The Application of MicroRNAs in Cancer Diagnostics - RNA Interference from Biology to Therapeutics - page 273

lysosomal machinery [ 173 ]. For some cell types (e.g., T cells and resting B cells),
activation of cell surface receptors is required for secretion [ 174, 175 ] .

13.4.4 Biological Function of Circulating Exosome-

Encapsulated miRNAs

Two opposing hypotheses currently exist to explain the biological functions of
exosomes: (1) that vesicles are secreted from cells to carry out an active paracrine
cell signaling role by the transfer to recipient cells of exosome content, such as
miRNAs. By doing so, cancer cells may enhance local tumor growth and invasion,
or prime distant sites for establishment of tumor metastases and (2) that vesicles are
used as an alternative route to cellular degradation of unwanted material, which is then
packed into exosomes and exocytosed. No data exists yet that can clearly discrimi-
nate between the two proposed models. It is currently unknown whether freely circu-
lating AGO2-miRNA complexes can interact specifically with recipient cells to
actively target mRNA downregulation [ 157, 158 ]. In contrast, complexes of HDL and
exogenous miR-223 have been shown to increase the level of miR-223 by 250-fold in
recipient Huh-7 hepatocarcinoma cells and to decrease the level of the miR-223 tar-
gets Ras homolog gene family, member B (RHOB) and Ephrin A1 (EFNA1) [ 160 ] .
Several studies indicate that exosomes represent vehicles for intercellular com-
munication and for active paracrine cell signaling. In 2007, Valadi and coworkers
demonstrated that mRNA and miRNAs could be transferred to recipient cells, and
the transferred mRNA was actively transcribed [ 176 ]. Uptake of mast cell-derived
exosomal RNA was observed in other mast cell lines, but not in CD4+ T cells.
Fluorescence-labeled vesicle monitoring has been used to show that ovarian cancer
exosomes are transferred to natural killer cell lines, but not Jurkat T cells [ 177 ] .
These studies demonstrate selective vesicle uptake that could occur either by specific
endocytosis, receptor-mediated uptake, or membrane fusion. Transfer of mRNA
molecules linked to cell cycle regulation and angiogenesis, and enriched in exo-
somes, has been demonstrated for glioblastoma and colorectal cancer cells.
Furthermore, vesicular transfer stimulated the proliferation of U87 malignant glioma
cells and endothelial cells [ 178, 179 ] . Microvesicle secretion from EGFRvIII + glioma
tumor cells has been shown to result in transfer of this oncogenic receptor to
EGFRvIII-negative cancer cells, leading to activation of oncogenic pathways, trig-
gered production of vascular endothelial growth factor (VEGF), and anchorage-
independent growth of the recipient cells [ 180 ]. Exosomes may, however, also have
an anti-tumorigenic function, as has been observed for pancreatic cancer cell-
derived exosomes [ 181 ] .
The ability of exosomes to promote tumor metastasis was addressed by Hood
et al . in a murine model of metastatic melanoma [ 152 ]. In this study, prior injection
with melanoma exosomes showed sentinel lymph node homing with subsequent