Electron microscopic approaches have been preferred for direct observation of
the morphology and size of EVs [20]. Transmission electron microscopic analysis
of EVs deposited on grids displays their broad sizes around 30–1000 nm in
diameter and cup-shaped morphological features [19, 20], although the shape is
now considered as an artifact induced by fixation and dehydration during the
specimen preparation. Indeed, they exhibited spherical shape when observed by
cryo-EM [28, 34]. Another important defining character of membrane-enclosed
vesicles is their floatation feature in density gradient analysis, although exact
densities of exosomes and ectosomes were not yet clearly identified [27, 31].
Analysis for these features of EVs derived from conditioned medium of cultured
cells and biological fluids must be validated to confirm the purified EV entities.
6.3 Biological Function of EVs
Although there is a long way to decode a comprehensive understanding of
EV-mediated complex pathophysiological functions, explosively growing evidences are supporting the emerging roles of EVs as critical mechanisms for
intercellular communication in various biological events. Although their complex
diverse pathophysiological roles have been investigated in the field of cardiovascular, diabetic, inflammatory, and neurodegenerative diseases, EVs have been most
intensively studied in cancer biology by far.
Cancer cell-derived EVs have played a significant role in cancer development,
progression, and metastasis in complex tumor tissue microenvironment. First of all,
cancer EVs are involved in angiogenic process to support the growth of primary
and metastasized tumors as well as to facilitate the complicate metastatic processes
[2, 21]. Furthermore, to promote tumor progression, cancerous cells have smart way
to evade the host immune system. Cancer EVs are enriched with immunoregulatory
factors so that their roles are escaping immune system. Cancer EVs can deliver
immune-suppressive cargos as a form of mRNA and miRNA to immune cells to
reprogram the condition of immune-related cells as supporters of tumor progression
[35, 36]. Vesicular cargos that induce apoptotic signals are directly delivered to the
activated immune cells or indirectly induces the proliferation of regulatory T cells
and immune suppressor cells. For instance, cancer EVs can directly transfer inhibitory signals to cognate receptors on immune cells: negative signaling induced by
cancer EVs results in an abortive immune response [37]. Additionally, cancer EVs
downregulate the activation level of natural killer (NK) cells by NKG2D, activating
receptor for NK cells, and as a result, the cytotoxic capability of NK cells is
suppressed [38]. Cancer patients with downregulated antitumor immunity have high
level of cancer cell-derived EVs in their body fluid. Their cargos acquired from
parent cancer cells facilitates tumor growth by modification of surrounding environment and interference of antitumor immunotherapies. Cancer EVs also play a
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C. Lee et al.
the morphology and size of EVs [20]. Transmission electron microscopic analysis
of EVs deposited on grids displays their broad sizes around 30–1000 nm in
diameter and cup-shaped morphological features [19, 20], although the shape is
now considered as an artifact induced by fixation and dehydration during the
specimen preparation. Indeed, they exhibited spherical shape when observed by
cryo-EM [28, 34]. Another important defining character of membrane-enclosed
vesicles is their floatation feature in density gradient analysis, although exact
densities of exosomes and ectosomes were not yet clearly identified [27, 31].
Analysis for these features of EVs derived from conditioned medium of cultured
cells and biological fluids must be validated to confirm the purified EV entities.
6.3 Biological Function of EVs
Although there is a long way to decode a comprehensive understanding of
EV-mediated complex pathophysiological functions, explosively growing evidences are supporting the emerging roles of EVs as critical mechanisms for
intercellular communication in various biological events. Although their complex
diverse pathophysiological roles have been investigated in the field of cardiovascular, diabetic, inflammatory, and neurodegenerative diseases, EVs have been most
intensively studied in cancer biology by far.
Cancer cell-derived EVs have played a significant role in cancer development,
progression, and metastasis in complex tumor tissue microenvironment. First of all,
cancer EVs are involved in angiogenic process to support the growth of primary
and metastasized tumors as well as to facilitate the complicate metastatic processes
[2, 21]. Furthermore, to promote tumor progression, cancerous cells have smart way
to evade the host immune system. Cancer EVs are enriched with immunoregulatory
factors so that their roles are escaping immune system. Cancer EVs can deliver
immune-suppressive cargos as a form of mRNA and miRNA to immune cells to
reprogram the condition of immune-related cells as supporters of tumor progression
[35, 36]. Vesicular cargos that induce apoptotic signals are directly delivered to the
activated immune cells or indirectly induces the proliferation of regulatory T cells
and immune suppressor cells. For instance, cancer EVs can directly transfer inhibitory signals to cognate receptors on immune cells: negative signaling induced by
cancer EVs results in an abortive immune response [37]. Additionally, cancer EVs
downregulate the activation level of natural killer (NK) cells by NKG2D, activating
receptor for NK cells, and as a result, the cytotoxic capability of NK cells is
suppressed [38]. Cancer patients with downregulated antitumor immunity have high
level of cancer cell-derived EVs in their body fluid. Their cargos acquired from
parent cancer cells facilitates tumor growth by modification of surrounding environment and interference of antitumor immunotherapies. Cancer EVs also play a
132
C. Lee et al.