role in downregulating the function of T effector cells: vesicular CD39 and CD73
are responsible for ATP-dependent adenosine production which results in negative
immune modulation of T effector cells [39, 40].
In addition, EVs also can manipulate the microenvironment locally to form a
pro-tumorigenic niche. Especially, vesicular miRNAs are involved in every step
from initiation to metastasis of cancer. For example, miR-200 family present in
breast cancer EVs plays crucial role in promotion of mesenchymal-to-epithelial
transition by transfer of miR-200 to non-metastatic cancer cells [41]. In addition,
the angiogenic miR-210 present in cancer EVs is targeted to the endothelial cells,
which resulting in promoting angiogenesis [42]. Moreover, oncogenic receptor or
proteins including mutant EGFR or KRAS are exchanged via EVs between cancer
cells to activate genes responsible for anti-apoptotic function in recipient cancer
cells [43]. In order to promote their survival and proliferation, cancer cells continuously communicate with their stromal cells and develop the appropriate
cancer-prone microenvironments. Cancer EVs activate fibroblast cells, which
degrades extracellular matrix and promote cancer-promoting cytokine secretion [44,
45]. Furthermore, cancer EVs regulate the neovascularization for tumor growth and
thrive [2, 21]. Because hypoxic condition around tumor requires provision of
oxygen and nutrition, cancer cells release EVs containing angiogenic signaling
molecules and stimulate angiogenesis by activating endothelial and stromal cells
[21, 46, 47]. EV-associated miR-9 secreted by cancer cells was taken up by
endothelial cells, which effectively suppressed SOCS5 expression, resulting in
activation of JAK-STAT signaling cascade involved in promoting tumor angiogenesis [48]. Moreover, recent studies have demonstrated that EVs act as a key
player to drive a pre-metastatic niche formation by communicating with stromal
cells [49]. Different subtype integrin in cancer EVs was capable of determining
organ tropism, showing that a 6 b 4 integrin EVs preferentially induce lung metastasis. The similar interesting study suggested that highly metastatic pancreatic
ductal adenocarcinomas (PDACs)-derived EVs were preferentially accumulated in
liver tissue before PDAC liver metastasis and established liver pre-metastatic niche
[50]. These EVs were selectively taken up by Kupffer cells to secrete TGF-b and to
produce fibronectin from hepatic stellate cells, leading to forming fibrotic environment and macrophage recruitment to eventually support metastasis in liver
tissue.
In summary, cancer EVs have played critical roles in regulating tumor survival
and fate ranging from tumor initiation to tumor metastasis by activating tumor
angiogenesis, and creating immunosuppressive and tumor-supporting niche environments. Thus, the deep investigation of EVs or further controlling
cancer-associated EVs in cancer research could help understand the mode of action
on tumor development and progression.
6 Endogenous Radionanomedicine: Extracellular Vesicles
133
are responsible for ATP-dependent adenosine production which results in negative
immune modulation of T effector cells [39, 40].
In addition, EVs also can manipulate the microenvironment locally to form a
pro-tumorigenic niche. Especially, vesicular miRNAs are involved in every step
from initiation to metastasis of cancer. For example, miR-200 family present in
breast cancer EVs plays crucial role in promotion of mesenchymal-to-epithelial
transition by transfer of miR-200 to non-metastatic cancer cells [41]. In addition,
the angiogenic miR-210 present in cancer EVs is targeted to the endothelial cells,
which resulting in promoting angiogenesis [42]. Moreover, oncogenic receptor or
proteins including mutant EGFR or KRAS are exchanged via EVs between cancer
cells to activate genes responsible for anti-apoptotic function in recipient cancer
cells [43]. In order to promote their survival and proliferation, cancer cells continuously communicate with their stromal cells and develop the appropriate
cancer-prone microenvironments. Cancer EVs activate fibroblast cells, which
degrades extracellular matrix and promote cancer-promoting cytokine secretion [44,
45]. Furthermore, cancer EVs regulate the neovascularization for tumor growth and
thrive [2, 21]. Because hypoxic condition around tumor requires provision of
oxygen and nutrition, cancer cells release EVs containing angiogenic signaling
molecules and stimulate angiogenesis by activating endothelial and stromal cells
[21, 46, 47]. EV-associated miR-9 secreted by cancer cells was taken up by
endothelial cells, which effectively suppressed SOCS5 expression, resulting in
activation of JAK-STAT signaling cascade involved in promoting tumor angiogenesis [48]. Moreover, recent studies have demonstrated that EVs act as a key
player to drive a pre-metastatic niche formation by communicating with stromal
cells [49]. Different subtype integrin in cancer EVs was capable of determining
organ tropism, showing that a 6 b 4 integrin EVs preferentially induce lung metastasis. The similar interesting study suggested that highly metastatic pancreatic
ductal adenocarcinomas (PDACs)-derived EVs were preferentially accumulated in
liver tissue before PDAC liver metastasis and established liver pre-metastatic niche
[50]. These EVs were selectively taken up by Kupffer cells to secrete TGF-b and to
produce fibronectin from hepatic stellate cells, leading to forming fibrotic environment and macrophage recruitment to eventually support metastasis in liver
tissue.
In summary, cancer EVs have played critical roles in regulating tumor survival
and fate ranging from tumor initiation to tumor metastasis by activating tumor
angiogenesis, and creating immunosuppressive and tumor-supporting niche environments. Thus, the deep investigation of EVs or further controlling
cancer-associated EVs in cancer research could help understand the mode of action
on tumor development and progression.
6 Endogenous Radionanomedicine: Extracellular Vesicles
133