafter, cancer-derived exosomes are still critical components for preparing the tumor microenvironment by (i) enabling tumor cells to escape from the immunological surveillance and (ii) arranging the pre-metastatic site for the engraftment of detached cancer cells. In this review, we discuss the multifaceted role of EVs in the multiple steps of metastasis. Future research directions draw attention to EVs as biological targets for cancer diagnosis, prognosis and therapy. However, due to their significant role in cell communication, they may become a valuable drug delivery system. Epithelial-mesenchymal transition (EMT) is a hallmark of cancer progression and metastasis. Accumulating evidence indicates that extracellular vesicles, especially exosomes, play an important role in this process. 1 Exosomes have been associated with the initiation, development and prognosis of different types of cancer including pancreatic, 2 lung, 3 breast 4 and prostate cancer. 5 These extracellular vesicles (EVs) are capable of transferring oncogenic proteins and nucleic acids that modulate the activity of recipient cells and play decisive roles in tumorigenesis, growth, progression, drug resistance and metastasis. 6-11 Metastases are responsible for approximately 90% of all cancer-related deaths. Although the death rate is elevated, metastasis is a poorly understood phenomenon of cancer pathogenesis. 12 The establishment of a metastatic niche requires a complete series of distinct steps, which include invasion through the basement membrane, extravasation into the bloodstream, dissemination through circulation to the distal tissue parenchyma, and adaptation to the new microenvironment. 13,14 The EMT must occur prior to physical dissemination of cancer cells to distant organs by which epithelial cells acquire mesenchymal characteristics showing reduced intercellular adhesion and increased motility, 15 endowing the incipient cancer cells with invasive and metastatic properties, 16 a key event for tumor progression. However, the EMT switch may not be sufficient to describe all types of migratory phenotypes observed within carcinoma cells, but may represent one subtype of invasive behavior important for metastasis. The EMT complex may be influenced by different pathways and has many potential mechanisms of regulation by miRNA that can influence multiple steps in cancer cell metastasis; miR-NAs are well-established as key regulators of the EMT program in epithelial cells. 17 The exosomes from tumor cells