Abstract
The development of human cancers is a multistep process in which normal cells acquire characteristics that ultimately lead to their conversion into cancer cells. Many obstacles must be overcome for this process to occur; of these obstacles, is the ability to survive an inhospitable microenvironment. It is recognized that the intercommunication between tumor cells and their surrounding microenvironment is essential to overcoming this obstacle and for the tumor to progress, metastasize and establish itself at distant sites. Exosomes are membrane-derived vesicles that have recently been recognized as important mediators of intercellular communication, as they carry lipids, proteins, mRNAs and microRNAs that can be transferred to a recipient cell via fusion of the exosome with the target cell membrane. In the context of cancer cells, this process entails the transfer of cancer-promoting cellular contents to surrounding cells within the tumor microenvironment or into the circulation to act at distant sites, thereby enabling cancer progression. In this process, the transfer of exosomal microRNAs to a recipient cell where they can regulate target gene expression is of particular interest, both in understanding the basic biology of cancer progression and for the development of therapeutic approaches. This review discusses the exosome-mediated intercellular communication via microRNAs within the tumor microenvironment in human cancers, with a particular focus on breast cancer exosomes.
Highlights
When breast cancer cells were cultured under hypoxic conditions (1% to 0.1% O2), their exosome secretion was significantly enhanced, whereas siRNA knockdown of HIF-1α prior to hypoxic exposure prevented this increase in exosome secretion [30]
Using standard RNA and DNA extraction techniques of exosomes isolated by ultracentrifugation, Valadi et al discovered the presence of small RNAs and mRNAs from approximately 1300 genes present in exosomes that are not present in the parental cell and proposed that these RNAs be referred to as exosomal shuttle RNAs to distinguish them from circulating microRNAs [45]
One of the first studies to show that this unique intercellular method of communication could contribute to the initiation and progression of cancer demonstrated that hepatocellular carcinoma cells produce exosomes that can be internalized by other cells. These exosomes were shown to transmit microRNAs that modulated the expression of transforming growth factor β activated kinase-1 (TAK1), whose loss is implicated in hepatocarcinogenesis [109]
Summary
Most cell types are known to continually release soluble factors and to exfoliate membrane derived vesicles into the extracellular space, including mast cells, dendritic cells, B-lymphocytes, platelets, neurons, adipocytes, endothelial cells and epithelial cells [1] These membrane-derived vesicles are generally discriminated by size with two major classes; the larger class is called microvesicles (200–1000 nm) and the smaller class of nanometer size vesicles is called exosomes (30–200 nm). It was shown that during reticulocyte maturation, the transferrin receptor and many membrane-associated proteins were shed in small membrane vesicles via an unknown secretory process [3,4] This process was considered as a way for cells to eliminate unwanted proteins and molecules, with exosomes functioning as cellular garbage disposals. Cancer cells have been shown to secrete exosomes in greater amounts than normal cells [13], indicating their potential use as biomarkers for diagnosis of disease
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